Obesity-Related Genomic Loci Are Associated with Type 2 Diabetes in a Han Chinese Population

Background and AimsObesity is a well-known risk factor for type 2 diabetes. Genome-wide association studies have identified a number of genetic loci associated with obesity. The aim of this study is to examine the contribution of obesity-related genomic loci to type 2 diabetes in a Chinese population.MethodsWe successfully genotyped 18 obesity-related single nucleotide polymorphisms among 5338 type 2 diabetic patients and 4663 controls. Both individual and joint effects of these single nucleotide polymorphisms on type 2 diabetes and quantitative glycemic traits (assessing β-cell function and insulin resistance) were analyzed using logistic and linear regression models, respectively.ResultsTwo single nucleotide polymorphisms near MC4R and GNPDA2 genes were significantly associated with type 2 diabetes before adjusting for body mass index and waist circumference (OR (95% CI) = 1.14 (1.06, 1.22) for the A allele of rs12970134, P = 4.75×10−4; OR (95% CI) = 1.10 (1.03, 1.17) for the G allele of rs10938397, P = 4.54×10−3). When body mass index and waist circumference were further adjusted, the association of MC4R with type 2 diabetes remained significant (P = 1.81×10−2) and that of GNPDA2 was attenuated (P = 1.26×10−1), suggesting the effect of the locus including GNPDA2 on type 2 diabetes may be mediated through obesity. Single nucleotide polymorphism rs2260000 within BAT2 was significantly associated with type 2 diabetes after adjusting for body mass index and waist circumference (P = 1.04×10−2). In addition, four single nucleotide polymorphisms (near or within SEC16B, BDNF, MAF and PRL genes) showed significant associations with quantitative glycemic traits in controls even after adjusting for body mass index and waist circumference (all P valuesConclusionsThis study indicates that obesity-related genomic loci were associated with type 2 diabetes and glycemic traits in the Han Chinese population.研究背景与目的 肥胖是公认的2型糖尿病危险因素。全基因组关联研究（Genome-wide association study）已筛选出多个与肥胖相关的遗传基因座。本研究旨在探究中国人群中肥胖相关遗传基因座对2型糖尿病的贡献度。 研究方法 本研究成功对5338名2型糖尿病患者与4663名对照个体的18个肥胖相关单核苷酸多态性（single nucleotide polymorphism, SNP）进行了基因分型。分别采用logistic回归与线性回归模型，分析这些SNP对2型糖尿病以及量化血糖表型（用于评估β细胞功能与胰岛素抵抗）的单独效应与联合效应。 研究结果 在未校正体质量指数（body mass index, BMI）与腰围的分析中，MC4R与GNPDA2基因附近的2个SNP与2型糖尿病显著相关：rs12970134的A等位基因比值比（odds ratio, OR）与95%置信区间（confidence interval, CI）为1.14（1.06, 1.22），P=4.75×10⁻⁴；rs10938397的G等位基因OR与95%CI为1.10（1.03, 1.17），P=4.54×10⁻³。进一步校正BMI与腰围后，MC4R与2型糖尿病的关联仍具有统计学意义（P=1.81×10⁻²），而GNPDA2相关关联则有所减弱（P=1.26×10⁻¹），提示包含GNPDA2的基因座对2型糖尿病的效应可能通过肥胖介导。校正BMI与腰围后，BAT2基因内的SNP rs2260000与2型糖尿病显著相关（P=1.04×10⁻²）。此外，即便校正BMI与腰围后，SEC16B、BDNF、MAF与PRL基因附近或内部的4个SNP仍与对照人群的量化血糖表型存在显著关联（所有P值 研究结论 本研究表明，在中国汉族人群中，肥胖相关遗传基因座与2型糖尿病及血糖表型存在关联。