MRC Epidemiology Unit, Institute of Metabolic Science, Box 285, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
Diabetologia. 2011 Apr;54(4):776-82. doi: 10.1007/s00125-011-2044-5. Epub 2011 Jan 26.
AIMS/HYPOTHESIS: Obesity is a major risk factor for type 2 diabetes. Recent genome-wide association (GWA) studies have identified multiple loci robustly associated with BMI and risk of obesity. However, information on their associations with type 2 diabetes is limited. Such information could help increase our understanding of the link between obesity and type 2 diabetes. We examined the associations of 12 obesity susceptibility loci, individually and in combination, with risk of type 2 diabetes in the population-based European Prospective Investigation of Cancer (EPIC) Norfolk cohort.
We genotyped 12 SNPs, identified by GWA studies of BMI, in 20,428 individuals (aged 39-79 years at baseline) with an average follow-up of 12.9 years, during which 729 individuals developed type 2 diabetes. A genetic predisposition score was calculated by adding the BMI-increasing alleles across the 12 SNPs. Associations with incidence of type 2 diabetes were examined by logistic regression models.
Of the 12 SNPs, eight showed a trend with increased risk of type 2 diabetes, consistent with their BMI-increasing effects. Each additional BMI-increasing allele in the genetic predisposition score was associated with a 4% increased odds of developing type 2 diabetes (OR 1.041, 95% CI 1.005-1.078; p = 0.02). Adjustment for BMI completely abolished the association with incident type 2 diabetes (OR 1.003, 95% CI 0.967-1.039; p = 0.89).
CONCLUSIONS/INTERPRETATION: The genetic predisposition to obesity leads to increased risk of developing type 2 diabetes, which is completely mediated by its obesity-predisposing effect.
目的/假设：肥胖是 2 型糖尿病的主要危险因素。最近的全基因组关联（GWA）研究已经确定了多个与 BMI 和肥胖风险密切相关的基因位点。然而，关于它们与 2 型糖尿病的关联信息有限。这些信息可以帮助我们更好地理解肥胖与 2 型糖尿病之间的联系。我们在基于人群的欧洲癌症前瞻性调查（EPIC）诺福克队列中，检查了 12 个肥胖易感性基因座单独和联合与 2 型糖尿病风险的关联。
我们对 20428 名年龄在 39-79 岁基线时有平均 12.9 年随访的个体进行了 12 个 SNP 的基因分型，这些 SNP 是通过 BMI 的 GWA 研究确定的，其中有 729 人发生了 2 型糖尿病。通过在 12 个 SNP 中添加 BMI 增加的等位基因来计算遗传易感性评分。通过逻辑回归模型检查与 2 型糖尿病发病风险的关联。
在这 12 个 SNP 中，有 8 个显示出与 2 型糖尿病风险增加的趋势，与它们增加 BMI 的作用一致。遗传易感性评分中每增加一个 BMI 增加的等位基因，患 2 型糖尿病的几率就会增加 4%（OR 1.041，95%CI 1.005-1.078；p = 0.02）。调整 BMI 后，与 2 型糖尿病发病的关联完全消失（OR 1.003，95%CI 0.967-1.039；p = 0.89）。
结论/解释：肥胖的遗传倾向导致患 2 型糖尿病的风险增加，而这种风险完全是由其肥胖倾向的作用介导的。
