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Obesity and Increased Susceptibility : Role of FTO and MGAT1 Genetic Variants
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Obesity is a complex and a highly individualized disease and the molecular mechanisms behind this disorder need to be better elucidated. Identification of genes and genetic variants that are involved provide opportunities to establish a genetic understanding of the disease. These findings may also provide more rational approaches to therapy, either by identifying underlying causes or point out the need for different treatments. In addition, the timing and severity of obesity may provide insights into the aetiology of obesity and also identify age-specific determinants of weight gain. Recently, genome-wide association studies have led to a rapid progress in our understanding of the genetic basis of various diseases and candidate genes for obesity have been identified. The overall aim of this thesis was to investigate the genetic impact on severity of childhood obesity and the associations between obesity and genetic variants in the fat mass and obesity associated gene, FTO, and MGAT1, the gene encoding mannosyl (α-1,3-)-glycoprotein β-1,2-N-acetyl-glucosaminyltransferase.

We show that the impact of parental body mass index (BMI) on the severity of obesity in children is strengthened as the child grows older, whereas the age at obesity onset is of limited importance.

By association studies, we show that single nucleotide polymorphisms downstream MGAT1 influence susceptibility to obesity. Moreover, these variants affect the levels of unsaturated fatty acids and desaturase indices, variables previously shown to correlate with obesity. Furthermore, one variant in the first intronic region of FTO is associated with obesity among children but not with BMI or other measures of adiposity at older ages. However, this variant shows a weight-dependent association with cognitive function among elderly men. By direct sequencing, we identified novel variants in FTO, affecting glucose homeostasis in a BMI-independent manner. Furthermore, we found gender specific effects for FTO, both regarding obesity susceptibility and related phenotypes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , 68 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 658
Keyword [en]
Obesity, BMI, SNP, haplotype, association study, FTO, MGAT1
National Category
Pharmacology and Toxicology
Research subject
Pharmacology
Identifiers
URN: urn:nbn:se:uu:diva-149332ISBN: 978-91-554-8039-4OAI: oai:DiVA.org:uu-149332DiVA: diva2:406173
Public defence
2011-05-07, B22, BMC, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2011-04-14 Created: 2011-03-17 Last updated: 2011-06-13Bibliographically approved
List of papers
1. Associations between severity of obesity in childhood and adolescence, obesity onset andparental BMI: a longitudinal cohort study
Open this publication in new window or tab >>Associations between severity of obesity in childhood and adolescence, obesity onset andparental BMI: a longitudinal cohort study
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2011 (English)In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 35, no 1, 46-52 p.Article in journal (Refereed) Published
Abstract [en]

Objective: To explore the relationship between severity of obesity at age 7 and age 15, age at onset of obesity, and parental body mass index (BMI) in obese children and adolescents. Design:Longitudinal cohort study. Subjects:Obese children (n=231) and their parents (n=462) from the Swedish National Childhood Obesity Centre. Methods: Multivariate regression analyses were applied with severity of obesity (BMI standard deviation score (BMI SDS)) and onset of obesity as dependent variables. The effect of parental BMI was evaluated and in the final models adjusted for gender, parental education, age at onset of obesity, severity of obesity at age 7 and obesity treatment. Results: For severity of obesity at age 7, a positive correlation with maternal BMI was indicated (P=0.05). Severity of obesity at this age also showed a strong negative correlation with the age at onset of obesity. Severity of obesity at age 15 was significantly correlated with both maternal and paternal BMI (P<0.01). In addition, BMI SDS at age 15 differed by gender (higher for boys) and was positively correlated with severity of obesity at age 7 and negatively correlated with treatment. Also, a negative correlation was indicated at this age for parental education. No correlation with age at onset was found at age 15. For age at onset of obesity there was no relevant correlation with parental BMI. Children within the highest tertile of the BMI SDS range were more likely to have two obese parents. Conclusion: The impact of parental BMI on the severity of obesity in children is strengthened as the child grows into adolescence, whereas the age at onset is probably of less importance than previously thought. The influence of parental relative weight primarily affects the severity of childhood obesity and not the timing.

Keyword
childhood obesity, parental BMI, maternal BMI, paternal BMI, age at onset of obesity, severity of obesity
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-149751 (URN)10.1038/ijo.2010.189 (DOI)000286094900006 ()20856258 (PubMedID)
Available from: 2011-03-22 Created: 2011-03-22 Last updated: 2011-07-08Bibliographically approved
2. Major gender difference in association of FTO gene variant among severely obese children with obesity and obesity related phenotypes.
Open this publication in new window or tab >>Major gender difference in association of FTO gene variant among severely obese children with obesity and obesity related phenotypes.
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2008 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 368, no 3, 476-482 p.Article in journal (Refereed) Published
Abstract [en]

Recent studies have shown that SNPs in the FTO gene predispose to childhood and adult obesity. In this study, we examined the association between variants in FTO and KIAA1005, a gene that maps closely to FTO, and obesity, as well as obesity related traits among 450 well characterised severely obese children and 512 normal weight controls. FTO showed significant association with several obesity related traits while SNPs in KIAA1005 did not. When stratified by gender, the FTO variant rs9939609 showed association with obesity and BMI among girls (P=0.006 and 0.004, respectively) but not among boys. Gender differences were also found in the associations of the FTO rs9939609 with obesity related traits such as insulin sensitivity and plasma glucose. This study suggests that FTO may have an important role for gender specific development of severe obesity and insulin resistance in children.

Keyword
FTO, obesity, SNP, diabetes, children, body mass index, insulin, glucose
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-99137 (URN)10.1016/j.bbrc.2008.01.087 (DOI)000253925900005 ()18249188 (PubMedID)
Available from: 2009-03-09 Created: 2009-03-09 Last updated: 2011-05-05Bibliographically approved
3. Novel genetic variant in FTO influences insulin levels and insulin resistance in severely obese children and adolescents.
Open this publication in new window or tab >>Novel genetic variant in FTO influences insulin levels and insulin resistance in severely obese children and adolescents.
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2008 (English)In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 32, no 11, 1730-1735 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND

The global prevalence of obesity and overweight is increasing rapidly among adults as well as among children and adolescents. Recent genome-wide association studies have provided strong support for association between variants in the FTO gene and obesity. We sequenced regions of the FTO gene to identify novel variants that are associated with obesity and related metabolic traits.

RESULTS

We screened exons 3 and 4 including exon-intron boundaries in FTO in 48 obese children and adolescents and identified three novel single nucleotide polymorphism in the fourth intronic region, (c.896+37A>G, c.896+117C>G and c.896+223A>G). We further genotyped c.896+223A>G in 962 subjects, 450 well-characterized obese children and adolescents and 512 adolescents with normal weight. Evidence for differences in genotype frequencies were not detected for the c.896+223A>G variant between extremely obese children and adolescents and normal weight adolescents (P=0.406, OR=1.154 (0.768-1.736)). Obese subjects with the GG genotype, however, had 30% increased fasting serum insulin levels (P=0.017) and increased degree of insulin resistance (P=0.025). There were in addition no differences in body mass index (BMI) or BMI standard deviation score (SDS) levels among the obese subjects according to genotype and the associations with insulin levels and insulin resistance remained significant when adjusting for BMI SDS.

CONCLUSION

These findings suggest that this novel variant in FTO is affecting metabolic phenotypes such as insulin resistance, which are not mediated through differences in BMI levels.

Keyword
FTO, polymorphism, metabolic phenotypes, children, adolescents
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-99025 (URN)10.1038/ijo.2008.168 (DOI)000260925300019 ()18794893 (PubMedID)
Available from: 2009-03-06 Created: 2009-03-06 Last updated: 2011-05-05Bibliographically approved
4. The common FTO variant rs9939609 is not associated with BMI in a longitudinal study on a cohort of Swedish men born 1920-1924
Open this publication in new window or tab >>The common FTO variant rs9939609 is not associated with BMI in a longitudinal study on a cohort of Swedish men born 1920-1924
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2009 (English)In: BMC Medical Genetics, ISSN 1471-2350, Vol. 10, no 131, 131- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Common FTO (fat mass and obesity associated) gene variants have recently been strongly associated with body mass index and obesity in several large studies. Here we set out to examine the association of the FTO variant rs9939609 with BMI in a 32 year follow up study of men born 1920-1924. Moreover, we analyzed the effect of physical activity on the different genotypes. METHODS: The FTO rs9936609 was genotyped using an Illumina golden gate assay. BMI was calculated using standard methods and body fat was estimated by measuring skinfold thickness using a Harpenden caliper. Physical activity was assessed using a four question medical questionnaire. RESULTS: FTO rs9939609 was genotyped in 1153 elderly Swedish men taking part of a population-based cohort study, the ULSAM cohort. The risk of obesity and differences in BMI according to genotype at the ages of 50, 60, 70, 77 and 82 were investigated. We found no increased risk of obesity and no association with BMI at any age with the FTO rs9939609 variant. We found however interaction between physical activity at the age of 50 years and genotype on BMI levels (p = 0.039) and there was a clear trend towards larger BMI differences between the TT and AA carriers as well as between AT and AA carriers in the less physically active subjects. CONCLUSION: Here we found that the well established obesity risk allele for a common variant in FTO does not associate with increased BMI levels in a Swedish population of adult men which reached adulthood before the appearance of today's obesogenic enviroment. There is an interaction between physical activity and the effect of the FTO genotype on BMI levels suggesting that lack of physical activity is a requirement for an association of FTO gene variants to obesity.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-122795 (URN)10.1186/1471-2350-10-131 (DOI)000273006900001 ()20003232 (PubMedID)
Available from: 2010-04-20 Created: 2010-04-20 Last updated: 2011-05-05Bibliographically approved
5. Detailed Analysis of Variants in FTO in Association with Body Composition in a Cohort of 70-Year-Olds Suggests a Weakened Effect among Elderly
Open this publication in new window or tab >>Detailed Analysis of Variants in FTO in Association with Body Composition in a Cohort of 70-Year-Olds Suggests a Weakened Effect among Elderly
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2011 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 6, no 5, e20158- p.Article in journal (Refereed) Published
Abstract [en]

Background

 The rs9939609 single-nucleotide polymorphism (SNP) in the fat mass and obesity (FTO) gene has previously been associated with higher BMI levels in children and young adults. In contrast, this association was not found in elderly men. BMI is a measure of overweight in relation to the individuals' height, but offers no insight into the regional body fat composition or distribution.

Objective

To examine whether the FTO gene is associated with overweight and body composition-related phenotypes rather than BMI, we measured waist circumference, total fat mass, trunk fat mass, leg fat mass, visceral and subcutaneous adipose tissue, and daily energy intake in 985 humans (493 women) at the age of 70 years. In total, 733 SNPs located in the FTO gene were genotyped in order to examine whether rs9939609 alone or the other SNPs, or their combinations, are linked to obesity-related measures in elderly humans.

Design

Cross-sectional analysis of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort.

Results

 Neither a single SNP, such as rs9939609, nor a SNP combination was significantly linked to overweight, body composition-related measures, or daily energy intake in elderly humans. Of note, these observations hold both among men and women.

Conclusions

Due to the diversity of measurements included in the study, our findings strengthen the view that the effect of FTO on body composition appears to be less profound in later life compared to younger ages and that this is seemingly independent of gender.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-149324 (URN)10.1371/journal.pone.0020158 (DOI)000291052500035 ()21637715 (PubMedID)
Available from: 2011-03-17 Created: 2011-03-17 Last updated: 2015-02-23Bibliographically approved
6. The fat mass and obesity gene is linked to reduced verbal fluency in overweight and obese elderly men
Open this publication in new window or tab >>The fat mass and obesity gene is linked to reduced verbal fluency in overweight and obese elderly men
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2011 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 32, no 6, 1159.e1-1159.e5 p.Article in journal (Refereed) Published
Abstract [en]

Humans carrying the prevalent rs9939609 A allele of the fat mass and obesity-associated (FTO) gene are more susceptible to developing obesity than noncarries. Recently, polymorphisms in the FTO gene of elderly subjects have also been linked to a reduced volume in the frontal lobe as well as increased risk for incident Alzheimer disease. However, so far there is no evidence directly linking the FTO gene to functional cognitive processes. Here we examined whether the FTO rs9939609 A allele is associated with verbal fluency performance in 355 elderly men at the age of 82 years who have no clinically apparent cognitive impairment. Retrieval of verbal memory is a good surrogate measure reflecting frontal lobe functioning. Here we found that obese and overweight but not normal weight FTO A allele carriers showed a lower performance on verbal fluency than non-carriers (homozygous for rs9939609 T allele). This effect was not observed for a measure of general cognitive performance (i.e., Mini-Mental State Examination score), thereby indicating that the FTO gene primarily affects frontal lobe-dependent cognitive processes in elderly men.

National Category
Geriatrics Neurosciences
Identifiers
urn:nbn:se:uu:diva-149331 (URN)10.1016/j.neurobiolaging.2011.02.006 (DOI)000291160000017 ()21458110 (PubMedID)
Available from: 2011-03-17 Created: 2011-03-17 Last updated: 2015-08-13Bibliographically approved
7. Genetic variants near the MGAT1 gene are associated with body weight, BMI and fatty acid metabolism among adults and children
Open this publication in new window or tab >>Genetic variants near the MGAT1 gene are associated with body weight, BMI and fatty acid metabolism among adults and children
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2012 (English)In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 36, no 1, 119-129 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Recently a genome-wide association analysis from five European populations identified a polymorphism located downstream of the mannosyl-(α-1,3)-glycoprotein-β-1,2-N-acetylglucosaminyltransferase (MGAT1) gene that was associated with body-weight. In the present study, associations between MGAT1 variants combined with obesity and insulin measurements were investigated in three cohorts. Levels of fatty acids and estimated measures of Δ desaturases were also investigated among adult men.

Design: Six polymorphisms downstream of MGAT1 were genotyped in a cross-sectional cohort of 1152 Swedish men. Three polymorphisms were further analyzed in a case-control study of 1076 Swedish children and in a cross-sectional study of 2249 Greek children.

Results: Three polymorphisms, rs12186500 (odds ratio (OR): 1.892, 95% confidence interval (CI): 1.237-2.895, P=0.003), rs1021001 (OR: 2.102, 95% CI: 1.280-3.455, P=0.003) and rs4285184 (OR: 1.587, 95% CI: 1.024-2.459, P=0.038) were associated with a higher prevalence of obesity among the adult men and a trend for obesity was observed for rs4285184 among the Swedish (OR: 1.205, 95% CI: 0.987-1.471, P=0.067) and Greek children (OR: 1.192, 95%CI: 0.978-1.454, P=0.081). Association with body weight was observed for rs12186500 (P=0.017) and rs4285184 (P=0.024) among the men. The rs1021001 and rs4285184 were also associated with body mass index (BMI) in the two Swedish cohorts and similar trends were observed among the Greek children. The combined effect size for rs1021001 and rs4285184 on BMI z-score from a meta-analysis was 0.233 (95% CI:0.093-0.373, P=0.001) and 0.147 (95% CI:0.057-0.236, P=0.001), respectively. We further observed associations between the genetic variants and fatty acids (P<0.039) and estimated measures of Δ desaturases (P<0.040), as well as interactions for rs12186500 (P<0.019) with an effect on BMI. No association was found with homeostatic model assessment-insulin resistance in any cohort but increased insulin levels, insulin response and decreased insulin sensitivity were observed among the children (P<0.038).

Conclusion: Genetic variants downstream MGAT1 seem to influence susceptibility to obesity. Moreover, these genetic variants affect the levels of serum unsaturated fatty acids and Δ desaturase indices, variables previously shown to correlate with obesity.

Keyword
MGAT1, body weight, BMI, insulin, fatty acids
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-146214 (URN)10.1038/ijo.2011.11 (DOI)000299306700018 ()21304485 (PubMedID)
Available from: 2011-02-15 Created: 2011-02-15 Last updated: 2012-02-24Bibliographically approved

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