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  • 1.
    Albagha, O M E
    et al.
    University of Aberdeen.
    Pettersson, Ulrika
    University of Aberdeen .
    Stewart, A
    University of Aberdeen.
    McGuigan, F E A
    University of Aberdeen.
    MacDonald, H M
    University of Aberdeen.
    Reid, D M
    University of Aberdeen.
    Ralston, S H
    University of Aberdeen.
    Association of oestrogen receptor alpha gene polymorphisms with postmenopausal bone loss, bone mass, and quantitative ultrasound properties of bone.2005In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 42, no 3, p. 240-6Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The gene encoding oestrogen receptor alpha (ESR1) appears to regulate bone mineral density (BMD) and other determinants of osteoporotic fracture risk.

    OBJECTIVE: To investigate the relation between common polymorphisms and haplotypes of the ESR1 gene and osteoporosis related phenotypes in a population based cohort of 3054 Scottish women.

    RESULTS: There was a significant association between a common haplotype "px", defined by the PvuII and XbaI restriction fragment length polymorphisms within intron 1 of the ESR1 gene, and femoral neck bone loss in postmenopausal women who had not received hormone replacement therapy (n = 945; p = 0.009). Annual rates of femoral neck bone loss were approximately 14% higher in subjects who carried one copy of px and 22% higher in those who carried two copies, compared with those who did not carry the px haplotype. The px haplotype was associated with lower femoral neck BMD in the postmenopausal women (p = 0.02), and with reduced calcaneal broadband ultrasound attenuation (BUA) values in the whole study population (p = 0.005). There was no association between a TA repeat polymorphism in the ESR1 promoter and any phenotype studied, though on long range haplotype analysis subjects with a smaller number of TA repeats who also carried the px haplotype had reduced BUA values.

    CONCLUSIONS: The ESR1px haplotype is associated with reduced hip BMD values and increased rates of femoral neck bone loss in postmenopausal women. An association with BUA may explain the fact that ESR1 intron 1 alleles predict osteoporotic fractures by a mechanism partly independent of differences in BMD.

  • 2. Barnekow-Bergkvist, M
    et al.
    Hedberg, G
    Pettersson, U
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Lorentzon, R
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Relationships between physical activity and physical capacity in adolescent females and bone mass in adulthood.2006In: Scand J Med Sci Sports, ISSN 0905-7188, Vol. 16, no 6, p. 447-55Article in journal (Refereed)
  • 3. Benetou, V.
    et al.
    Orfanos, P
    Feskanich, D
    Michaëlsson, K
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ahmed, L A
    Peasey, A
    Wolk, A
    Brenner, H
    Bobak, M
    Wilsgaard, T
    Schöttker, B
    Saum, K-U
    Bellavia, A
    Grodstein, F
    Klinaki, E
    Valanou, E
    Papatesta, E-M
    Boffetta, P
    Trichopoulou, A
    Education, marital status, and risk of hip fractures in older men and women: the CHANCES project2015In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 26, no 6, p. 1733-1746Article in journal (Refereed)
    Abstract [en]

    The role of socioeconomic status in hip fracture incidence is unclear. In a diverse population of elderly, higher education was found to be associated with lower, whereas living alone, compared to being married/cohabiting, with higher hip fracture risk. Educational level and marital status may contribute to hip fracture risk.

    INTRODUCTION: The evidence on the association between socioeconomic status and hip fracture incidence is limited and inconsistent. We investigated the potential association of education and marital status with hip fracture incidence in older individuals from Europe and USA.

    METHODS: A total of 155,940 participants (79 % women) aged 60 years and older from seven cohorts were followed up accumulating 6456 incident hip fractures. Information on education and marital status was harmonized across cohorts. Hip fractures were ascertained through telephone interviews/questionnaires or through record linkage with registries. Associations were assessed through Cox proportional hazard regression adjusting for several factors. Summary estimates were derived using random effects models.

    RESULTS: Individuals with higher education, compared to those with low education, had lower hip fracture risk [hazard ratio (HR) = 0.84, 95 % confidence interval (CI) 0.72-0.95]. Respective HRs were 0.97 (95 % CI 0.82-1.13) for men and 0.75 (95 % CI 0.65-0.85) for women. Overall, individuals living alone, especially those aged 60-69 years, compared to those being married/cohabiting, tended to have a higher hip fracture risk (HR = 1.12, 95 % CI 1.02-1.22). There was no suggestion for heterogeneity across cohorts (P heterogeneity > 0.05).

    CONCLUSIONS: The combined data from >150,000 individuals 60 years and older suggest that higher education may contribute to lower hip fracture risk. Furthermore, this risk may be higher among individuals living alone, especially among the age group 60-69 years, when compared to those being married/cohabiting.

  • 4. Benetou, V.
    et al.
    Orfanos, P.
    Feskanich, D.
    Michaëlsson, K.
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Byberg, L.
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Grodstein, F.
    Wolk, A.
    Jankovic, N.
    de Groot, L. C. P. G. M.
    Boffetta, P.
    Trichopoulou, A.
    Mediterranean diet and hip fracture incidence among older adults: the CHANCES project2018In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 29, no 7, p. 1591-1599Article in journal (Refereed)
    Abstract [en]

    The association between adherence to Mediterranean diet (MD) and hip fracture incidence is not yet established. In a diverse population of elderly, increased adherence to MD was associated with lower hip fracture incidence. Except preventing major chronic diseases, adhering to MD might have additional benefits in lowering hip fracture risk.

    INTRODUCTION: Hip fractures constitute a major public health problem among older adults. Latest evidence links adherence to Mediterranean diet (MD) with reduced hip fracture risk, but still more research is needed to elucidate this relationship. The potential association of adherence to MD with hip fracture incidence was explored among older adults.

    METHODS: A total of 140,775 adults (116,176 women, 24,599 men) 60 years and older, from five cohorts from Europe and the USA, were followed-up for 1,896,219 person-years experiencing 5454 hip fractures. Diet was assessed at baseline by validated, cohort-specific, food-frequency questionnaires, and hip fractures were ascertained through patient registers or telephone interviews/questionnaires. Adherence to MD was evaluated by a scoring system on a 10-point scale modified to be applied also to non-Mediterranean populations. In order to evaluate the association between MD and hip fracture incidence, cohort-specific hazard ratios (HR), adjusted for potential confounders, were estimated using Cox proportional-hazards regression and pooled estimates were subsequently derived implementing random-effects meta-analysis.

    RESULTS: A two-point increase in the score was associated with a significant 4% decrease in hip fracture risk (pooled adjusted HR 0.96; 95% confidence interval (95% CI) 0.92-0.99, pheterogeneity = 0.446). In categorical analyses, hip fracture risk was lower among men and women with moderate (HR 0.93; 95% CI 0.87-0.99) and high (HR 0.94; 95% CI 0.87-1.01) adherence to the score compared with those with low adherence.

    CONCLUSIONS: In this large sample of older adults from Europe and the USA, increased adherence to MD was associated with lower hip fracture incidence.

  • 5. Benetou, V
    et al.
    Orfanos, P
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Bergström, Ulrica
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Berrino, F
    Tumino, R
    Borch, K B
    Lund, E
    Peeters, P H M
    Grote, V
    Li, K
    Altzibar, J M
    Key, T
    Boeing, H
    von Ruesten, A
    Norat, T
    Wark, P A
    Riboli, E
    Trichopoulou, A
    Mediterranean diet and incidence of hip fractures in a European cohort2013In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 24, no 5, p. 1587-1598Article in journal (Refereed)
    Abstract [en]

    Prevention of hip fractures is of critical public health importance. In a cohort of adults from eight European countries, evidence was found that increased adherence to Mediterranean diet, measured by a 10-unit dietary score, is associated with reduced hip fracture incidence, particularly among men. INTRODUCTION: Evidence on the role of dietary patterns on hip fracture incidence is scarce. We explored the association of adherence to Mediterranean diet (MD) with hip fracture incidence in a cohort from eight European countries. METHODS: A total of 188,795 eligible participants (48,814 men and 139,981 women) in the European Prospective Investigation into Cancer and nutrition study with mean age 48.6 years (±10.8) were followed for a median of 9 years, and 802 incident hip fractures were recorded. Diet was assessed at baseline through validated dietary instruments. Adherence to MD was evaluated by a MD score (MDs), on a 10-point scale, in which monounsaturated were substituted with unsaturated lipids. Association with hip fracture incidence was assessed through Cox regression with adjustment for potential confounders. RESULTS: Increased adherence to MD was associated with a 7 % decrease in hip fracture incidence [hazard ratio (HR) per 1-unit increase in the MDs 0.93; 95 % confidence interval (95 % CI) = 0.89-0.98]. This association was more evident among men and somewhat stronger among older individuals. Using increments close to one standard deviation of daily intake, in the overall sample, high vegetable (HR = 0.86; 95 % CI = 0.79-0.94) and high fruit (HR = 0.89; 95 % CI = 0.82-0.97) intake was associated with decreased hip fracture incidence, whereas high meat intake (HR = 1.18; 95 % CI = 1.06-1.31) with increased incidence. Excessive ethanol consumption (HR high versus moderate = 1.74; 95 % CI = 1.32-2.31) was also a risk factor. CONCLUSIONS: In a prospective study of adults, increased adherence to MD appears to protect against hip fracture occurrence, particularly among men.

  • 6. Benetou, Vassiliki
    et al.
    Orfanos, Philippos
    Benetos, Ioannis S
    Pala, Valeria
    Evangelista, Alberto
    Frasca, Graziella
    Giurdanella, Maria Concetta
    Peeters, Petra HM
    van der Schouw, Yvonne T
    Rohrmann, Sabine
    Linseisen, Jakob
    Boeing, Heiner
    Weikert, Cornelia
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bueno-de-Mesquita, H Bas
    Altzibar, Jone
    Boffetta, Paolo
    Trichopoulou, Antonia
    Anthropometry, physical activity and hip fractures in the elderly2011In: Injury, ISSN 0020-1383, E-ISSN 1879-0267, Vol. 42, no 2, p. 188-193Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Hip fractures constitute a major and growing public health problem amongst the elderly worldwide. We examined the association of anthropometry and physical activity with hip fracture incidence in a cohort of elderly Europeans, participants in the European Prospective Investigation into Cancer and nutrition (EPIC) study.

    MATERIALS AND METHODS: The study population consisted of 27982 volunteers (10553 men and 17429 women) aged 60 years and above from five European countries. Information on anthropometry, physical activity, medical history and other characteristics was collected at baseline. During a median follow-up of 8 years, 261 incident hip fractures (203 women and 58 men) were recorded. Data were analysed through Cox proportional hazard regression with adjustment for potential confounders.

    RESULTS: A higher body mass index (BMI) was associated with lower hip fracture risk (hazard ratio (HR) per increasing sex-specific-quintile: 0.85, 95% confidence interval (95% CI): 0.77-0.94). Body height was associated with increased hip fracture risk (HR per 5cm: 1.13, 95% CI: 1.01-1.25). Waist-to-hip ratio was not related to hip fracture risk. Increasing levels of leisure-time physical activity were related to lower risk (HR per increasing tertile: 0.84, 95% CI: 0.70-0.99, p for trend: 0.039).

    CONCLUSIONS: In a prospective cohort study of elderly Europeans, we found evidence that high body stature increased and high BMI decreased the incidence of hip fractures. After adjustment for BMI, waist-to-hip ratio was not associated with hip fracture risk. Leisure-time physical activity appears to play a beneficial role in the prevention of hip fractures.

  • 7. Benetou, Vassiliki
    et al.
    Orfanos, Philippos
    Feskanich, Diane
    Michaëlsson, Karl
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Grodstein, Francine
    Wolk, Alicja
    Bellavia, Andrea
    Ahmed, Luai A
    Boffeta, Paolo
    Trichopoulou, Antonia
    Fruit and Vegetable Intake and Hip Fracture Incidence in Older Men and Women: The CHANCES Project2016In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 31, no 9, p. 1743-1752Article in journal (Refereed)
    Abstract [en]

    The role of fruit and vegetable intake in relation to fracture prevention during adulthood and beyond is not adequately understood. We investigated the potential association between fruit and vegetable intake and hip fracture incidence in a large sample of elderly from Europe and United States. A total of 142,018 individuals (among which 116,509 women), aged ≥60 years old, from five cohorts, were followed-up prospectively for 1,911,482 person-years accumulating 5,552 hip fractures. Fruit and vegetable intake was assessed by validated, cohort-specific, food-frequency questionnaires. Ηip fractures were ascertained through national patient registers or telephone interviews/questionnaires. Adjusted hazard ratios (HR) derived by Cox proportional-hazards regression were estimated for each cohort and subsequently pooled using random-effects meta-analysis. Intake of ≤ 1 servings/day of fruit and vegetables combined was associated with 39% higher hip fracture risk [pooled adjusted HR:1.39, 95% Confidence Intervals (CIs): 1.20, 1.58] in comparison to moderate intake (>3 and ≤5 servings/day) (pfor heterogeneity  = 0.505), whereas higher intakes (>5 servings/day) were not associated with lower risk in comparison to the same reference. Associations were more evident among women. We concluded that a daily intake of one or less servings of fruits and vegetables was associated with increased hip fracture risk in relation to moderate daily intakes. Older adults with such low fruit and vegetable consumption may benefit from raising their intakes to moderate amounts in order to reduce their hip fracture risk. 

  • 8.
    Bergström, Ulrica
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Gustafson, Yngve
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    The hip fracture incidence curve is shifting to the right: a forecast of the age-quake2009In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 80, no 5, p. 520-524Article in journal (Refereed)
    Abstract [en]

    Background The number of hip fractures has doubled in the last 30–40 years in many countries. Age-adjusted incidence has been reported to be decreasing in Europe and North America, but is there a decreasing trend in all age groups? Patients and methods This population-based study included all hip-fracture patients over 50 years of age (a total of 2,919 individuals, 31% of whom were men) admitted to Umeå University Hospital, Sweden, from 1993 through 2005. Results The incidence of hip fracture declined between the periods 1993–1996 and 2001–2005: from 706 to 625 hip fractures per 105 women and from 390 to 317 hip fractures per 105 men. However, there was a 114% increase in the number of fractures in women aged 90 or older (12 and 25 hip fractures/year, respectively, in the two time periods). For the period 2001–05, women ≥ 90 years of age accounted for almost the same numbers of hip fractures as women aged 75–79 (27 fractures/year). The rate increased during this period, from 2,700 per 105 women to 3,900 per 105 women > 90 years. In men there were declining trends for both relative and absolute numbers. Interpretation Although age-adjusted incidence declined in the population > 50 years of age, absolute fracture rate and incidence increased in the very old. Women over 90 now have the same absolute number of hip fractures every year as women aged 75–79 years. There was a right-shift in hip fracture distribution towards the oldest old, probably due to an increased number of octo/nonagenarians, a new population of particularly frail old people that hardly existed earlier. Better health among septuagenarians may also have delayed the age at which fractures occurred. This changing pattern will strain orthopedic and geriatric resources even more.

  • 9. Conaway, H Herschel
    et al.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Halén, Marie
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Granholm, Susanne
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Lie, Anita
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Retinoids inhibit differentiation of hematopoietic osteoclast progenitors2009In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 23, no 10, p. 3526-3538Article in journal (Refereed)
    Abstract [en]

    Whether vitamin A promotes skeletal fragility, has no effect on fracture rate, or protects against bone loss is unclear. In the present study, effects of retinoids on osteoclast differentiation in cultured mouse bone marrow cells (BMCs), bone marrow macrophages (BMMs), spleen cells, and RAW264.7 cells were evaluated by analyzing osteoclast formation and expression of genes important in signal transduction and osteoclast function. All-trans-retinoic acid (ATRA) did not stimulate osteoclastogenesis in BMCs, but inhibited hormone and RANKL-induced gene expression and formation of osteoclasts. In BMMs, spleen cells, and RAW264.7 cells, osteoclast differentiation and formation stimulated by M-CSF/RANKL were inhibited (IC(50) = 0.3 nM) by ATRA. The effect was exerted at an early step of RANKL-induced differentiation. ATRA also abolished increases of the transcription factors c-Fos and NFAT2 stimulated by RANKL and suppressed down-regulation of the antiosteoclastogenic transcription factor MafB. By comparing effects of several compounds structurally related to ATRA, as well as by using receptor antagonists, evaluation pointed to inhibition being mediated by RARalpha, with no involvement of PPARbeta/delta. The results suggest that activation of RARalpha by retinoids in myeloid hematopoietic precursor cells decreases osteoclast formation by altering expression of the transcription factors c-Fos, NFAT2, and MafB.

  • 10.
    Conaway, H. Herschel
    et al.
    Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
    Pirhayati, Amir
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lindholm, Catharina
    Center for Bone and Arthritis Research at the Institute for Medicine, Sahlgrenska Academy at the University of Gothenburg.
    Henning, Petra
    Center for Bone and Arthritis Research at the Institute for Medicine, Sahlgrenska Academy at the University of Gothenburg.
    Tuckermann, Jan
    Tissue-specific Hormone Action, Leibniz Institute for Age Research, Fritz Lipmann Institute, D-07745 Jena, Germany.
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Retinoids Stimulate Periosteal Bone Resorption by Enhancing the Protein RANKL: a Response Inhibited by Monomeric Glucocorticoid Receptor2011In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, p. 31425-31436Article in journal (Refereed)
    Abstract [en]

    Increased vitamin A (retinol) intake has been suggested to increase bone fragility. In the present study, we investigated effects of retinoids on bone resorption in cultured neonatal mouse calvarial bones and their interaction with glucocorticoids (GC). All-trans-retinoic acid (ATRA), retinol, retinalaldehyde, and 9-cis-retinoic acid stimulated release of (45)Ca from calvarial bones. The resorptive effect of ATRA was characterized by mRNA expression of genes associated with osteoclast differentiation, enhanced osteoclast number, and bone matrix degradation. In addition, the RANKL/OPG ratio was increased by ATRA, release of (45)Ca stimulated by ATRA was blocked by exogenous OPG, and mRNA expression of genes associated with bone formation was decreased by ATRA. All retinoid acid receptors (RAR alpha/beta/gamma) were expressed in calvarial bones. Agonists with affinity to all receptor subtypes or specifically to RAR alpha enhanced the release of (45)Ca and mRNA expression of Rankl, whereas agonists with affinity to RAR beta/gamma or RAR gamma had no effects. Stimulation of Rankl mRNA by ATRA was competitively inhibited by the RAR alpha antagonist GR110. Exposure of calvarial bones to GC inhibited the stimulatory effects of ATRA on 45Ca release and Rankl mRNA and protein expression. This inhibitory effect was reversed by the glucocorticoid receptor (GR) antagonist RU 486. Increased Rankl mRNA stimulated by ATRA was also blocked by GC in calvarial bones from mice with a GR mutation that blocks dimerization (GR(dim) mice). The data suggest that ATRA enhances periosteal bone resorption by increasing the RANKL/OPG ratio via RAR alpha receptors, a response that can be inhibited by monomeric GR.

  • 11.
    Englund, Undis
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Littbrand, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Sondell, Anna
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Bucht, Gustaf
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    The beneficial effects of exercise on BMC are lost after cessation: a 5-year follow-up in older post-menopausal women2009In: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 19, no 3, p. 381-388Article in journal (Refereed)
    Abstract [en]

    This study investigates whether the positive effects on bone mineral density (BMD, g/cm2) and neuromuscular function following a combined weight-bearing program are sustained in older women, a longer period after cessation of training. Thirty-four women (18 exercisers and 16 controls) aged 73–88 years, who completed a 12-month randomized-controlled trial, were invited to a 5-year follow-up assessment of BMD and neuromuscular function. Both groups sustained significant losses in BMD of the femoral neck, trochanter, and Ward's triangle during the follow-up period. Significant losses were also seen in all neuromuscular function tests. The inter-group change was, however, significant only for maximal walking speed where the exercise group had a significantly greater loss. In conclusion, this study suggests that gains in bone density and neuromuscular functions achieved by training are lost after cessation of training. Continuous high-intensity weight-loading physical activity is probably necessary to preserve bone density and neuromuscular function in older women.

  • 12.
    Englund, Undis
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Littbrand, Håkan
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Sondell, Anna
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Bucht, Gustaf
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    A 1-year combined weight-bearing training program is beneficial for bone mineral density and neuromuscular function in older women2005In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 16, no 9, p. 1117-1123Article in journal (Refereed)
    Abstract [en]

    Forty-eight community living women 66–87 years old volunteered to participate in a 12-month prospective, randomized, controlled, trial. The aim was to determine if a combined weight-bearing training program twice a week would be beneficial to bone mineral density and neuromuscular function. The participants were pairwise age-matched and randomly assigned to either an exercise group (n=24) or a control group (n=24). Twenty-one subjects in the intervention group and 19 in the control group completed the study. The exercise program lasted for 50 min and consisted of a combination of strengthening, aerobic, balance and coordination exercises. The mean percentage of scheduled sessions attended for the exercise group was 67%. At the completion of the study, the intervention group showed significant increments in bone mineral density of the Wards triangle (8.4%, P<0.01) as well as improvement in maximum walking speed (11.4%, P<0.001) and isometric grip strength (9.9%, P<0.05), as compared to the control group. The conclusion was that a combined weight-bearing training program might reduce fracture risk factors by improving bone density as well as muscle strength and walking ability. This program could be suitable for older community living women in general, and might, therefore, have important implications for fracture prevention.

  • 13.
    Englund, Undis
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Nilsson, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Bucht, Gustaf
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Björnstig, Ulf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Pettersson Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Physical activity in middle-aged women and hip fracture risk: the UFO study2011In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 22, no 2, p. 499-505Article in journal (Refereed)
    Abstract [en]

    Summary: In a population-based case-control study, we demonstrate that middle-aged women who were active with walking or in different physical spare time activities were at lower risk of later sustaining a hip fracture compared to more sedentary women.

    Introduction: In middle-aged women participating in the Umeå Fracture and Osteoporosis (UFO) study, we investigated whether physical activity is associated with a subsequent decreased risk of sustaining a hip fracture.

    Methods: The UFO study is a nested case-control study investigating associations between bone markers, lifestyle, and osteoporotic fractures. We identified 81 female hip fracture cases that had reported lifestyle data before they sustained their fracture. Each case was compared with two female controls who were identified from the same cohort and matched for age and week of reporting data, yielding a total cohort of 237 subjects. Mean age at baseline was 57.2 ± 5.0 years, and mean age at fracture was 65.4 ± 6.4 years.

    Results: Conditional logistic regression analysis with adjustments for height, weight, smoking, and menopausal status showed that subjects who were regularly active with walking or had a moderate or high frequency of physical spare time activities (i.e. berry/mushroom picking and snow shovelling) were at reduced risk of sustaining a hip fracture (OR 0.14; 95% CI; 0.05–0.53 for walking and OR 0.19; 95% CI; 0.08–0.46, OR 0.17, 95% CI; 0.05–0.64 for moderate and high frequency of spare time activities, respectively) compared to more sedentary women.

    Conclusion: An active lifestyle in middle age seems to reduce the risk of future hip fracture. Possible mechanisms may include improved muscle strength, coordination, and balance resulting in a decreased risk of falling and perhaps also direct skeletal benefits.

  • 14.
    Englund, Undis
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Nilsson, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Bergström, Ulrica
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Pettersson Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Active commuting reduces the risk of wrist fractures in middle-aged women: the UFO study2013In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 24, no 2, p. 533-540Article in journal (Refereed)
    Abstract [en]

    Middle-aged women with active commuting had significantly lower risk for wrist fracture than women commuting by car/bus.

    INTRODUCTION: Our purpose was to investigate whether a physically active lifestyle in middle-aged women was associated with a reduced risk of later sustaining a low-trauma wrist fracture.

    METHODS: The Umeå Fracture and Osteoporosis (UFO) study is a population-based nested case-control study investigating associations between lifestyle and fragility fractures. From a cohort of ~35,000 subjects, we identified 376 female wrist fracture cases who had reported data regarding their commuting habits, occupational, and leisure physical activity, before they sustained their fracture. Each fracture case was compared with at least one control drawn from the same cohort and matched for age and week of reporting data, yielding a total of 778 subjects. Mean age at baseline was 54.3 ± 5.8 years, and mean age at fracture was 60.3 ± 5.8 years.

    RESULTS: Conditional logistic regression analysis with adjustments for height, body mass index, smoking, and menopausal status showed that subjects with active commuting (especially walking) were at significantly lower risk of sustaining a wrist fracture (OR 0.48; 95 % CI 0.27-0.88) compared with those who commuted by car or bus. Leisure time activities such as dancing and snow shoveling were also associated with a lower fracture risk, whereas occupational activity, training, and leisure walking or cycling were unrelated to fracture risk.

    CONCLUSION: This study suggests that active commuting is associated with a lower wrist fracture risk, in middle-aged women.

  • 15. Eriksson, Anna L.
    et al.
    Böttiger, Ylva
    Ekman, Agneta
    Reis, Margareta
    Persson, Katarina
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Wallerstedt, Susanna M.
    Läkemedelsarbete behöver vara integrerat i klinisk utbildning: Att göra många läkemedelsgenomgångar ökar trygghet och reflektion över patientens behandling, visar enkätstudie2019In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 116, article id FHCTArticle in journal (Refereed)
    Abstract [en]

    A prerequisite for rational use of medicines is adequate prescribing skills; drug treatment is a complex task requiring diagnostic competence combined with pharmacologic knowledge and patient communication skills. Acquiring professional confidence in the art of prescribing is essential during medical training. The results of this questionnaire study, conducted in four medical schools in Sweden after the course in internal medicine (252 respondents; response rate: 74%; median age: 24 years, 61% female), show that 45% and 62% were confident in performing medication reviews and writing medication summary reports, respectively, i.e. the basics of prescribing. The confidence increased by the number of reviews and reports performed, i.e. the extent of practice (correlation coefficients: 0.41 and 0.38, respectively, both p<0.0001), as did the extent of the students' reflection on important aspects of drug treatment such as adherence, adverse reactions, renal function, dosing, and drug interactions. In multivariate regression analyses, major predictors for confidence in performing medication reviews were extent of practice and extent of clinical supervision. The results suggest that these factors are keys to acquiring professional confidence in the art of prescribing.

  • 16. Estrada, Karol
    et al.
    Styrkarsdottir, Unnur
    Evangelou, Evangelos
    Hsu, Yi-Hsiang
    Duncan, Emma L
    Ntzani, Evangelia E
    Oei, Ling
    Albagha, Omar ME
    Amin, Najaf
    Kemp, John P
    Koller, Daniel L
    Li, Guo
    Liu, Ching-Ti
    Minster, Ryan L
    Moayyeri, Alireza
    Vandenput, Liesbeth
    Willner, Dana
    Xiao, Su-Mei
    Yerges-Armstrong, Laura M
    Zheng, Hou-Feng
    Alonso, Nerea
    Eriksson, Joel
    Kammerer, Candace M
    Kaptoge, Stephen K
    Leo, Paul J
    Thorleifsson, Gudmar
    Wilson, Scott G
    Wilson, James F
    Aalto, Ville
    Alen, Markku
    Aragaki, Aaron K
    Aspelund, Thor
    Center, Jacqueline R
    Dailiana, Zoe
    Duggan, David J
    Garcia, Melissa
    Garcia-Giralt, Natàlia
    Giroux, Sylvie
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hocking, Lynne J
    Husted, Lise Bjerre
    Jameson, Karen A
    Khusainova, Rita
    Kim, Ghi Su
    Kooperberg, Charles
    Koromila, Theodora
    Kruk, Marcin
    Laaksonen, Marika
    Lacroix, Andrea Z
    Lee, Seung Hun
    Leung, Ping C
    Lewis, Joshua R
    Masi, Laura
    Mencej-Bedrac, Simona
    Nguyen, Tuan V
    Nogues, Xavier
    Patel, Millan S
    Prezelj, Janez
    Rose, Lynda M
    Scollen, Serena
    Siggeirsdottir, Kristin
    Smith, Albert V
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Trompet, Stella
    Trummer, Olivia
    van Schoor, Natasja M
    Woo, Jean
    Zhu, Kun
    Balcells, Susana
    Brandi, Maria Luisa
    Buckley, Brendan M
    Cheng, Sulin
    Christiansen, Claus
    Cooper, Cyrus
    Dedoussis, George
    Ford, Ian
    Frost, Morten
    Goltzman, David
    González-Macías, Jesús
    Kähönen, Mika
    Karlsson, Magnus
    Khusnutdinova, Elza
    Koh, Jung-Min
    Kollia, Panagoula
    Langdahl, Bente Lomholt
    Leslie, William D
    Lips, Paul
    Ljunggren, Osten
    Lorenc, Roman S
    Marc, Janja
    Mellström, Dan
    Obermayer-Pietsch, Barbara
    Olmos, José M
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Reid, David M
    Riancho, José A
    Ridker, Paul M
    Rousseau, François
    Lagboom, P Eline S
    Tang, Nelson LS
    Urreizti, Roser
    Van Hul, Wim
    Viikari, Jorma
    Zarrabeitia, María T
    Aulchenko, Yurii S
    Castano-Betancourt, Martha
    Grundberg, Elin
    Herrera, Lizbeth
    Ingvarsson, Thorvaldur
    Johannsdottir, Hrefna
    Kwan, Tony
    Li, Rui
    Luben, Robert
    Medina-Gómez, Carolina
    Th Palsson, Stefan
    Reppe, Sjur
    Rotter, Jerome I
    Sigurdsson, Gunnar
    van Meurs, Joyce BJ
    Verlaan, Dominique
    Williams, Frances MK
    Wood, Andrew R
    Zhou, Yanhua
    Gautvik, Kaare M
    Pastinen, Tomi
    Raychaudhuri, Soumya
    Cauley, Jane A
    Chasman, Daniel I
    Clark, Graeme R
    Cummings, Steven R
    Danoy, Patrick
    Dennison, Elaine M
    Eastell, Richard
    Eisman, John A
    Gudnason, Vilmundur
    Hofman, Albert
    Jackson, Rebecca D
    Jones, Graeme
    Jukema, J Wouter
    Khaw, Kay-Tee
    Lehtimäki, Terho
    Liu, Yongmei
    Lorentzon, Mattias
    McCloskey, Eugene
    Mitchell, Braxton D
    Nandakumar, Kannabiran
    Nicholson, Geoffrey C
    Oostra, Ben A
    Peacock, Munro
    Pols, Huibert AP
    Prince, Richard L
    Raitakari, Olli
    Reid, Ian R
    Robbins, John
    Sambrook, Philip N
    Sham, Pak Chung
    Shuldiner, Alan R
    Tylavsky, Frances A
    van Duijn, Cornelia M
    Wareham, Nick J
    Cupples, L Adrienne
    Econs, Michael J
    Evans, David M
    Harris, Tamara B
    Kung, Annie Wai Chee
    Psaty, Bruce M
    Reeve, Jonathan
    Spector, Timothy D
    Streeten, Elizabeth A
    Zillikens, M Carola
    Thorsteinsdottir, Unnur
    Ohlsson, Claes
    Karasik, David
    Richards, J Brent
    Brown, Matthew A
    Stefansson, Kari
    Uitterlinden, André G
    Ralston, Stuart H
    Ioannidis, John PA
    Kiel, Douglas P
    Rivadeneira, Fernando
    Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture2012In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, p. 491-501Article in journal (Refereed)
    Abstract [en]

    Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

  • 17. Hemminki, Kari
    et al.
    Chen, Bowang
    Kumar, Abhishek
    Melander, Olle
    Manjer, Jonas
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ohlsson, Claes
    Folprecht, Gunnar
    Löffler, Harald
    Krämer, Alwin
    Försti, Asta
    Germline genetics of cancer of unknown primary (CUP) and its specific subtypes2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 16, p. 22140-22149Article in journal (Refereed)
    Abstract [en]

    Cancer of unknown primary site (CUP) is a fatal cancer diagnosed through metastases at various organs. Little is known about germline genetics of CUP which appears worth of a search in view of reported familial associations in CUP. In the present study, samples from CUP patients were identified from 2 Swedish biobanks and a German clinical trial, totaling 578 CUP patients and 7628 regionally matched controls. Diagnostic data specified the organ where metastases were diagnosed. We carried out a genome-wide association study on CUP cases and controls. In the whole sample set, 6 loci reached an allelic p-value in the range of 10-7 and were supported by data from the three centers. Three associations were located next to non-coding RNA genes. rs2660852 flanked 5'UTR of LTA4H (leukotriene A4 hydrolase), rs477145 was intronic to TIAM1 (T-cell lymphoma invasion and metastases) and rs2835931 was intronic to KCNJ6 (potassium channel, inwardly rectifying subfamily J, member 6). In analysis of subgroups of CUP patients (smokers, non-smokers and CUP with liver metastases) genome-wide significant associations were noted. For patients with liver metastases associations on chromosome 6 and 11, the latter including a cluster of genes DHCR7 and NADSYN1, encoding key enzymes in cholesterol and NAD synthesis, and KRTAP5-7, encoding a keratin associated protein. This first GWAS on CUP provide preliminary evidence that germline genes relating to inflammation (LTA4H), metastatic promotion (TIAM1) in association with lipid metabolic disturbance (chromosome 11 cluster) may contribute to the risk of CUP.

  • 18. Henning, P.
    et al.
    Kindlund, B.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Conaway, H. H.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Inhibition of osteoclast formation in human peripheral CD14+cells by vitamin A2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no Supplement 1, p. S92-S92Article in journal (Refereed)
  • 19. Katsoulis, M
    et al.
    Benetou, V
    Karapetyan, T
    Feskanich, D
    Grodstein, F
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Wilsgaard, T
    Jørgensen, L
    Ahmed, L A
    Schöttker, B
    Brenner, H
    Bellavia, A
    Wolk, A
    Kubinova, R
    Stegeman, B
    Bobak, M
    Boffetta, P
    Trichopoulou, A
    Excess mortality after hip fracture in elderly persons from Europe and the USA: the CHANCES project2017In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 281, no 3, p. 300-310Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Hip fractures are associated with diminished quality of life and survival especially amongst the elderly.

    OBJECTIVE: All-cause mortality after hip fracture was investigated to assess its magnitude.

    METHODS: A total of 122 808 participants from eight cohorts in Europe and the USA were followed up for a mean of 12.6 years, accumulating 4273 incident hip fractures and 27 999 deaths. Incident hip fractures were assessed through telephone interviews/questionnaires or national inpatient/fracture registries, and causes of death were verified with death certificates. Cox proportional hazards models and the time-dependent variable methodology were used to assess the association between hip fracture and mortality and its magnitude at different time intervals after the injury in each cohort. We obtained the effect estimates through a random-effects meta-analysis.

    RESULTS: Hip fracture was positively associated with increased all-cause mortality; the hazard ratio (HR) in the fully adjusted model was 2.12, 95% confidence interval (CI) 1.76-2.57, after adjusting for potential confounders. This association was stronger amongst men [HR: 2.39, 95% CI: 1.72-3.31] than amongst women [HR: 1.92, 95% CI: 1.54-2.39], although this difference was not significant. Mortality was higher during the first year after the hip fracture [HR: 2.78, 95% CI: 2.12-3.64], but it remained elevated without major fluctuations after longer time since hip fracture [HR (95% CI): 1.89 (1.50-2.37) after 1-4 years; 2.15 (1.81-2.55) after 4-8 years; 1.79 (1.57-2.05) after 8 or more years].

    CONCLUSION: In this large population-based sample of older persons across eight cohorts, hip fracture was associated with excess short- and long-term all-cause mortality in both sexes.

  • 20. Leo, Paul J
    et al.
    Madeleine, Margaret M
    Wang, Sophia
    Schwartz, Stephen M
    Newell, Felicity
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hemminki, Kari
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Tiews, Sven
    Steinberg, Winfried
    Rader, Janet S
    Castro, Felipe
    Safaeian, Mahboobeh
    Franco, Eduardo L
    Coutlée, François
    Ohlsson, Claes
    Cortes, Adrian
    Marshall, Mhairi
    Mukhopadhyay, Pamela
    Cremin, Katie
    Johnson, Lisa G
    Garland, Suzanne
    Tabrizi, Sepehr N
    Wentzensen, Nicolas
    Sitas, Freddy
    Little, Julian
    Cruickshank, Maggie
    Frazer, Ian H
    Hildesheim, Allan
    Brown, Matthew A
    Defining the genetic susceptibility to cervical neoplasia: A genome-wide association study2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 8, article id e1006866Article in journal (Refereed)
    Abstract [en]

    A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.

  • 21.
    Lorentzon, Ronny
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    The Achilles heel of exercise.2000In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 355, no 9218, p. 1909-10; author reply 1911Article in journal (Refereed)
  • 22. Müezzinler, Aysel
    et al.
    Mons, Ute
    Gellert, Carolin
    Schöttker, Ben
    Jansen, Eugène
    Kee, Frank
    O'Doherty, Mark G
    Kuulasmaa, Kari
    Freedman, Neal D
    Abnet, Christian C
    Wolk, Alicja
    Håkansson, Niclas
    Orsini, Nicola
    Wilsgaard, Tom
    Bueno-de-Mesquita, Bas
    van der Schouw, Yvonne T
    Peeters, Petra H M
    de Groot, Lisette C P G M
    Peters, Annette
    Orfanos, Philippos
    Linneberg, Allan
    Pisinger, Charlotta
    Tamosiunas, Abdonas
    Baceviciene, Migle
    Luksiene, Dalia
    Bernotiene, Gailute
    Jousilahti, Pekka
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Jansson, Jan Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Jankovic, Nicole
    Sánchez, María-José
    Veronesi, Giovanni
    Sans, Susana
    Drygas, Wojciech
    Trichopoulou, Antonia
    Boffetta, Paolo
    Brenner, Hermann
    Smoking and All-cause Mortality in Older Adults: Results From the CHANCES Consortium2015In: American Journal of Preventive Medicine, ISSN 0749-3797, E-ISSN 1873-2607, Vol. 49, no 5, p. e53-e63Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Smoking is known to be a major cause of death among middle-aged adults, but evidence on its impact and the benefits of smoking cessation among older adults has remained limited. Therefore, we aimed to estimate the influence of smoking and smoking cessation on all-cause mortality in people aged ≥60 years.

    METHODS: Relative mortality and mortality rate advancement periods (RAPs) were estimated by Cox proportional hazards models for the population-based prospective cohort studies from Europe and the U.S. (CHANCES [Consortium on Health and Ageing: Network of Cohorts in Europe and the U.S.]), and subsequently pooled by individual participant meta-analysis. Statistical analyses were performed from June 2013 to March 2014.

    RESULTS: A total of 489,056 participants aged ≥60 years at baseline from 22 population-based cohort studies were included. Overall, 99,298 deaths were recorded. Current smokers had 2-fold and former smokers had 1.3-fold increased mortality compared with never smokers. These increases in mortality translated to RAPs of 6.4 (95% CI=4.8, 7.9) and 2.4 (95% CI=1.5, 3.4) years, respectively. A clear positive dose-response relationship was observed between number of currently smoked cigarettes and mortality. For former smokers, excess mortality and RAPs decreased with time since cessation, with RAPs of 3.9 (95% CI=3.0, 4.7), 2.7 (95% CI=1.8, 3.6), and 0.7 (95% CI=0.2, 1.1) for those who had quit <10, 10 to 19, and ≥20 years ago, respectively.

    CONCLUSIONS: Smoking remains as a strong risk factor for premature mortality in older individuals and cessation remains beneficial even at advanced ages. Efforts to support smoking abstinence at all ages should be a public health priority.

  • 23.
    Nilsson Sommar, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Lundh, Thomas
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hip Fracture Risk and Cadmium in Erythrocytes: A Nested Case-Control Study with Prospectively Collected Samples2014In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 94, no 2, p. 183-190Article in journal (Refereed)
    Abstract [en]

    Several studies have investigated the relation between bone mass density and cadmium exposure, but only few studies have been performed on fractures and biomarkers of cadmium. This study analyzed the association between hip fracture risk and cadmium in erythrocytes (Ery-Cd). Prospective samples from the Northern Sweden Health and Disease Study's biobank were used for 109 individuals who later in life had sustained a low-trauma hip fracture, matched with two controls of the same age and gender. The mean concentration of Ery-Cd (±SD) in case samples was 1.3 ± 1.4 versus 0.9 ± 1.0 μg/L in controls. The odds ratio (OR) was 1.63 [95 % confidence interval (CI) 1.10-2.42] for suffering a hip fracture for each microgram per liter increase in Ery-Cd. However, when taking smoking into consideration (never, former, or current), neither Ery-Cd nor smoking showed a statistically significant increase in fracture risk. Using multiple conditional logistic regression with BMI, height, and smoking, the estimated OR for a 1-μg/L increase in Ery-Cd was 1.52 (95 % CI 0.77-2.97). Subgroup analysis showed an increased fracture risk among women (OR = 1.94, 95 % CI 1.18-3.20, for a 1 μg/L increase), which also remained in the multiple analysis (OR = 3.33, 95 % CI 1.29-8.56). This study shows that fracture risk is associated with Ery-Cd. It is, however, not possible to draw firm conclusions on whether cadmium is the causal factor or whether other smoking-related factors cause this association. Subgroup analysis shows that cadmium is a risk factor for hip fracture among women.

  • 24.
    Nordström, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Type of physical activity, muscle strength, and pubertal stage as determinants of bone mineral density and bone area in adolescent boys.1998In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 13, no 7, p. 1141-8Article in journal (Refereed)
    Abstract [en]

    The present study was conducted to evaluate the influence of different types of weight-bearing physical activity, muscle strength, and puberty on bone mineral density (BMD, g/cm2) and bone area in adolescent boys. Three different groups were investigated. The first group consisted of 12 adolescent badminton players (age 17.0 +/- 0.8 years) training for 5.2 +/- 1.9 h/week. The second group consisted of 28 ice hockey players (age 16.9 +/- 0.3 years) training for 8.5 +/- 2.2 h/week. The third group consisted of 24 controls (age 16.8 +/- 0.3 years) training for 1.4 +/- 1.4h/week. The groups were matched for age, height, and pubertal stage. BMD, bone mineral content (BMC, g), and the bone area of the total body, lumbar spine, hip, femur and tibia diaphyses, distal femur, proximal tibia, and humerus were measured using dual-energy X-absorptiometry. When adjusting for the difference in body weight between the groups, the badminton players were found to have significantly higher BMD (p < 0.05) of the trochanter and distal femur compared with the ice hockey players despite a significantly lower weekly average training. The badminton players had higher BMD compared with the control with the control group at all weight-bearing BMD sites, except at the diaphyses of the femur and tibia and lumbar spine. The independent predictors of bone density were estimated by adjusting BMC for the bone area in a multivariate analysis among all subjects (n = 64). Accordingly, the bone density of all sites except the spine was significantly related to muscle strength and height, and the bone density of the total body, neck, trochanter, distal femur, and proximal tibia was significantly related to type of physical activity (beta = 0.09-0.33, p < 0.05). The bone area values at different sites were strongly related to muscle strength and height and less strongly related to the type of physical activity and pubertal stage. In conclusion, it seems that during late puberty in adolescent boys the type of weight-bearing physical activity is an important determinant of bone density, while the bone area is largely determined by parameters related to body size. The higher BMD at weight-bearing sites in badminton players compared with ice hockey players, despite significantly less average weekly training, indicates that physical activity including jumps in unusual directions has a great osteogenic potential.

  • 25. Oei, Ling
    et al.
    Hsu, Yi-Hsiang
    Styrkarsdottir, Unnur
    Eussen, Bert H
    de Klein, Annelies
    Peters, Marjolein J
    Halldorsson, Bjarni
    Liu, Ching-Ti
    Alonso, Nerea
    Kaptoge, Stephen K
    Thorleifsson, Gudmar
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hocking, Lynne J
    Husted, Lise Bjerre
    Jameson, Karen A
    Kruk, Marcin
    Lewis, Joshua R
    Patel, Millan S
    Scollen, Serena
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Trompet, Stella
    van Schoor, Natasja M
    Zhu, Kun
    Buckley, Brendan M
    Cooper, Cyrus
    Ford, Ian
    Goltzman, David
    González-Macías, Jesús
    Langdahl, Bente Lomholt
    Leslie, William D
    Lips, Paul
    Lorenc, Roman S
    Olmos, José M
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Reid, David M
    Riancho, José A
    Slagboom, P Eline
    Garcia-Ibarbia, Carmen
    Ingvarsson, Thorvaldur
    Johannsdottir, Hrefna
    Luben, Robert
    Medina-Gómez, Carolina
    Arp, Pascal
    Nandakumar, Kannabiran
    Palsson, Stefan Th
    Sigurdsson, Gunnar
    van Meurs, Joyce B J
    Zhou, Yanhua
    Hofman, Albert
    Jukema, J Wouter
    Pols, Huibert A P
    Prince, Richard L
    Cupples, L Adrienne
    Marshall, Christian R
    Pinto, Dalila
    Sato, Daisuke
    Scherer, Stephen W
    Reeve, Jonathan
    Thorsteinsdottir, Unnur
    Karasik, David
    Richards, J Brent
    Stefansson, Kari
    Uitterlinden, André G
    Ralston, Stuart H
    Ioannidis, John P A
    Kiel, Douglas P
    Rivadeneira, Fernando
    Estrada, Karol
    A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus2014In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 51, no 2, p. 122-131Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk.

    AIM: To identify CNVs associated with osteoporotic bone fracture risk.

    METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies.

    RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk.

    CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

  • 26. Ordóñez-Mena, José Manuel
    et al.
    Schöttker, Ben
    Fedirko, Veronika
    Jenab, Mazda
    Olsen, Anja
    Halkjær, Jytte
    Kampman, Ellen
    de Groot, Lisette
    Jansen, Eugene
    Bueno-de-Mesquita, H Bas
    Peeters, Petra H
    Siganos, Galatios
    Wilsgaard, Tom
    Perna, Laura
    Holleczek, Bernd
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Orfanos, Philippos
    Trichopoulou, Antonia
    Boffetta, Paolo
    Brenner, Hermann
    Pre-diagnostic vitamin D concentrations and cancer risks in older individuals: an analysis of cohorts participating in the CHANCES consortium2016In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 31, no 3, p. 311-323Article in journal (Refereed)
    Abstract [en]

    The associations of circulating 25-hydroxyvitamin D [25(OH)D] concentrations with total and site-specific cancer incidence have been examined in several epidemiological studies with overall inconclusive findings. Very little is known about the association of vitamin D with cancer incidence in older populations. We assessed the association of pre-diagnostic serum 25(OH)D levels with incidence of all cancers combined and incidence of lung, colorectal, breast, prostate and lymphoid malignancies among older adults. Pre-diagnostic 25(OH)D concentrations and cancer incidence were available in total for 15,486 older adults (mean age 63, range 50-84 years) participating in two cohort studies: ESTHER (Germany) and TROMSØ (Norway); and a subset of previously published nested-case control data from a another cohort study: EPIC-Elderly (Greece, Denmark, Netherlands, Spain and Sweden) from the CHANCES consortium on health and aging. Cox proportional hazards or logistic regression were used to derive multivariable adjusted hazard and odds ratios, respectively, and their 95 % confidence intervals across 25(OH)D categories. Meta-analyses with random effects models were used to pool study-specific risk estimates. Overall, lower 25(OH)D concentrations were not significantly associated with increased incidence of most of the cancers assessed. However, there was some evidence of increased breast cancer and decreased lymphoma risk with higher 25(OH)D concentrations. Our meta-analyses with individual participant data from three large European population-based cohort studies provide at best limited support for the hypothesis that vitamin D may have a major role in cancer development and prevention among European older adults.

  • 27. Papadimitriou, Nikos
    et al.
    Tsilidis, Konstantinos K.
    Orfanos, Philippos
    Benetou, Vassiliki
    Ntzani, Evangelia E.
    Soerjomataram, Isabelle
    Kuenn-Nelen, Annemarie
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Brenner, Hermann
    Schoettker, Ben
    Saum, Kai-Uwe
    Holleczek, Bernd
    Grodstein, Francine D.
    Feskanich, Diane
    Orsini, Nicola
    Wolk, Alicja
    Bellavia, Andrea
    Wilsgaard, Tom
    Jorgensen, Lone
    Boffetta, Paolo
    Trichopoulos, Dimitrios
    Trichopoulou, Antonia
    Burden of hip fracture using disability-adjusted life-years: a pooled analysis of prospective cohorts in the CHANCES consortium2017In: Lancet Public Health, ISSN 2468-2667, Vol. 2, no 5, p. E239-E246Article in journal (Refereed)
    Abstract [en]

    Background: No studies have estimated disability-adjusted life-years (DALYs) lost due to hip fractures using real-life follow-up cohort data. We aimed to quantify the burden of disease due to incident hip fracture using DALYs in prospective cohorts in the CHANCES consortium, and to calculate population attributable fractions based on DALYs for specific risk factors.

    Methods: We used data from six cohorts of participants aged 50 years or older at recruitment to calculate DALYs. We applied disability weights proposed by the National OsteoporosisFoundation and did a series of sensitivity analyses to examine the robustness of DALY estimates. We calculated population attributable fractions for smoking, body-mass index (BMI), physical activity, alcohol intake, type 2 diabetes and parity, use of hormone replacement therapy, and oral contraceptives in women. We calculated summary risk estimates across cohorts with pooled analysis and random-effects meta-analysis methods.

    Findings: 223 880 men and women were followed up for a mean of 13 years (SD 6). 7724 (3·5%) participants developed an incident hip fracture, of whom 413 (5·3%) died as a result. 5964 DALYs (27 per 1000 individuals) were lost due to hip fractures, 1230 (20·6%) of which were in the group aged 75–79 years. 4150 (69·6%) DALYs were attributed to disability. Current smoking was the risk factor responsible for the greatest hip fracture burden (7·5%, 95% CI 5·2–9·7) followed by physical inactivity (5·5%, 2·1–8·5), history of diabetes (2·8%, 2·1–4·0), and low to average BMI (2·0%, 1·4–2·7), whereas low alcohol consumption (0·01–2·5 g per day) and high BMI had a protective effect.

    Interpretation: Hip fracture can lead to a substantial loss of healthy life-years in elderly people. National public health policies should be strengthened to reduce hip fracture incidence and mortality. Primary prevention measures should be strengthened to prevent falls, and reduce smoking and a sedentary lifestyle.

  • 28.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Bone mass in the young athlete1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Bone mass and bone size accumulate during childhood and adolescence and peak in the twenties. The obtained peak bone mass has been suggested to be a major determinant of bone mass even in the very elderly. Although, genetic factors are the main determinants, environmental and lifestyle factors also play a crucial role in modulating maximal bone mass. Assessing these lifestyle factors would be of great importance for the intervention strategies against osteoporosis.  

    The first aim of this thesis was to compare the bone mass and bone size in male and female young adults on a high level of physical activity with males or females on a low level of physical activity. Furthermore, it also aimed to investigate the influence of pubertal maturity, menstrual disturbances, and different body constitutional factors on bone mass and size during adolescence and young adulthood.  

    The female activity groups consisted of cross-county skiers, soccer players, and rope skippers. Compared to their age-matched inactive controls, all these athletic groups demonstrated a significantly higher bone mineral density (BMD) at those sites subjected to the sport-specific loading. Rope-skipping, a very high impact activity was associated with a higher bone size, preferentially in the lower extremity, suggesting an effect of weight-bearing activity also on bone geometry. The effect of menstrual disturbances was evaluated in a group of long-distance runners, where amenorrheic runners had significantly lower BMD in both trabecular and also cortical bone in the lower extremity compared to eumenorrheic runners, suggesting that weight-bearing activity cannot compensate for the shortfall of reduced estrogen levels.  

    The male activity groups consisted of ice hockey players and badminton players. Compared to their age-matched controls, both athletic groups demonstrated a significantly higher BMD at those sites subjected to the sport-specific loading. Especially badminton was associated with a high BMD, suggesting that physical activity, including jumps in unusual directions has a great osteogenic potential.  

    The main determinants of BMD in both male and females were, except for type of physical activity, activity, muscle strength, height, and different body constitutional factors. However, the relationships with muscle strength and body constitution were somewhat weaker in the athletic groups, especially in the males, indicating that impact forces may be of greater importance in regulating bone mass in highly trained athletes. Yet bone size was largely determined by parameters related to body size and less strongly to physical activity. In a prospective study on adolescent boys, the changes in bone mass during late puberty were mainly accounted for by growth and development, including height and pubertal maturation, and less to physical activity level. Thus, the osteogenic effect from physical activity seems to be of importance for bone mass achievement predominantly before late puberty.

  • 29.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    D-vitaminstatus och frakturer hos äldre kvinor i Sverige2008In: Nordisk Nutrition, ISSN 1654-8337, no 1, p. 16-17Article in journal (Other academic)
  • 30.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Fysisk aktivitet hos ungdomar och framtida risk för besnkörhet.2000In: Svensk Idrottsmedicin, ISSN 1103-7652, no 1, p. 7-9Article in journal (Other academic)
  • 31.
    Pettersson, Ulrika
    et al.
    Bone research group, Institution of Medical Sciences, University of Aberdeen .
    Albagha, Omar M E
    Bone research group, Institution of Medical Sciences, University of Aberdeen .
    Mirolo, Max
    Institute of Biomedical technology, CNR, Via Fratelli Cervi, Milano, Italy.
    Taranta, Anna
    Department of Experimental Medicine, University of L'Aquila, Italy.
    Frattini, Annalisa
    Institute of Biomedical technology, CNR, Via Fratelli Cervi, Milano, Italy.
    McGuigan, Fiona E A
    Bone research group, Institution of Medical Sciences, University of Aberdeen .
    Vezzoni, Paolo
    Institute of Biomedical technology, CNR, Via Fratelli Cervi, Milano, Italy.
    Teti, Anna
    Institute of Biomedical technology, CNR, Via Fratelli Cervi, Milano, Italy.
    van Hul, Wim
    Department of Medical Genetics, University Hospital of Antwerp, Belgium.
    Reid, David M
    Bone research group, Institution of Medical Sciences, University of Aberdeen .
    Villa, Anna
    Ralston, Stuart H
    Bone research group, Institution of Medical Sciences, University of Aberdeen .
    Polymorphisms of the CLCN7 gene are associated with BMD in women.2005In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 20, no 11, p. 1960-7Article in journal (Refereed)
    Abstract [en]

    UNLABELLED: Here we show that a common polymorphism causing a valine to methionine amino acid substitution at codon 418 (V418M) in the CLCN7 gene is associated with femoral neck BMD in women. Our study adds to accumulating evidence that shows that common allelic variants in monogenic bone disease genes often contribute to BMD regulation in normal subjects.

    INTRODUCTION: The CLCN7 gene is a strong candidate for regulation of BMD, because mutations in CLCN7 cause some forms of osteopetrosis, a disease characterized by impaired osteoclast function and increased BMD. In this study, we sought to determine whether common allelic variation within CLCN7 was associated with BMD in the normal population.

    MATERIALS AND METHODS: We conducted mutation screening of the exons and intron-exon boundaries in CLCN7 by DNA sequencing in 50 normal subjects. We conducted an association study between common polymorphisms in CLCN7 and haplotypes defined by these polymorphisms and BMD values at the lumbar spine and femoral neck in a population-based cohort study of 1077 Scottish women 45-55 years of age.

    RESULTS: We identified 24 polymorphisms, but most were rare and only 4 had allele frequencies of >5%. These were a conservative single nucleotide polymorphism (SNP) in exon 1 (rs3751884), a 50-bp tandem repeat polymorphism within intron 8, and two SNPs within exon 15 (rs12926089 and rs12926669), of which one (rs12926669) predicts an amino acid change from valine to methionine at codon 418 (V418M). The exon 15 SNPs were in strong linkage disequilibrium and were both associated with femoral neck BMD (p = 0.001-0.003). None of the other polymorphisms were associated with BMD, and long-range haplotypes showed a much weaker association with BMD than the exon 15 SNPs. The V418M polymorphism was an independent predictor of femoral neck BMD on multiple regression analysis accounting for 1% of the variance in BMD at this site.

    CONCLUSIONS: Our study indicates that the V418M polymorphism of CLCN7 contributes to the genetic regulation of femoral neck BMD in women and adds to accumulating evidence that indicates that subtle polymorphic variation in genes that cause monogenic bone diseases also contribute to regulation of BMD in normal subjects.

  • 32.
    Pettersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Henriksson-Larsén, Karin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Bone mass in female cross-country skiers: relationship between muscle strength and different BMD sites.2000In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 67, no 3, p. 199-206Article in journal (Refereed)
    Abstract [en]

    In this cross-sectional study, bone mass and muscle strength of the thigh were investigated in 16 Caucasian female cross-country skiers, age 16.2 +/- 0.3 years, that had been ski-training for 6.4 +/- 1.8 years (range 3-9 years) and were now training for 6.3 +/- 2.4 hours/week (range 3-12 hours). They were compared with 16 nonactive females, age 16.4 +/- 0.7 years. The groups were matched according to age, weight, height, and pubertal status. Areal bone mineral density (BMD) was measured using dual energy X-ray absorptiometry, in the total body, head, both total humerus and humerus diaphyses, spine, and in the right femoral neck, greater trochanter, femoral diaphysis, distal femur, proximal tibia, and tibia diaphysis. Bone mineral apparent density (BMAD) was also calculated for the femoral neck and humerus diaphyses. Isokinetic muscle strength of the quadricep and hamstring muscles was measured in an isokinetic dynamometer. Compared with the controls, the cross-country skiing group had significantly higher BMD in the right whole humerus (6.9%), left whole humerus (9.2%), left humerus diaphysis (8.1%), femoral neck (8.9%), greater trochanter (9.3%), femur diaphysis (7.6%), and BMAD of the femoral neck (+19.4%). In the nonactive group there were significant side-to-side differences in BMD of the whole humeri, humerus diaphyses, and BMAD of the humerus diaphyses (3.1%, 5.4%, and 8.8% higher in the right arm, respectively). No such differences were found in the cross-country skiing group. Lean body mass was significantly higher in the cross-country skiers (21.7%), and fat mass (-25.5%) and body fat percent (-28.0%) were significantly lower compared with the nonactive group. There were, however, no significant differences in concentric peak torque of the thigh muscles between the two groups. Stepwise regression analyses revealed that BMI was the best predictor of several sites in the nonactive group. In the cross-country group, on the other hand, muscle strength was a strong predictor of BMD, both at adjacent and more distant BMD sites. In conclusion, it seems that this type of endurance training is associated with a site-specific higher bone mass that may be associated with the type and magnitude of loading during off-season and during the main sports activity, cross-country skiing.

  • 33.
    Pettersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Dahlqvist, Rune
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Fish oil for prevention of thromobosis and blood lipd lowering?2007In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 104, no 4, p. 250-251Article in journal (Refereed)
  • 34.
    Pettersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Nilsson, Martin
    Institutionen för Internmedicin, Sahlgrenska Universitetssjukhus.
    Sundh, Valter
    Institutionen för Geriatrik, Sahlgrenska Universitetssjukhus.
    Mellström, Dan
    Göteborgs universitet och Institutionen för Internmedicin, Sahlgrenska Universitetssjukhus.
    Lorentzon, Mattias
    Göteborgs universitet och Institutionen för Internmedicin, Sahlgrenska Universitetssjukhus.
    Physical activity is the strongest predictor of calcaneal peak bone mass in young Swedish men2010In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 21, no 3, p. 447-455Article in journal (Refereed)
    Abstract [en]

    In a highly representative sample of young adult Swedish men (n = 2,384), we demonstrate that physical activity during childhood and adolescence was the strongest predictor of calcaneal bone mineral density (BMD), and that peak bone mass was reached at this site at the age of 18 years.

    INTRODUCTION: The purpose of the present study was to determine if physical activity during growth is associated with peak calcaneal BMD in a large, highly representative cohort of young Swedish men.

    METHODS: In this study, 2,384 men, 18.3 +/- 0.3 (mean +/- SD) years old, were included from a population attending the mandatory tests for selection to compulsory military service in Sweden. BMD (g/cm(2)) of the calcaneus was measured using dual-energy X-ray absorptiometry. Training habits were investigated using a standardized questionnaire.

    RESULTS: Regression analysis (with age, height, weight, smoking, and calcium intake as covariates) demonstrated that history of regular physical activity was the strongest predictor and could explain 10.1% of the variation in BMD (standardized beta = 0.31, p < 0.001). A regression model with quadratic age effect revealed maximum BMD at 18.4 years.

    CONCLUSIONS: We found that history of physical activity during growth was the strongest predictor of peak calcaneal BMD in young men.

  • 35.
    Pettersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Henriksson-Larsen, Karin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Effect of high impact activity on bone mass and size in adolescent females: A comparative study between two different types of sports.2000In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 67, no 3, p. 207-214Article in journal (Refereed)
    Abstract [en]

    The purpose of this cross-sectional study was to investigate the influence of two different types of weight-bearing activity, muscle strength, and body composition on bone mineral density (BMD), bone mineral content (BMC), and bone area in three different groups of late adolescent girls. The first group consisted of 10 females participating in competitive rope-skipping (age 17.8 +/- 0.8 years) training for 6.7 +/- 3.1 hours/week; the second group consisted of 15 soccer players (age 17.4 +/- 0.8 years) training for 6.1 +/- 2.0 hours/week; and the third group consisted of 25 controls (age 17.6 +/- 0.8 years) with physical activity of 0.9 +/- 1.1 hours/week. The groups were matched for age, height, and weight. BMD (g/cm(2)), BMC (g), and bone area (cm(2)) of the total body, lumbar spine, hip, total femur, distal femur, diaphyses of femur and tibia, proximal tibia, and humerus were measured using dual-energy X-ray absorptiometry (DXA). Bone density was also assessed in the radial forearm site of the dominant limb in the rope skippers and in 10 matched controls. The rope skippers had 22% higher BMD at the ultradistal site (P < 0.01). Both high-activity groups had significantly higher BMD (P < 0.05) at most loaded sites compared with the control group. When adjusting for differences in lean mass and starting age of sport-specific training between the activity groups, the rope-skipping group had a higher BMD of the total body, lumbar spine, and right humerus compared with the soccer group. They also had a significantly higher bone area of the total body, total femur, and the proximal femur than both other groups, and a significantly higher bone area of the tibia diaphysis, compared with the soccer group. In a multivariate analysis among all subjects (n = 50), all BMD sites, except the femur diaphysis, distal femur, and proximal tibia, were significantly related to type of physical activity (beta = 0.25-0.43, P < 0.05). The bone area values at different sites were strongly related to muscle strength and parameters related to body size [height, weight, lean mass, fat mass, and body mass index (BMI)]. In conclusion, it appears that in late adolescent women, weight-bearing activities are an important determinant for bone density, and high impact activities such as jumping also seem to be associated with a modification of the bone geometry (hence, the bone width) at the loaded sites.

  • 36.
    Pettersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Lorentzon, R
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    A comparison of bone mineral density and muscle strength in young male adults with different exercise level.1999In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 64, no 6, p. 490-8Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate any differences in bone mass at different sites between young adults subjected to a high physical activity and a group of young adults with a low level of physical activity. In addition, we compared the relationship among bone mass, muscle strength, and body constitution in these two groups. The reference group consisted of 20 men, age 24.6 +/- 2.3 years, not training for more than 3 hours per week. The ice hockey players consisted of 20 players, age 23.4 +/- 4.9 years, from an ice hockey team in the second highest national Swedish league, training for about 10 hours per week. The groups were matched according to age, height, and weight. Areal bone mineral density (BMD) was measured in total body, head, humerus, spine, pelvis, femur, femoral neck, Ward's triangle, trochanter, femur diaphysis, proximal tibia, and tibia diaphysis using dual energy X-ray absorptiometry. BMD was significantly higher in the total body (8.1%), humerus (11.4%), spine (12.7%), pelvis (12.4%), femoral neck (10.3%), femur (7.4%), proximal tibia (9.8%), and tibia diaphysis (7.5%) in the high activity group. Fat mass was significantly lower in the high activity group (18.7%). The high activity group also had a significantly higher lean body mass (5.4%) and a significantly higher isokinetic muscle strength of the quadriceps muscle compared with the reference group. In the reference group, there was a general strong independent relationship between muscle strength of the thigh and all BMD sites, except for the head, tibia diaphysis, and proximal tibia. Furthermore, in the same group, body mass index (BMI) independently predicted pelvis BMD. On the contrary, in the high activity group, muscle strength did not predict any BMD site at all. In the same group, body constitutional parameters (weight, height, and fat mass) independently predicted pelvis BMD, and BMI was shown to be an independent predictor of humerus BMD. The differences in BMD between the groups seem to be site-specific and may be associated with the type and magnitude of loading during off season training and preferentially during ice hockey. High physical activity seems to weaken the relationship between BMD and muscle strength. Hence, impact forces may be of greater importance in regulating bone mass than muscle strength in itself in highly trained athletes.

  • 37.
    Pettersson, Ulrika
    et al.
    Department of Medicne and Therapuetics, University of Aberdeen.
    Reid, David M
    Department of Medicine and Therapeutics, University of Aberdeen.
    Antiresorptive and anabolic treatment for osteoporosis.2004In: Managing the menopaus withhout oestrogen.: Handbook of the British menpausal society. / [ed] Rees M, Mander T, Marlow, UK: BMS Publications LTD , 2004, 4, p. 9-15Chapter in book (Refereed)
  • 38.
    Pettersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Stålnacke, Britt-Marie
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Ahlénius, Gerd-Marie
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Henriksson-Larsén, Karin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Low bone mass density at multiple skeletal sites, including the appendicular skeleton in amenorrheic runners1999In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 64, no 2, p. 117-125Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate any difference in bone mass at different sites between female long-distance runners with amenorrhea and those with eumenorrhea. We compared 10 amenorrheic and 10 eumenorrheic athletes to determine whether athletes with amenorrhea have lower BMD in multiple skeletal regions, including weight-bearing lower limbs. The amenorrheic group had experienced menstrual dysfunction ranging from 3 to 43 months. As a further control group, 16 eumenorrheic soccer players were compared with the former two running groups regarding their BMD measurements. The two groups were matched for age, height, and amount of training. Areal bone mineral density (BMD) was measured and was found to be significantly lower in the total body, humerus, spine, lumbar spine, pelvis, femoral neck, trochanter, total femur, femur diaphysis, tibia diaphysis and in the nonweight-bearing head of the femur in the amenorrheic group. Body weight, BMI, fat mass, and body fat percent were significantly lower in the amenorrheic group. The differences in the BMD of the head, humerus, femoral neck, total femur, femur diaphysis, and tibia diaphysis disappeared when adjusted for body weight. Compared with the soccer group, the amenorrheic subjects had significantly lower BMD values at all sites except for the head, Ward's triangle, and femur diaphysis. Blood samples were obtained in the two running groups for analysis of osteocalcin, carboxy terminal telopeptide (ICTP), procollagen I (PICP), and estradiol. There were no significant differences between the groups but there was a strong tendency towards a lower estradiol level and a higher osteocalcin level in the amenorrheic group. A free estradiol index (FE2) was derived as the ratio of estradiol to sex hormone binding globulin (SHBG) and was significantly lower in the amenorrheic group. No difference in their daily intake of total energy, protein, carbohydrates, fiber, calcium, and vitamin D was observed. However, both groups showed a surprisingly low energy intake in relation to their training regimens. Stepwise regression analyses revealed that weight was the best predictor of spine BMD in both groups. Estradiol and FE2 were significant predictors of the BMD of the proximal femur in the eumenorrheic group, but did not predict any BMD site in the amenorrheic group. In conclusion, amenorrhea in athletic women affects trabecular and cortical bone in both axial and appendicular skeleton. However, some of the discrepancy can be explained by a lower body weight. Physical weight-bearing activity does not seem to completely compensate for the side effects of reduced estrogen levels even in weight-bearing bones in the lower extremity and spine.

  • 39.
    Pettersson-Kymmer, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hanson, Aimee L
    Madeleine, Margaret M
    Wang, Sophia S
    Schwartz, Stephen M
    Newell, Felicity
    Pettersson-Kymmer, Ulrika
    Hemminki, Kari
    Tiews, Sven
    Steinberg, Winfried
    Rader, Janet S
    Castro, Felipe
    Safaeian, Mahboobeh
    Franco, Eduardo L
    Coutlée, François
    Ohlsson, Claes
    Cortes, Adrian
    Marshall, Mhairi
    Mukhopadhyay, Pamela
    Cremin, Katie
    Johnson, Lisa G
    Garland, Suzanne M
    Tabrizi, Sepehr N
    Wentzensen, Nicolas
    Sitas, Freddy
    Trimble, Cornelia
    Little, Julian
    Cruickshank, Maggie
    Frazer, Ian H
    Hildesheim, Allan
    Brown, Matthew A
    Duncan, Emma L
    Sun, YingPu
    Leo, Paul J
    HLA and KIR Associations of Cervical Neoplasia2018In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 218, no 12, p. 2006-2015Article in journal (Refereed)
    Abstract [en]

    Background: Cervical cancer is the fourth most common cancer in women, and we recently reported human leukocyte antigen (HLA) alleles showing strong associations with cervical neoplasia risk and protection. HLA ligands are recognised by killer immunoglobulin-like receptors (KIRs) expressed on a range of immune cell subsets, governing their proinflammatory activity. We hypothesized that the inheritance of particular HLA-KIR combinations would increase cervical neoplasia risk.

    Methods: Here, we used HLA and KIR dosages imputed from SNP genotype data from 2,143 cervical neoplasia cases and 13,858 healthy controls of European decent.

    Results: Four novel HLA alleles were identified in association with cervical neoplasia: HLA-DRB3*9901 (OR=1.24, P=2.49×10-9), HLA-DRB5*0101 (OR=1.29, P=2.26×10-8), HLA-DRB5*9901 (OR=0.77, P=1.90×10-9) and HLA-DRB3*0301 (OR=0.63, P=4.06×10-5), due to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles. We also found homozygosity of HLA-C1 group alleles is a protective factor for HPV16-related cervical neoplasia (C1/C1, OR=0.79, P=0.005). This protective association was restricted to carriers of either KIR2DL2 (OR=0.67, P=0.00045) or KIR2DS2 (OR=0.69, P=0.0006).

    Conclusions: Our findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism.

  • 40.
    Pettersson-Kymmer, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lacroix, Andrea
    Eriksson, Joel
    Bergström, Ulrica
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Vandenput, Liesbeth
    Rajaraman, Preetha
    Hartge, Patricia
    Chanock, Stephen
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Duggan, David
    Kooperberg, Charles
    Handelman, Samuel
    Aragaki, Aaron
    Nethander, Maria
    Uitterlinden, Andre
    Rivadeneira, Fernando
    Jackson, Rebecca
    Ohlsson, Claes
    Genome-wide association study meta-analysis identifies the SOAT1/AXDND1 locus to be associated with hip and forearm fracture risk2013In: Bone Abstracts, 2013, Vol. 1Conference paper (Other academic)
    Abstract [en]

    Hip and forearm fractures are the two clinically most important non-vertebral fractures. Twin studies have demonstrated a high heritability of these fractures and the heritable component of fracture risk is largely independent of BMD. To identify common genetic variants associated with hip and forearm fractures, we performed a genome-wide association study (GWAS ~ 2.5 million SNPs) meta-analysis of two large fracture data sets within the well-characterized UFO cohort (UFO-hip; 1014 hip fractures and 862 controls, and UFO-forearm; 1060 forearm fractures and 1055 controls). All fractures were confirmed through radiographic reports. Replication was performed in the Women’s Health Initiative (WHI) cohort (1845 hip fractures verified by medical records and 2120 controls). We identified one SNP within the SOAT1/AXDND1 locus (1q25.2) that was associated with fracture risk at genome wide significance (OR per allele=1.33; P=3.1×10−8) in the UFO discovery meta-analysis. This SNP was associated with fracture risk both in the WHI replication cohort (OR 1.16, P=2.1×10−3) and in the combined analyses comprising 7956 subjects (3919 cases and 4037 controls; OR=1.24, P=5.6×10−10). However, it was not associated with BMD or biochemical bone markers, suggesting that its association with fractures is BMD-independent. A genetic score (GS), including information from 63 SNPs earlier shown to be reproducibly associated with BMD, was significantly associated with both hip (P=7.9×10−4) and forearm (P=8.6×10−5) fractures. Models including both the SNP in the SOAT1/AXDND1 locus and the GS demonstrated that the impact of the SNP in the SOAT1/AXDND1 locus on fracture risk was independent of the BMD-associated GS. In summary, both a BMD-associated GS and a non-BMD associated genetic variant in the SOAT1/AXDND1 locus are associated with hip and forearm fractures.

  • 41.
    Ramnemark, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Norberg, Margareta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Arctic Research Centre at Umeå University.
    Adequate vitamin D levels in a Swedish population living above latitude 63°N: The 2009 Northern Sweden MONICA study2015In: International Journal of Circumpolar Health, ISSN 1239-9736, E-ISSN 2242-3982, Vol. 74, no 1, article id 27963Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Even though vitamin D is mainly produced by exposure to sunlight, little is known regarding vitamin D levels in populations living in sub-Arctic areas with little or no daylight during winter.

    OBJECTIVE: We describe distributions of vitamin D3 and the prevalence of adequate levels in a population living above 63°N.

    DESIGN: We sampled 1,622 randomly selected subjects, aged 25-74 years, between January and May, 2009, as part of the Northern Sweden MONICA study (69.2% participation rate). By using HPLC, 25(OH) vitamin D3 was analysed. Levels used for definitions were deficient, D3<25 nmol/l (<10 ng/ml); insufficient, D3 25-49.9 nmol/l (10-20 ng/ml); and adequate, D3≥50 nmol/l (20 ng/ml).

    RESULTS: Mean (median) level of vitamin D3 was 65.2 (63.6) nmol/l in men and 71.0 (67.7) nmol/l in women. Adequate levels were found in 79.2%, more often in women (82.7%) than in men (75.6%). Only 0.7% of the population were vitamin D3-deficient but 23.1% of men and 17.1% of women had insufficient levels. Levels of vitamin D3 increased with age and insufficient status was most common among those aged 25-34 years, 41.0% in men and 22.3% in women. If subjects using vitamin D-supplementation are excluded, the population level of D3 is 1-2 nmol/l lower than in the general population across sex- and age groups. There were no differences between the northern or the southern parts, between urban or rural living or according to educational attainment. Those subjects born outside of Sweden or Finland had lower levels.

    CONCLUSION: The large majority living close to the Arctic Circle in Sweden have adequate D3 levels even during the second half of the dark winter. Subjects with D3 deficiency were uncommon but insufficient levels were often found among young men.

  • 42.
    Sjödén, Göran
    et al.
    Ortopedkliniken, Sundsvalls sjukhus.
    Sayed-Noor, Arkan
    Ortopedkliniken, Sundsvalls sjukhus.
    Kadum, Bakir
    Ortopedkliniken, Sundsvalls sjukhus.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Bisfosfonatbehandlingkan orsakastressfraktur: men behandlingsnyttan ärbetydligt större än risken2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 41, p. 2482-3Article in journal (Refereed)
  • 43. Trajanoska, Katerina
    et al.
    Morris, John A.
    Oei, Ling
    Zheng, Hou-Feng
    Evans, David M.
    Kiel, Douglas P.
    Ohlsson, Claes
    Richards, J. Brent
    Rivadeneira, Fernando
    Assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study2018In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 362, article id k3225Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To identify the genetic determinants of fracture risk and assess the role of 15 clinical risk factors on osteoporotic fracture risk.

    DESIGN: Meta-analysis of genome wide association studies (GWAS) and a two-sample mendelian randomisation approach.

    SETTING: 25 cohorts from Europe, United States, east Asia, and Australia with genome wide genotyping and fracture data.

    PARTICIPANTS: A discovery set of 37 857 fracture cases and 227 116 controls; with replication in up to 147 200 fracture cases and 150 085 controls. Fracture cases were defined as individuals (>18 years old) who had fractures at any skeletal site confirmed by medical, radiological, or questionnaire reports. Instrumental variable analyses were performed to estimate effects of 15 selected clinical risk factors for fracture in a two-sample mendelian randomisation framework, using the largest previously published GWAS meta-analysis of each risk factor.

    RESULTS: Of 15 fracture associated loci identified, all were also associated with bone mineral density and mapped to genes clustering in pathways known to be critical to bone biology (eg, SOST, WNT16, and ESR1) or novel pathways (FAM210A, GRB10, and ETS2). Mendelian randomisation analyses showed a clear effect of bone mineral density on fracture risk. One standard deviation decrease in genetically determined bone mineral density of the femoral neck was associated with a 55% increase in fracture risk (odds ratio 1.55 (95% confidence interval 1.48 to 1.63; P=1.5×10-68). Hand grip strength was inversely associated with fracture risk, but this result was not significant after multiple testing correction. The remaining clinical risk factors (including vitamin D levels) showed no evidence for an effect on fracture.

    CONCLUSIONS: This large scale GWAS meta-analysis for fracture identified 15 genetic determinants of fracture, all of which also influenced bone mineral density. Among the clinical risk factors for fracture assessed, only bone mineral density showed a major causal effect on fracture. Genetic predisposition to lower levels of vitamin D and estimated calcium intake from dairy sources were not associated with fracture risk.

  • 44. Tsilidis, Konstantinos K
    et al.
    Papadimitriou, Nikos
    Capothanassi, Despoina
    Bamia, Christina
    Benetou, Vassiliki
    Jenab, Mazda
    Freisling, Heinz
    Kee, Frank
    Nelen, Annemarie
    O'Doherty, Mark G
    Scott, Angela
    Soerjomataram, Isabelle
    Tjønneland, Anne
    May, Anne M
    Ramón Quirós, J
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Brenner, Hermann
    Schöttker, Ben
    Ordóñez-Mena, José M
    Karina Dieffenbach, Aida
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Bøgeberg Mathiesen, Ellisiv
    Njølstad, Inger
    Siganos, Galatios
    Wilsgaard, Tom
    Boffetta, Paolo
    Trichopoulos, Dimitrios
    Trichopoulou, Antonia
    Burden of Cancer in a Large Consortium of Prospective Cohorts in Europe2016In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 108, no 10, article id djw127Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Disability-adjusted life-years (DALYs) are an indicator of mortality, morbidity, and disability. We calculated DALYs for cancer in middle-aged and older adults participating in the Consortium on Health and Ageing Network of Cohorts in Europe and the United States (CHANCES) consortium.

    METHODS: A total of 90 199 participants from five European cohorts with 10 455 incident cancers and 4399 deaths were included in this study. DALYs were calculated as the sum of the years of life lost because of premature mortality (YLLs) and the years lost because of disability (YLDs). Population-attributable fractions (PAFs) were also estimated for five cancer risk factors, ie, smoking, adiposity, physical inactivity, alcohol intake, and type II diabetes.

    RESULTS: After a median follow-up of 12 years, the total number of DALYs lost from cancer was 34 474 (382 per 1000 individuals) with a similar distribution by sex. Lung cancer was responsible for the largest number of lost DALYs (22.9%), followed by colorectal (15.3%), prostate (10.2%), and breast cancer (8.7%). Mortality (81.6% of DALYs) predominated over disability. Ever cigarette smoking was the risk factor responsible for the greatest total cancer burden (24.0%, 95% confidence interval [CI] = 22.2% to 26.0%), followed by physical inactivity (4.9%, 95% CI = 0.8% to 8.1%) and adiposity (1.8%, 95% CI = 0.2% to 2.8%).

    CONCLUSIONS: DALYs lost from cancer were substantial in this large European sample of middle-aged and older adults. Even if the burden of disease because of cancer is predominantly caused by mortality, some cancers have sizeable consequences for disability. Smoking remained the predominant risk factor for total cancer burden.

  • 45. van der Eerden, B. C. J.
    et al.
    Oei, L.
    Roschger, P.
    Fratzl-Zelman, N.
    Hoenderop, J. G. J.
    van Schoor, N. M.
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Schreuders-Koedam, M.
    Uitterlinden, A. G.
    Hofman, A.
    Suzuki, M.
    Klaushofer, K.
    Ohlsson, C.
    Lips, P. J. A.
    Rivadeneira, F.
    Bindels, R. J. M.
    van Leeuwen, J. P. T. M.
    TRPV4 deficiency causes sexual dimorphism in bone metabolism and osteoporotic fracture risk2013In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 57, no 2, p. 443-454Article in journal (Refereed)
    Abstract [en]

    We explored the role of transient receptor potential vanilloid 4 (TRPV4) in murine bone metabolism and association of TRPV4 gene variants with fractures in humans. Urinary and histomorphometrical analyses demonstrated reduced osteoclast activity and numbers in male Trpv4(-/-) mice, which was confirmed in bone marrow-derived osteoclast cultures. Osteoblasts and bone formation as shown by serum procollagen type 1 amino-terminal propeptide and histomorphometry, including osteoid surface, osteoblast and osteocyte numbers were not affected in vivo. Nevertheless, osteoblast differentiation was enhanced in Trpv4(-/-) bone marrow cultures. Cortical and trabecular bone mass was 20% increased in male Trpv4(-/-) mice, compared to sex-matched wild type (Trpv4(+/+)) mice. However, at the same time intracortical porosity was increased and bone matrix mineralization was reduced. Together, these lead to a maximum load, stiffness and work to failure of the femoral bone, which were not different compared to Trpv4(+/+) mice, while the bone material was less resistant to stress and less elastic. The differential impacts on these determinants of bone strength were likely responsible for the lack of any changes in whole bone strength in the Trpv4(-/-) mice. None of these skeletal parameters were affected in female Trpv4(-/-) mice. The T-allele of rs1861809 SNP in the TRPV4 locus was associated with a 30% increased risk (95% Cl: 1.1-1.6; p = 0.013) for non-vertebral fracture risk in men, but not in women, in the Rotterdam Study. Meta-analyses with the population-based LASA study confirmed the association with non-vertebral fractures in men. This was lost when the non-population-based studies Mr. OS and UFO were included. In conclusion, TRPV4 is a male-specific regulator of bone metabolism, a determinant of bone strength, and a potential risk predictor for fractures through regulation of bone matrix mineralization and intra-cortical porosity. This identifies TRPV4 as a unique sexually dimorphic therapeutic and/or diagnostic candidate for osteoporosis.

  • 46. van Meurs, Joyce B J
    et al.
    Trikalinos, Thomas A
    Ralston, Stuart H
    Balcells, Susana
    Brandi, Maria Luisa
    Brixen, Kim
    Kiel, Douglas P
    Langdahl, Bente L
    Lips, Paul
    Ljunggren, Osten
    Lorenc, Roman
    Obermayer-Pietsch, Barbara
    Ohlsson, Claes
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Reid, David M
    Rousseau, Francois
    Scollen, Serena
    Van Hul, Wim
    Agueda, Lidia
    Akesson, Kristina
    Benevolenskaya, Lidia I
    Ferrari, Serge L
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hofman, Albert
    Husted, Lise Bjerre
    Kruk, Marcin
    Kaptoge, Stephen
    Karasik, David
    Karlsson, Magnus K
    Lorentzon, Mattias
    Masi, Laura
    McGuigan, Fiona E A
    Mellström, Dan
    Mosekilde, Leif
    Nogues, Xavier
    Pols, Huibert A P
    Reeve, Jonathan
    Renner, Wilfried
    Rivadeneira, Fernando
    van Schoor, Natasja M
    Weber, Kurt
    Ioannidis, John P A
    Uitterlinden, André G
    Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis.2008In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 299, no 11, p. 1277-1290Article in journal (Refereed)
    Abstract [en]

    Context: Mutations in the low-density lipoprotein receptor–related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population.

    Objective: To generate large-scale evidence on whether 2 common variants ofLRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk.

    Design and Setting: Prospective, multicenter, collaborative study of individual-level data on 37 534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures.

    Main Outcome Measures: Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures.

    Results: The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25 052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 × 10−8), as was the Val1330 allele (n = 24 812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 × 10−9). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2(P = 3.8 × 10−5) and 8 mg/cm2 (P = 5.0 × 10−6) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for bothLRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20 096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31 435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments.

    Conclusions: Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10−7] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.

  • 47. Zheng, H. -F
    et al.
    Duncan, E.
    Eriksson, J.
    Bergström, Ulrica
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Yerges-Armstrong, L.
    Leo, P.
    Vandenput, L.
    Nicholson, G.
    Ladouceur, M.
    Prince, R.
    Leslie, W.
    Eisman, J.
    Goltzman, D.
    Jones, G.
    Xiao, Y.
    Liu, J.
    Reid, I.
    Sambrook, P.
    Dennison, E.
    Danoy, P.
    Wilson, S.
    McCloskey, E.
    Eastell, R.
    Spector, T.
    Mitchell, B.
    Streeten, E.
    Brommage, R.
    Lorentzon, M.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Brown, M.
    Ohlsson, C.
    Richards, J. B.
    The 7Q31 locus, containing WNT16, is associated with bone mineral density, osteoporotic fracture and bone strength2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no Supplement 1, p. S33-S34Article in journal (Refereed)
  • 48. Zheng, Hou-Feng
    et al.
    Duncan, Emma L.
    Yerges-Armstrong, Laura M.
    Eriksson, Joel
    Bergström, Ulrica
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Leo, Paul J.
    Leslie, William D.
    Goltzman, David
    Blangero, John
    Hanley, David A.
    Carless, Melanie A.
    Streeten, Elizabeth A.
    Lorentzon, Mattias
    Brown, Matthew A.
    Spector, Tim D.
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Ohlsson, Claes
    Mitchell, Braxton D.
    Richards, J. Brent
    Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm2013In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 50, no 7, p. 473-478Article in journal (Refereed)
    Abstract [en]

    Background Forearm fractures affect 1.7 million individuals worldwide each year and most occur earlier in life than hip fractures. While the heritability of forearm bone mineral density (BMD) and fracture is high, their genetic determinants are largely unknown. Aim To identify genetic variants associated with forearm BMD and forearm fractures. Methods BMD at distal radius, measured by dual-energy x-ray absorptiometry, was tested for association with common genetic variants. We conducted a meta-analysis of genome-wide association studies for BMD in 5866 subjects of European descent and then selected the variants for replication in 715 Mexican American samples. Gene-based association was carried out to supplement the single-nucleotide polymorphism (SNP) association test. We then tested the BMD-associated SNPs for association with forearm fracture in 2023 cases and 3740 controls. Results We found that five SNPs in the introns of MEF2C were associated with forearm BMD at a genome-wide significance level (p<5x10(-8)) in meta-analysis (lead SNP, rs11951031[T] -0.20 SDs per allele, p=9.01x10(-9)). The gene-based association test suggested an association between MEF2C and forearm BMD (p=0.003). The association between MEF2C variants and risk of fracture did not achieve statistical significance (SNP rs12521522[A]: OR=1.14 (95% CI 0.92 to 1.35), p=0.14). Meta-analysis also revealed two genome-wide suggestive loci at CTNNA2 and 6q23.2. Conclusions These findings demonstrate that variants at MEF2C were associated with forearm BMD, implicating this gene in the determination of BMD at forearm.

  • 49. Zheng, Hou-Feng
    et al.
    Forgetta, Vincenzo
    Hsu, Yi-Hsiang
    Estrada, Karol
    Rosello-Diez, Alberto
    Leo, Paul J.
    Dahia, Chitra L.
    Park-Min, Kyung Hyun
    Tobias, Jonathan H.
    Kooperberg, Charles
    Kleinman, Aaron
    Styrkarsdottir, Unnur
    Liu, Ching-Ti
    Uggla, Charlotta
    Evans, Daniel S.
    Nielson, Carrie M.
    Walter, Klaudia
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    McCarthy, Shane
    Eriksson, Joel
    Kwan, Tony
    Jhamai, Mila
    Trajanoska, Katerina
    Memari, Yasin
    Min, Josine
    Huang, Jie
    Danecek, Petr
    Wilmot, Beth
    Li, Rui
    Chou, Wen-Chi
    Mokry, Lauren E.
    Moayyeri, Alireza
    Claussnitzer, Melina
    Cheng, Chia-Ho
    Cheung, Warren
    Medina-Gomez, Carolina
    Ge, Bing
    Chen, Shu-Huang
    Choi, Kwangbom
    Oei, Ling
    Fraser, James
    Kraaij, Robert
    Hibbs, Matthew A.
    Gregson, Celia L.
    Paquette, Denis
    Hofman, Albert
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Tranah, Gregory J.
    Marshall, Mhairi
    Gardiner, Brooke B.
    Cremin, Katie
    Auer, Paul
    Hsu, Li
    Ring, Sue
    Tung, Joyce Y.
    Thorleifsson, Gudmar
    Enneman, Anke W.
    van Schoor, Natasja M.
    de Groot, Lisette C. P. G. M.
    van der Velde, Nathalie
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Kemp, John P.
    Christiansen, Claus
    Sayers, Adrian
    Zhou, Yanhua
    Calderari, Sophie
    van Rooij, Jeroen
    Carlson, Chris
    Peters, Ulrike
    Berlivet, Soizik
    Dostie, Josee
    Uitterlinden, Andre G.
    Williams, Stephen R.
    Farber, Charles
    Grinberg, Daniel
    LaCroix, Andrea Z.
    Haessler, Jeff
    Chasman, Daniel I.
    Giulianini, Franco
    Rose, Lynda M.
    Ridker, Paul M.
    Eisman, John A.
    Nguyen, Tuan V.
    Center, Jacqueline R.
    Nogues, Xavier
    Garcia-Giralt, Natalia
    Launer, Lenore L.
    Gudnason, Vilmunder
    Mellstrom, Dan
    Vandenput, Liesbeth
    Amin, Najaf
    van Duijn, Cornelia M.
    Karlsson, Magnus K.
    Ljunggren, Osten
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Rousseau, Francois
    Giroux, Sylvie
    Bussiere, Johanne
    Arp, Pascal P.
    Koromani, Fjorda
    Prince, Richard L.
    Lewis, Joshua R.
    Langdahl, Bente L.
    Hermann, A. Pernille
    Jensen, Jens-Erik B.
    Kaptoge, Stephen
    Khaw, Kay-Tee
    Reeve, Jonathan
    Formosa, Melissa M.
    Xuereb-Anastasi, Angela
    Akesson, Kristina
    McGuigan, Fiona E.
    Garg, Gaurav
    Olmos, Jose M.
    Zarrabeitia, Maria T.
    Riancho, Jose A.
    Ralston, Stuart H.
    Alonso, Nerea
    Jiang, Xi
    Goltzman, David
    Pastinen, Tomi
    Grundberg, Elin
    Gauguier, Dominique
    Orwoll, Eric S.
    Karasik, David
    Davey-Smith, George
    Smith, Albert V.
    Siggeirsdottir, Kristin
    Harris, Tamara B.
    Zillikens, M. Carola
    van Meurs, Joyce B. J.
    Thorsteinsdottir, Unnur
    Maurano, Matthew T.
    Timpson, Nicholas J.
    Soranzo, Nicole
    Durbin, Richard
    Wilson, ScottG.
    Ntzani, Evangelia E.
    Brown, Matthew A.
    Stefansson, Kari
    Hinds, David A.
    Spector, Tim
    Cupples, L. Adrienne
    Ohlsson, Claes
    Greenwood, Celia M. T.
    Jackson, Rebecca D.
    Rowe, David W.
    Loomis, Cynthia A.
    Evans, David M.
    Ackert-Bicknell, Cheryl L.
    Joyner, Alexandra L.
    Duncan, Emma L.
    Kiel, Douglas P.
    Rivadeneira, Fernando
    Richards, J. Brent
    Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 526, no 7571, p. 112-+Article in journal (Refereed)
    Abstract [en]

    The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

  • 50. Zheng, Hou-Feng
    et al.
    Tobias, Jon H
    Duncan, Emma
    Evans, David M
    Eriksson, Joel
    Paternoster, Lavinia
    Yerges-Armstrong, Laura M
    Lehtimäki, Terho
    Bergström, Ulrica
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Kähönen, Mika
    Leo, Paul J
    Raitakari, Olli
    Laaksonen, Marika
    Nicholson, Geoffrey C
    Viikari, Jorma
    Ladouceur, Martin
    Lyytikäinen, Leo-Pekka
    Medina-Gomez, Carolina
    Rivadeneira, Fernando
    Prince, Richard L
    Sievanen, Harri
    Leslie, William D
    Mellström, Dan
    Eisman, John A
    Movérare-Skrtic, Sofia
    Goltzman, David
    Hanley, David A
    Jones, Graeme
    St Pourcain, Beate
    Xiao, Yongjun
    Timpson, Nicholas J
    Smith, George Davey
    Reid, Ian R
    Ring, Susan M
    Sambrook, Philip N
    Karlsson, Magnus
    Dennison, Elaine M
    Kemp, John P
    Danoy, Patrick
    Sayers, Adrian
    Wilson, Scott G
    Nethander, Maria
    McCloskey, Eugene
    Vandenput, Liesbeth
    Eastell, Richard
    Liu, Jeff
    Spector, Tim
    Mitchell, Braxton D
    Streeten, Elizabeth A
    Brommage, Robert
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Brown, Matthew A
    Ohlsson, Claes
    Richards, J Brent
    Lorentzon, Mattias
    WNT16 influences bone mineral density, Cortical bone thickness, bone strength, and Osteoporotic fracture risk2012In: PLoS genetics, ISSN 1553-7404, Vol. 8, no 7, p. e1002745-Article in journal (Refereed)
    Abstract [en]

    We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2×10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3×10(-12), and -0.16 SD per G allele, P = 1.2×10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10(-6) and rs2707466: OR = 1.22, P = 7.2×10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5×10(-13)<P<5.9×10(-4)) at both femur and tibia, compared with their wild-type littermates. Natural variation in humans and targeted disruption in mice demonstrate that WNT16 is an important determinant of CBT, BMD, bone strength, and risk of fracture.

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