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Genome-wide association of single-nucleotide polymorphisms with weight loss outcomes after Roux-en-Y gastric bypass surgery.

ABSTRACT: Roux-en-Y gastric bypass (RYGB) is among the most effective treatments for extreme obesity and obesity-related complications. However, despite its potential efficacy, many patients do not achieve and/or maintain sufficient weight loss.Our objective was to identify genetic factors underlying the variability in weight loss outcomes after RYGB surgery.We conducted a genome-wide association study using a 2-stage phenotypic extreme study design.Patients were recruited from a comprehensive weight loss program at an integrated health system.Eighty-six obese (body mass index >35 kg/m(2)) patients who had the least percent excess body weight loss (%EBWL) and 89 patients who had the most %EBWL at 2 years after surgery were genotyped using Affymetrix version 6.0 single-nucleotide polymorphism (SNP) arrays. A second group from the same cohort consisting of 164 patients in the lower quartile of %EBWL and 169 from the upper quartile were selected for evaluation of candidate regions using custom SNP arrays.We performed RYGB surgery.We assessed %EBWL at 2 years after RYGB and SNPs.We identified 111 SNPs in the first-stage analysis whose frequencies were significantly different between 2 phenotypic extremes of weight loss (allelic ?(2) test P < .0001). Linear regression of %EBWL at 2 years after surgery revealed 17 SNPs that approach P < .05 in the validation stage and cluster in or near several genes with potential biological relevance including PKHD1, HTR1A, NMBR, and IGF1R.This is the first genome-wide association study of weight loss response to RYGB. Variation in weight loss outcomes after RYGB may be influenced by several common genetic variants.

SUBMITTER: Rinella ES

PROVIDER: S-EPMC3667258 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Genome-wide association of single-nucleotide polymorphisms with weight loss outcomes after Roux-en-Y gastric bypass surgery.

Rinella Erica S ES Still Christopher C Shao Yongzhao Y Wood G Craig GC Chu Xin X Salerno Brenda B Gerhard Glenn S GS Ostrer Harry H

The Journal of clinical endocrinology and metabolism 20130430 6

<h4>Context</h4>Roux-en-Y gastric bypass (RYGB) is among the most effective treatments for extreme obesity and obesity-related complications. However, despite its potential efficacy, many patients do not achieve and/or maintain sufficient weight loss.<h4>Objective</h4>Our objective was to identify genetic factors underlying the variability in weight loss outcomes after RYGB surgery.<h4>Design</h4>We conducted a genome-wide association study using a 2-stage phenotypic extreme study design.<h4>Set ...[more]

PMID: 23633212

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Project description:BackgroundThe mechanisms of weight loss and metabolic improvements following bariatric surgery in skeletal muscle are not well known; however, epigenetic modifications are likely to contribute. The aim of our study was to investigate skeletal muscle DNA methylation after weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery. Muscle biopsies were obtained basally from seven insulin-resistant obese (BMI > 40 kg/m2) female subjects (45.1 ± 3.6 years) pre- and 3-month post-surgery with euglycemic hyperinsulinemic clamps to assess insulin sensitivity. Four lean (BMI < 25 kg/m2) females (38.5 ± 5.8 years) served as controls. We performed reduced representation bisulfite sequencing next generation methylation on DNA isolated from the vastus lateralis muscle biopsies.ResultsGlobal methylation was significantly higher in the pre- (32.97 ± 0.02%) and post-surgery (33.31 ± 0.02%) compared to the lean (30.46 ± 0.02%), P < 0.05. MethylSig analysis identified 117 differentially methylated cytosines (DMCs) that were significantly altered in the post- versus pre-surgery (Benjamini-Hochberg q < 0.05). In addition, 2978 DMCs were significantly altered in the pre-surgery obese versus the lean controls (Benjamini-Hochberg q < 0.05). For the post-surgery obese versus the lean controls, 2885 DMCs were altered (Benjamini-Hochberg q < 0.05). Seven post-surgery obese DMCs were normalized to levels similar to those observed in lean controls. Of these, 5 were within intergenic regions (chr11.68,968,018, chr16.73,100,688, chr5.174,115,531, chr5.1,831,958 and chr9.98,547,011) and the remaining two DMCs chr17.45,330,989 and chr14.105,353,824 were within in the integrin beta 3 (ITGB3) promoter and KIAA0284 exon, respectively. ITGB3 methylation was significantly decreased in the post-surgery (0.5 ± 0.5%) and lean controls (0 ± 0%) versus pre-surgery (13.6 ± 2.7%, P < 0.05). This decreased methylation post-surgery was associated with an increase in ITGB3 gene expression (fold change + 1.52, P = 0.0087). In addition, we showed that ITGB3 promoter methylation in vitro significantly suppressed transcriptional activity (P < 0.05). Transcription factor binding analysis for ITGB3 chr17.45,330,989 identified three putative transcription factor binding motifs; PAX-5, p53 and AP-2alphaA.ConclusionsThese results demonstrate that weight loss after RYGB alters the epigenome through DNA methylation. In particular, this study highlights ITGB3 as a novel gene that may contribute to the metabolic improvements observed post-surgery. Future additional studies are warranted to address the exact mechanism of ITGB3 in skeletal muscle.

Dataset Information

Genome-wide association of single-nucleotide polymorphisms with weight loss outcomes after Roux-en-Y gastric bypass surgery.

Publications

Genome-wide association of single-nucleotide polymorphisms with weight loss outcomes after Roux-en-Y gastric bypass surgery.

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