Centre for Nutrition and Health, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
Int J Obes (Lond). 2010 May;34(5):840-5. doi: 10.1038/ijo.2009.302. Epub 2010 Feb 2.
Much of the genetic variation in glucose levels remains to be discovered. Especially, research on gene-environment interactions is scarce. Overweight is one of the main risk factors for hyperglycemia. As transcriptional regulation is important for both weight maintenance and glucose control, we analyzed 353 single nucleotide polymorphisms (SNPs), occurring in transcriptional pathways of glucose and lipid metabolism in interaction with body mass index (BMI) on glucose levels.
SNPs were measured in 3244 participants of the Doetichem cohort. Non-fasting glucose levels and BMI were measured twice in 6 years. SNP x BMI interactions were analyzed by mixed models and adjusted for age, sex, time since last meal, and follow-up time. False discovery rate (FDR) <0.2 was used to adjust for multiple testing.
Two SNPs in the PPARGC1A gene (rs8192678, FDR=0.07; rs3755863, FDR=0.17) showed a significant interaction with BMI. The rare allele of both SNPs was associated with significantly lower glucose levels in subjects with a BMI<or=25 kg m(-2) (rs8192678, P=0.02; rs3755863, P=0.03). An inverse association was suggested in subjects with a BMI>28 kg m(-2). A small intervention study (n=120) showed similar, though non-significant, results.
Using a pathway-based approach, we found that BMI significantly modified the association between two SNPs in the PPARGC1A gene and glucose levels. The association between glucose and PPARGC1A was only present in lean subjects. This suggests that the effect of the PPARGC1A gene, which is involved both in fatty acid oxidation and glucose metabolism, is modified by BMI.
大部分血糖水平的遗传变异仍有待发现。特别是，基因-环境相互作用的研究还很缺乏。超重是高血糖的主要危险因素之一。由于转录调控对体重维持和血糖控制都很重要，我们分析了葡萄糖和脂质代谢转录途径中与体重指数（BMI）相互作用的 353 个单核苷酸多态性（SNP）对血糖水平的影响。
在 Doetichem 队列的 3244 名参与者中测量了 SNP。6 年内两次测量非禁食血糖水平和 BMI。通过混合模型分析 SNP x BMI 相互作用，并调整年龄、性别、上次进餐时间和随访时间。采用错误发现率（FDR）<0.2 进行多重检验调整。
PPARGC1A 基因中的两个 SNP（rs8192678，FDR=0.07；rs3755863，FDR=0.17）与 BMI 存在显著相互作用。两个 SNP 的罕见等位基因与 BMI<或=25 kg m(-2)的受试者血糖水平显著降低相关（rs8192678，P=0.02；rs3755863，P=0.03）。在 BMI>28 kg m(-2)的受试者中，存在相反的关联。一项小型干预研究（n=120）显示了类似的、尽管非显著的结果。
使用基于途径的方法，我们发现 BMI 显著改变了 PPARGC1A 基因中的两个 SNP 与血糖水平之间的关联。血糖与 PPARGC1A 之间的关联仅存在于瘦受试者中。这表明，参与脂肪酸氧化和葡萄糖代谢的 PPARGC1A 基因的作用受到 BMI 的修饰。
