CNRS UMR-8199, Lille Pasteur Institute, Lille, France.
Int J Obes (Lond). 2013 Jul;37(7):980-5. doi: 10.1038/ijo.2012.175. Epub 2012 Oct 23.
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.
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.
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).
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.
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.
肥胖是 2 型糖尿病（T2D）的主要决定因素，可能通过其对胰岛素抵抗的影响。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 相关特征和风险的影响尚不清楚。
我们旨在分析 24 个肥胖风险等位基因单独和组合对胰岛素抵抗和β细胞功能障碍以及 T2D 风险的变化的影响。
我们对 24 个与肥胖相关的 SNP 进行了基因分型，并计算了个体的肥胖基因型评分（每个个体的肥胖风险等位基因之和）。我们分析了每个 SNP 和该评分对四个代谢指标的变化的贡献：稳态模型评估的胰岛素抵抗（HOMA-IR）、稳态模型评估的胰岛β细胞功能（HOMA-B）、胰岛素敏感性指数（ISI）和胰岛素原指数（II）（在多达 8050 名非糖尿病的法国个体中）以及 T2D 风险（在 2077 例 T2D 病例和 3085 例对照中）。
我们发现肥胖基因型评分对调整年龄和性别后的胰岛素抵抗有显著影响（β=0.02；P 值=7.16×10(-9) 用于 HOMA-IR）。单独来看，我们发现 FAIM2、FTO、GNPDA2、MC4R、NPC1、PTER 和 SH2B1 中的风险等位基因与增加的胰岛素抵抗之间存在名义或显著关联。大多数信号，包括肥胖基因型评分和 FTO 单核苷酸多态性，也与增加的β细胞功能相关（β=0.01；P 值=1.05×10(-6) 和 β=0.04；P 值=3.45×10(-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 基因座显著增加了 T2D 的风险（OR=1.03；P 值=9.99×10(-3) 和 OR=1.15；P 值=9.46×10(-4)）。调整 BMI 后，所有显著关联均消失。
肥胖的遗传易感性导致胰岛素抵抗增加，并通过增加β细胞功能进行补偿，并且轻微增加了 T2D 的风险。这些关联受 BMI 介导。
