Friedlander Yechiel, Li Guo, Fornage Myriam, Williams O Dale, Lewis Cora E, Schreiner Pamela, Pletcher Mark J, Enquobahrie Daniel, Williams Michelle, Siscovick David S
Unit of Epidemiology, Hebrew University-Hadassah School of Public Health, Jerusalem, Israel.
Ann Hum Genet. 2010 Sep 1;74(5):387-98. doi: 10.1111/j.1469-1809.2010.00596.x. Epub 2010 Jul 14.
Appetite regulatory neural network and adipocyte homeostasis molecular pathways are critical to long-term weight maintenance. Associations between obesity-related phenotypes and four genes in these pathways - leptin (LEP), leptin receptor (LEPR), neuropeptide Y2 receptor (NPY2R) and peptide YY (PYY) were examined in CARDIA Study participants (aged 18-30 at recruitment in 1985-6). Weight, BMI and waist circumference were measured at baseline and at years 2, 5, 7, 10, 15, and 20. Genotyping was conducted using tag SNPs characterising common genetic variations in these genes. Generalized estimating equation (GEE) models estimated associations between SNPs and repeated anthropometric measurements, controlling for sex and age. False discovery rate was used to adjust for multiple testing. In African-Americans, SNPs across the LEP gene demonstrated significant overall associations with all obesity-related phenotypes. The associations between LEP rs17151919 with weight tended to strengthen with time - the difference in weight associated with each additional minor allele increased from 2.6 kg at baseline to 4.8 kg at year 20 (SNP*time interaction p = 0.0193). NPY2R gene SNPs were associated with waist circumference among African-American men (p = 0.0462). In Caucasians, LEP SNPs also tended to be associated with weight (p = 0.0471), and PYY rs11684664 was associated with obesity-related phenotypes in women only (p = 0.010-0.026). Several LEP, and NPY2R and PYY SNPs were associated with obesity-related phenotypes in young adults, particularly among African-Americans.
食欲调节神经网络和脂肪细胞内稳态分子途径对长期体重维持至关重要。在CARDIA研究参与者(1985 - 1986年招募时年龄为18 - 30岁)中,研究了肥胖相关表型与这些途径中的四个基因——瘦素(LEP)、瘦素受体(LEPR)、神经肽Y2受体(NPY2R)和肽YY(PYY)之间的关联。在基线以及第2、5、7、10、15和20年测量体重、体重指数(BMI)和腰围。使用表征这些基因常见遗传变异的标签单核苷酸多态性(tag SNPs)进行基因分型。广义估计方程(GEE)模型估计了单核苷酸多态性与重复人体测量指标之间的关联,并对性别和年龄进行了控制。采用错误发现率对多重检验进行校正。在非裔美国人中,LEP基因上的单核苷酸多态性显示出与所有肥胖相关表型存在显著的总体关联。LEP rs17151919与体重之间的关联随时间推移有增强趋势——每增加一个次要等位基因所关联的体重差异从基线时的2.6千克增加到第20年时的4.8千克(单核苷酸多态性*时间交互作用p = 0.0193)。NPY2R基因的单核苷酸多态性与非裔美国男性的腰围相关(p = 0.0462)。在白种人中,LEP单核苷酸多态性也倾向于与体重相关(p = 0.0471),而PYY rs11684664仅与女性的肥胖相关表型有关(p = 0.010 - 0.026)。几个LEP、NPY2R和PYY单核苷酸多态性与年轻人的肥胖相关表型有关,尤其是在非裔美国人中。