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The role of genetics in regulation of weight loss and food intake
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.ORCID iD: 0000-0002-7071-9067
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

While obesity is a world leading health problem, the most efficient treatment option for severely obese patients is Roux-Y gastric bypass (RYGB) surgery. However, there are large inter-individual differences in weight loss after RYGB surgery. The reasons for this are not yet elucidated and the role of genetics in weight loss-regulation is still not fully understood. The main aim for this thesis was to investigate the effects of common obesity-associated genetic variants and their effect on weight loss and food intake.

We examined if the weight loss two years following RYGB surgery depends on the  FTO genotype, as well as pre-surgery vitamin D status. For FTO AA-carriers, the surgery resulted in a 3% per-allele increased excess BMI loss (EBMIL; P=0.02). When split by vitamin D baseline status, the EBMIL of vitamin D deficient patients carrying AA exceeded that of vitamin D deficient patients carrying TT by 14% (P=0.03). No such genotypic differences were found in patients without pre-surgery vitamin D deficiency.

As the influence of individual single nucleotide polymorphisms may be small, we identified a novel method to combine SNPs into a genetic risk score (GRS). Using the random forest model, SNPs with high impact on weight loss after RYGB surgery were filtered out. An up to 11% lower EBMIL with higher risk score was estimated for the GRS model (p=0.026) composed of seven BMI-associated SNPs (closest genes: MC4R, TMEM160, PTBP2, NUDT3, TFAP2B, ZNF608 and MAP2K5).

Pre-surgical hunger feelings were found to be associated with EBMIL and the SNP rs4846567. Before surgery, patients filled out the Three Factor Eating Questionnaire and were genotyped for known BMI and waist-hip ratio (WHR) associated SNPs. Patients with the lowest hunger scores had up to 32% greater EBMIL compared to the highest scoring patients (P=0.002). TT-allele carriers of rs4846567 showed a 58% lower hunger feelings. TT- carriers also showed a 51% decrease in disinhibition, but no significant impact on cognitive restraint was observed.

Due to the association of eating behaviour and weight loss, acute effects on DNA methylation in response to a food intake intervention of a standardized meal were also investigated.

After food intake, 1832 CpG sites were differentially methylated compared to the baseline after multiple testing correction. When adjusted for white blood cell fractions, 541 CpG sites remained. This may be interpreted as that the immune system is playing an active role in the response to food intake and highlights the dynamic nature of DNA-methylation.

These findings will contribute to a better care for morbidly obese patients. Post-surgical treatment may be optimized so that patients with a less favourable genetic profile may receive additional support for weight loss and weight management. This may be considered as a step in the transition towards personalized medicine.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 43 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1236
Keyword [en]
FTO, RYGB, LYPLAL1, TFEQ, Genetic Risk Score, methylation, food intake
National Category
Medical Genetics
Research subject
Bioinformatics; Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-297729ISBN: 978-91-554-9617-3OAI: oai:DiVA.org:uu-297729DiVA: diva2:943343
Public defence
2016-09-09, A1:107 BMC, Husargatan 3, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2016-08-19 Created: 2016-06-27 Last updated: 2016-08-26
List of papers
1. The Role of FTO and Vitamin D for the Weight Loss Effect of Roux-en-Y Gastric Bypass Surgery in Obese Patients
Open this publication in new window or tab >>The Role of FTO and Vitamin D for the Weight Loss Effect of Roux-en-Y Gastric Bypass Surgery in Obese Patients
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2015 (English)In: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 25, no 11, 2071-2077 p.Article in journal (Refereed) Published
Abstract [en]

A recent study in children demonstrated that the rs9939609 single-nucleotide polymorphism in the fat mass and obesity (FTO) gene influences prospective weight gain, however, only in those who were vitamin D-deficient. If this might also be the case for Roux-en-Y gastric bypass (RYGB), surgery-induced weight loss is however unknown. The objective of this study is to examine if the magnitude of RYGB surgery-induced weight loss after 2 years depends on patients' FTO rs9939609 genotype (i.e., TT, AT, and AA) and presurgery vitamin D status (< 50 nmol/L equals deficiency). Before and at 24 months after RYGB surgery, BMI was measured in 210 obese patients (mean BMI 45 kg/m(2), 72 % females). Serum 25-hydroxyvitamin D3 levels were also repeatedly measured. Following surgery, vitamin D was supplemented. Possible weight loss differences between genotypes were tested with multiple linear regressions. The per-allele effect of each FTO A-allele on excessive BMI loss (EBMIL) was 3 % (P = 0.02). When split by baseline status, the EBMIL of vitamin D-deficient patients carrying AA exceeded that of vitamin D-deficient patients carrying TT by similar to 14 % (P = 0.03). No such genotypic differences were found in patients without presurgery vitamin D deficiency. Post-surgery serum levels of vitamin D did not differ between groups. Our data suggest that presurgery vitamin D levels influence the size of genotype effects of FTO rs9939609 on RYGB surgery-induced weight loss in obese patients.

Keyword
Vitamin D, FTO, RYGB, Weight loss, Bariatric surgery
National Category
Surgery Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-266692 (URN)10.1007/s11695-015-1644-4 (DOI)000362578700049 ()25724814 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain FoundationNovo Nordisk
Available from: 2015-11-12 Created: 2015-11-10 Last updated: 2016-08-26Bibliographically approved
2. A genetic risk score is associated with weight loss following Roux-Y gastric bypass surgery
Open this publication in new window or tab >>A genetic risk score is associated with weight loss following Roux-Y gastric bypass surgery
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2016 (English)In: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 26, no 9, 2183-2189 p.Article in journal (Refereed) Published
Abstract [en]

Currently, Roux-en Y gastric bypass (RYGB) is the most efficient therapy for severe obesity. Weight loss after surgery is, however, highly variable and genetically influenced. Genome-wide association studies have identified several single nucleotide polymorphisms (SNP) associated with body mass index (BMI) and waist-hip ratio (WHR). We aimed to identify two genetic risk scores (GRS) composed of weighted BMI and WHR-associated SNPs to estimate their impact on excess BMI loss (EBMIL) after RYGB surgery. Two hundred and thirty-eight obese patients (BMI 45.1 +/- 6.2 kg/m(2), 74 % women), who underwent RYGB, were genotyped for 35 BMI and WHR-associated SNPs and were followed up after 2 years. SNPs with high impact on post-surgical weight loss were filtered out using a random forest model. The filtered SNPs were combined into a GRS and analyzed in a linear regression model. An up to 11 % lower EBMIL with higher risk score was estimated for two GRS models (P = 0.026 resp. P = 0.021) composed of seven BMI-associated SNPs (closest genes: MC4R, TMEM160, PTBP2, NUDT3, TFAP2B, ZNF608, MAP2K5, GNPDA2, and MTCH2) and of three WHR-associated SNPs (closest genes: HOXC13, LYPLAL1, and DNM3-PIGC). Patients within the lowest GRS quartile had higher EBMIL compared to patients within the other three quartiles in both models. We identified two GRSs composed of BMI and WHR-associated SNPs with significant impact on weight loss after RYGB surgery using random forest analysis as a SNP selection tool. The GRS may be useful to pre-surgically evaluate the risks for patients undergoing RYGB surgery.

Keyword
Genetic risk score; Roux-en Y gastric bypass surgery; Obesity; Random forest model; Post-operative weight loss
National Category
Medical Genetics
Research subject
Bioinformatics; Epidemiology
Identifiers
urn:nbn:se:uu:diva-295627 (URN)10.1007/s11695-016-2072-9 (DOI)000381759900028 ()26832135 (PubMedID)
External cooperation:
Funder
Swedish Research CouncilNovo NordiskThe Swedish Brain Foundation
Available from: 2016-06-08 Created: 2016-06-08 Last updated: 2016-09-15Bibliographically approved
3. A genetic variant in proximity to the gene LYPLAL1 is associated with lower hunger feelings and increased weight loss following Roux-en Y gastric bypass surgery
Open this publication in new window or tab >>A genetic variant in proximity to the gene LYPLAL1 is associated with lower hunger feelings and increased weight loss following Roux-en Y gastric bypass surgery
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2016 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708Article in journal (Refereed) Published
National Category
Public Health, Global Health, Social Medicine and Epidemiology Medical Genetics
Identifiers
urn:nbn:se:uu:diva-295634 (URN)10.3109/00365521.2016.1166519 (DOI)
Available from: 2016-06-08 Created: 2016-06-08 Last updated: 2016-08-26
4. Major difference in DNA methylation in blood between fasted and postprandial state; before and 160 min after meal
Open this publication in new window or tab >>Major difference in DNA methylation in blood between fasted and postprandial state; before and 160 min after meal
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2016 (English)In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207Article in journal (Refereed) Accepted
National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:uu:diva-295636 (URN)
Available from: 2016-06-08 Created: 2016-06-08 Last updated: 2016-08-26

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