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

CONTEXT: Obesity is the major determinant of type 2 diabetes (T2D), presumably through its effect on insulin resistance. Genomewide 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 beta-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 beta-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 ( beta = 0.02; P-value = 7.16 x 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 beta-cell function (beta = 0.01; P-value = 1.05 x 10(-6) and beta = 0.04; P-value = 3.45 x 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 x 10(-3) and OR = 1.15; P-value = 9.46 x 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 beta-cell function, and weakly increases the T2D risk. These associations are mediated by BMI.