Objective: To investigate possible effect of 6 obesity-associated SNPs in contribution to central obesity and examine whether there is an interaction in the 6 SNPs in the cause of central obesity in school-aged children in China. Methods: A total of 3 502 school-aged children who were included in Beijing Child and Adolescent Metabolic Syndrome (BCAMS) Study were selected, and based on the age and sex specific waist circumference (WC) standards in the BCAMS study, 1 196 central obese cases and 2 306 controls were identified. Genomic DNA was extracted from peripheral blood white cells using the salt fractionation method. A total of 6 single nucleotide polymorphisms (FTO rs9939609, MC4R rs17782313, BDNF rs6265, PCSK1 rs6235, SH2B1 rs4788102, and CSK rs1378942) were genotyped by TaqMan allelic discrimination assays with the GeneAmp 7900 sequence detection system (Applied Biosystems, Foster City, CA, USA). Logistic regression model was used to investigate the association between 6 SNPs and central obesity. Gene-gene interactions among 6 polymorphic loci were analyzed by using the Generalized Multifactor Dimensionality Reduction (GMDR) method, and then logistic regression model was constructed to confirm the best combination of loci identified in the GMDR. Results: After adjusting gender, age, Tanner stage, physical activity and family history of obesity, the FTO rs9939609-A, MC4R rs17782313-C and BDNF rs6265-G alleles were associated with central obesity under additive genetic model (OR=1.24, 95%CI: 1.06-1.45, P=0.008; OR=1.26, 95%CI: 1.11-1.43, P=2.98×10(-4); OR=1.18, 95% CI: 1.06-1.32, P=0.003). GMDR analysis showed a significant gene-gene interaction between MC4R rs17782313 and BDNF rs6265 (P=0.001). The best two-locus combination showed the cross-validation consistency of 10/10 and testing accuracy of 0.539. This interaction showed the maximum consistency and minimum prediction error among all gene-gene interaction models evaluated. Moreover, the combination of MC4R rs17782313-C and BDNF rs6265-G was associated with an increased risk of central obesity after adjustment for gender, age, Tanner stage, physical activity and family history of obesity. Conclusions: Our study showed that FTO rs9939609-A, MC4R rs17782313-C and BDNF rs6265-G alleles were associated with central obesity, and statistical interaction between MC4R rs17782313-C and BDNF rs6265-G increased risk of central obesity in school-aged children in China.
目的： 探讨我国学龄儿童6个肥胖相关基因多态性位点（SNPs）及其交互作用与腹型肥胖的关联。 方法： 以"北京市儿童青少年代谢综合征（BCAMS）研究"中1 196名肥胖儿童和2 306名非肥胖儿童为研究对象。采用盐析法从外周血白细胞中提取DNA。使用ABI Prisms(TM)-7900实时荧光定量PCR仪对6个SNPs（FTO rs9939609、MC4R rs17782313、BDNF rs6265、PCSK1 rs6235、SH2B1 rs4788102和CSK rs1378942）进行分型检测。采用BCAMS基线总人群腰围的性别年龄别第90百分位值判定腹型肥胖。运用logistic回归模型分析6个SNPs与腹型肥胖的关联。采用广义多因子降维法（GMDR）模型检测6个SNPs之间的基因-基因交互作用，并使用多因素logistic回归模型验证。 结果： 在加性遗传模型下，调整性别、年龄、Tanner分期、体力活动和肥胖家族史后，FTO rs9939609-A、MC4R rs17782313-C和BDNF rs6265-G等位基因增加儿童腹型肥胖罹患风险（OR=1.24，95%CI：1.06~1.45，P=0.008；OR=1.26，95%CI：1.11~1.43，P=2.98×10(-4)；OR=1.18，95%CI：1.06~1.32，P=0.003）。GMDR模型分析显示，在调整同样的影响因素后，MC4R rs17782313和BDNF rs6265之间交互作用的差异有统计学意义（P=0.001），交叉验证一致性为10/10，平均检验准确度为0.539，为最优模型；logistic回归分析显示，MC4R rs17782313-C和BDNF rs6265-G可能存在正交互作用。 结论：FTO rs9939609-A、MC4R rs17782313-C和BDNF rs6265-G增加儿童腹型肥胖罹患风险；MC4R rs17782313与BDNF rs6265可能存在交互作用，对学龄儿童腹型肥胖的罹患风险存在影响。.
Keywords: Childhood; Gene-gene; Generalized multifactor dimensionality reduction; Interaction; Obesity.