Contribution of 24 obesity-associated genetic variants to insulin resistance, pancreatic beta-cell function and type 2 diabetes risk in the French population

Robiou-du-Pont, S., Bonnefond, A., Yengo, L., Vaillant, E., Lobbens, S., Durand, E., Weill, J., Lantieri, O., Balkau, B., Charpentier, G., Marre, M., Froguel, P. and Meyre, D. (2013) Contribution of 24 obesity-associated genetic variants to insulin resistance, pancreatic beta-cell function and type 2 diabetes risk in the French population. International Journal of Obesity, 37 7: 980-985. doi:10.1038/ijo.2012.175


Author Robiou-du-Pont, S.
Bonnefond, A.
Yengo, L.
Vaillant, E.
Lobbens, S.
Durand, E.
Weill, J.
Lantieri, O.
Balkau, B.
Charpentier, G.
Marre, M.
Froguel, P.
Meyre, D.
Title Contribution of 24 obesity-associated genetic variants to insulin resistance, pancreatic beta-cell function and type 2 diabetes risk in the French population
Journal name International Journal of Obesity   Check publisher's open access policy
ISSN 0307-0565
1476-5497
Publication date 2013-01-01
Year available 2012
Sub-type Article (original research)
DOI 10.1038/ijo.2012.175
Open Access Status Not yet assessed
Volume 37
Issue 7
Start page 980
End page 985
Total pages 6
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Abstract Context: Obesity is the major determinant of type 2 diabetes (T2D), presumably through its effect on insulin resistance. Genome-wide association studies reported many single-nucleotide polymorphisms (SNPs) that increase obesity risk and body mass index (BMI), but their impact on T2D-related traits and risk is unclear. Objective: We aimed at analyzing the effect of 24 obesity risk alleles, separately and in combination, on variation of both insulin resistance and β-cell dysfunction, and on T2D risk. Design: We genotyped 24 obesity-associated SNPs and calculated an obesity genotype score (sum of the obesity risk alleles per individual). We analyzed the contribution of each SNP and this score to the variation of four metabolic indices: homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of the pancreatic β-cell function (HOMA-B), insulin sensitivity index (ISI) and insulinogenic index (II) (in up to 8050 nondiabetic French individuals) and to T2D risk (in 2077 T2D cases and 3085 controls). Results: We found a highly significant effect of the obesity genotype score on increased insulin resistance adjusted for age and gender (β=0.02; P-value=7.16 × 10−9 for HOMA-IR). Individually, we identified nominal or significant association between increased insulin resistance and risk alleles in FAIM2, FTO, GNPDA2, MC4R, NPC1, PTER and SH2B1. Most signals, including the obesity genotype score and FTO SNP, were also associated with increased β-cell function (β=0.01; P-value=1.05 × 10−6 and β=0.04; P-value=3.45 × 10−4, respectively). In our T2D case–control study, only the obesity genotype score and the well-known FTO locus significantly contributed to T2D risk (OR=1.03; P-value=9.99 × 10−3 and OR=1.15; P-value=9.46 × 10−4, respectively). Adjustment for BMI abolished all significant associations. Conclusions: Genetic predisposition to obesity contributes to increased insulin resistance and to its compensation through increased β-cell function, and weakly increases the T2D risk. These associations are mediated by BMI.
Keyword Insulin resistance
Pancreatic function
SNP
Type 2 diabetes
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 27 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 28 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Sat, 04 Mar 2017, 01:00:43 EST by Web Cron on behalf of Learning and Research Services (UQ Library)