Li P, Tiwari H K, Lin W-Y, Allison D B, Chung W K, Leibel R L, Yi N, Liu N
Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
Int J Obes (Lond). 2014 May;38(5):724-9. doi: 10.1038/ijo.2013.140. Epub 2013 Jul 31.
Obesity, which is frequently associated with diabetes, hypertension and cardiovascular diseases, is primarily the result of a net excess of caloric intake over energy expenditure. Human obesity is highly heritable, but the specific genes mediating susceptibility in non-syndromic obesity remain unclear. We tested candidate genes in pathways related to food intake and energy expenditure for association with body mass index (BMI).
We reanalyzed 355 common genetic variants of 30 candidate genes in seven molecular pathways related to obesity in 1982 unrelated European Americans from the New York Cancer Project. Data were analyzed by using a Bayesian hierarchical generalized linear model. The BMIs were log-transformed and then adjusted for covariates, including age, age(2), gender and diabetes status. The single-nucleotide polymorphisms (SNPs) were modeled as additive effects.
With the stipulated adjustments, nine SNPs in eight genes were significantly associated with BMI: ghrelin (GHRL; rs35683), agouti-related peptide (AGRP; rs5030980), carboxypeptidase E (CPE; rs1946816 and rs4481204), glucagon-like peptide-1 receptor (GLP1R; rs2268641), serotonin receptors (HTR2A; rs912127), neuropeptide Y receptor (NPY5R;Y5R1c52), suppressor of cytokine signaling 3 (SOCS3; rs4969170) and signal transducer and activator of transcription 3 (STAT3; rs4796793). We also found a gender-by-SNP interaction (rs1745837 in HTR2A), which indicated that variants in the gene HTR2A had a stronger association with BMI in males. In addition, NPY1R was detected as having a significant gene effect even though none of the SNPs in this gene was significant.
Variations in genes AGRP, CPE, GHRL, GLP1R, HTR2A, NPY1R, NPY5R, SOCS3 and STAT3 showed modest associations with BMI in European Americans. The pathways in which these genes participate regulate energy intake, and thus these associations are mechanistically plausible in this context.
肥胖常与糖尿病、高血压及心血管疾病相关，主要是热量摄入净超过能量消耗的结果。人类肥胖具有高度遗传性，但介导非综合征性肥胖易感性的具体基因仍不清楚。我们检测了与食物摄入和能量消耗相关途径中的候选基因与体重指数（BMI）的关联。
我们重新分析了来自纽约癌症项目的1982名无亲缘关系的欧裔美国人中7条与肥胖相关分子途径中30个候选基因的355个常见基因变异。使用贝叶斯分层广义线性模型分析数据。对BMI进行对数转换，然后针对协变量进行调整，包括年龄、年龄的平方、性别和糖尿病状态。将单核苷酸多态性（SNP）建模为加性效应。
经过规定的调整后，8个基因中的9个SNP与BMI显著相关：胃饥饿素（GHRL；rs35683）、刺鼠相关肽（AGRP；rs5030980）、羧肽酶E（CPE；rs1946816和rs4481204）、胰高血糖素样肽-1受体（GLP1R；rs2268641）、5-羟色胺受体（HTR2A；rs912127）、神经肽Y受体（NPY5R；Y5R1c52）、细胞因子信号转导抑制因子3（SOCS3；rs4969170）和信号转导及转录激活因子3（STAT3；rs4796793）。我们还发现了一个SNP与性别的相互作用（HTR2A中的rs1745837），这表明HTR2A基因中的变异在男性中与BMI的关联更强。此外，尽管该基因中的SNP均无显著性，但检测到神经肽Y1受体（NPY1R）具有显著的基因效应。
AGRP、CPE、GHRL、GLP1R、HTR2A、NPY1R、NPY5R、SOCS3和STAT3基因的变异在欧裔美国人中与BMI存在适度关联。这些基因参与的途径调节能量摄入，因此在这种情况下这些关联在机制上是合理的。
