Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden.
PLoS Genet. 2013;9(7):e1003607. doi: 10.1371/journal.pgen.1003607. Epub 2013 Jul 25.
Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, Pinteraction = 0.014 vs. n = 71,611, Pinteraction = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction = 0.003) and the SEC16B rs10913469 (Pinteraction = 0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.
大量肥胖相关基因座已通过全基因组关联研究确定。英国的一项研究表明，身体活动可能会减弱这 12 个基因座中 12 个基因座的累积效应，但缺乏复制研究。因此，我们测试了在报告高水平身体活动的欧洲血统成年人中，这些基因座的综合效应是否会减弱。在 111421 名参与者中对 12 个肥胖易感性基因座进行了基因分型或推断。通过将每个遗传变异与 BMI 相关的等位基因相加来计算遗传风险评分（GRS）。使用自我管理问卷评估身体活动。在线性和逻辑回归模型中，在每个队列中测试了 GRS 和身体活动对 BMI 的乘法交互作用，调整了年龄、年龄(2)、性别、研究中心（对于多中心研究）以及身体活动和 GRS 的边缘项。使用按队列样本量加权的荟萃分析对这些结果进行了组合。荟萃分析得出 GRS×身体活动相互作用效应估计值具有统计学意义（Pinteraction=0.015）。然而，仅在北美队列中观察到具有统计学意义的相互作用效应（n=39810，Pinteraction=0.014 vs. n=71611，Pinteraction=0.275 用于欧洲人）。在二次分析中，FTO rs1121980（Pinteraction=0.003）和 SEC16B rs10913469（Pinteraction=0.025）变异均显示出 SNP×身体活动相互作用的证据。这项对 111421 人的荟萃分析进一步支持了身体活动与肥胖易感性 GRS 之间的相互作用，尽管这些发现取决于北美队列的纳入，表明这些结果是特定于人群的或非因果关系的。
