Contribution of 24 obesity-associated genetic variants to insulin resistance, pancreatic beta-cell function and type 2 diabetes risk in the French population
Contribution of 24 obesity-associated genetic variants to insulin resistance, pancreatic beta-cell function and type 2 diabetes risk in the French population
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DOI：
10.1038/ijo.2012.175
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发表时间：
2013-07-01
影响因子：
4.9
通讯作者：
Meyre, D.
中科院分区：
文献类型：
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作者：
Robiou-du-Pont, S.;Bonnefond, A.;Meyre, D.
背景：肥胖是 2 型糖尿病 (T2D) 的主要决定因素，可能是通过其对胰岛素抵抗的影响来实现的。全基因组关联研究报告了许多增加肥胖风险和体重指数 (BMI) 的单核苷酸多态性 (SNP)，但它们对 T2D 相关性状和风险的影响尚不清楚。 目的：我们旨在分析 24 个肥胖风险等位基因（单独或组合）对胰岛素抵抗和 β 细胞功能障碍以及 T2D 风险的影响。 设计：我们对 24 个与肥胖相关的 SNP 进行基因分型，并计算肥胖和肥胖基因型评分（每个人的肥胖风险等位基因的总和）。我们分析了每个 SNP 和该评分对四个代谢指标变化的贡献：胰岛素抵抗的稳态模型评估 (HOMA-IR)、胰腺 β 细胞功能的稳态模型评估 (HOMA-B)、胰岛素敏感性指数 (ISI) 和胰岛素生成指数 (II)（在多达 8050 名非糖尿病法国个体中）以及对 T2D 风险（在 2077 名 T2D 病例和 3085 名对照者中）。 结果：我们发现根据年龄和性别调整后，肥胖基因型评分对胰岛素抵抗增加具有高度显着影响（β = 0.02；HOMA-IR 的 P 值 = 7.16 x 10(-9)）。单独而言，我们确定了 FAIM2、FTO、GNPDA2、MC4R、NPC1、PTER 和 SH2B1 中胰岛素抵抗增加与风险等位基因之间的名义或显着关联。大多数信号，包括肥胖基因型评分和 FTO SNP，也与 β 细胞功能增强相关（分别为 beta = 0.01；P 值 = 1.05 x 10(-6) 和 beta = 0.04；P 值 = 3.45 x 10(-4)）。在我们的 T2D 病例对照研究中，只有肥胖基因型评分和众所周知的 FTO 基因座对 T2D 风险有显着贡献（OR = 1.03；P 值 = 9.99 x 10(-3) 和 OR = 1.15；P 值 = 9.46 x 10(-4)）。 BMI 的调整消除了所有显着的关联。结论：肥胖的遗传倾向会增加胰岛素抵抗，并通过增加 β 细胞功能来补偿胰岛素抵抗，并轻微增加 T2D 风险。这些关联是由 BMI 介导的。
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.