Vimaleswaran Karani S, Franks Paul W, Brage Soren, Sardinha Luis B, Andersen Lars B, Wareham Nicholas J, Ekelund Ulf, Loos Ruth J F
MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK.
Obesity (Silver Spring). 2009 Jul;17(7):1453-7. doi: 10.1038/oby.2008.650. Epub 2009 Feb 5.
The first genome-wide association study for BMI identified a polymorphism, rs7566605, 10 kb upstream of the insulin-induced gene 2 (INSIG2) transcription start site, as the most significantly associated variant in children and adults. Subsequent studies, however, showed inconsistent association of this polymorphism with obesity traits. This polymorphism has been hypothesized to alter INSIG2 expression leading to inhibition of fatty acid and cholesterol synthesis. Hence, we investigated the association of the INSIG2 rs7566605 polymorphism with obesity- and lipid-related traits in Danish and Estonian children (930 boys and 1,073 girls) from the European Youth Heart Study (EYHS), a school-based, cross-sectional study of pre- and early pubertal children. The association between the polymorphism and obesity traits was tested using additive and recessive models adjusted for age, age-group, gender, maturity and country. Interactions were tested by including the interaction terms in the model. Despite having sufficient power (98%) to detect the previously reported effect size for association with BMI, we did not find significant effects of rs7566605 on BMI (additive, P = 0.68; recessive, P = 0.24). Accordingly, the polymorphism was not associated with overweight (P = 0.87) or obesity (P = 0.34). We also did not find association with waist circumference (WC), sum of four skinfolds, or with total cholesterol, triglycerides, low-density lipoprotein, or high-density lipoprotein. There were no gender-specific (P = 0.55), age-group-specific (P = 0.63) or country-specific (P = 0.56) effects. There was also no evidence of interaction between genotype and physical activity (P = 0.95). Despite an adequately powered study, our findings suggest that rs7566605 is not associated with obesity-related traits and lipids in the EYHS.
第一项针对体重指数（BMI）的全基因组关联研究确定，胰岛素诱导基因2（INSIG2）转录起始位点上游10 kb处的一个多态性位点rs7566605，是儿童和成人中最显著相关的变异体。然而，后续研究表明该多态性与肥胖特征之间的关联并不一致。据推测，这种多态性会改变INSIG2的表达，从而导致脂肪酸和胆固醇合成受到抑制。因此，我们在欧洲青少年心脏研究（EYHS）中，对丹麦和爱沙尼亚儿童（930名男孩和1073名女孩）中INSIG2 rs7566605多态性与肥胖及脂质相关特征之间的关联进行了调查。EYHS是一项基于学校的、针对青春期前和青春期早期儿童的横断面研究。使用针对年龄、年龄组、性别、成熟度和国家进行调整的加性模型和隐性模型，对多态性与肥胖特征之间的关联进行了检验。通过在模型中纳入交互项来检验交互作用。尽管有足够的检验效能（98%）来检测先前报道的与BMI关联的效应大小，但我们未发现rs7566605对BMI有显著影响（加性模型，P = 0.68；隐性模型，P = 0.24）。相应地，该多态性与超重（P = 0.87）或肥胖（P = 0.34）无关。我们也未发现其与腰围（WC）、四处皮褶厚度之和，或总胆固醇、甘油三酯、低密度脂蛋白或高密度脂蛋白之间存在关联。不存在性别特异性（P = 0.55）、年龄组特异性（P = 0.63）或国家特异性（P = 0.56）效应。也没有证据表明基因型与身体活动之间存在交互作用（P = 0.95）。尽管本研究检验效能充足，但我们的研究结果表明，在EYHS中rs7566605与肥胖相关特征及脂质无关。
