Genome-wide association scans identified CTNNBL1 as a novel gene for obesity
Genome-wide association scans identified CTNNBL1 as a novel gene for obesity
复制标题
DOI：
10.1093/hmg/ddn072
复制
发表时间：
2008-06-15
影响因子：
3.5
通讯作者：
Deng, Hong-Wen
中科院分区：
文献类型：
--
作者：
Liu, Yong-Jun;Liu, Xiao-Gang;Deng, Hong-Wen
肥胖是一个重大的公共卫生问题，具有很强的遗传决定性;然而，肥胖的遗传因素在很大程度上尚不清楚。在这项研究中，我们进行了一个全基因组关联扫描肥胖检查约50万单核苷酸多态性（SNPs）的样本中的1000无关的美国白人。我们发现了一个新的基因，CTNNBL 1，它有多个SNP与体重指数（BMI）和脂肪量。最显著的SNP rs6013029在BMI和脂肪量方面分别达到了2.69 x 10（-7）和4.99 x 10（-8）的实验P值。SNP rs6013029次要等位基因T与替代等位基因G相比，分别使BMI和脂肪量平均增加2.67 kg/m2和5.96 kg。我们进一步对法国病例对照样本中5个最显著的CTNNBL 1 SNP进行了基因分型，该样本包括896名III级肥胖成人（BMI >= 40 kg/m2）和2916名瘦型成人（BMI < 25 kg/m2）。所有5个SNP均显示与肥胖一致的相关性（8.83 x 10（-3）< P < 6.96 x 10（-4））。与没有T等位基因的受试者相比，那些rs6013029 T等位基因纯合子的受试者肥胖的几率增加了1.42倍。CTNNBL 1的蛋白质结构与β-连环蛋白同源，β-连环蛋白是一个含有犰狳重复序列的蛋白质家族，表明具有相似的生物学功能。β-连环蛋白参与Wnt/β-连环蛋白信号传导途径，该途径似乎有助于通过抑制脂肪形成基因表达来维持前脂肪细胞的未分化状态。因此，我们的研究提出了肥胖发展的新机制，其中CTNNBL 1可能发挥重要作用。我们的研究还为先前确定的肥胖与INSIG 2和PFKP之间的关联提供了支持性证据，但不是FTO。
Obesity is a major public health problem with strong genetic determination; however, the genetic factors underlying obesity are largely unknown. In this study, we performed a genome-wide association scan for obesity by examining approximately 500 000 single-nucleotide polymorphisms (SNPs) in a sample of 1000 unrelated US Caucasians. We identified a novel gene, CTNNBL1 , which has multiple SNPs associated with body mass index (BMI) and fat mass. The most significant SNP, rs6013029, achieved experiment-wise P-values of 2.69 x 10(-7) for BMI and of 4.99 x 10(-8) for fat mass, respectively. The SNP rs6013029 minor allele T confers an average increase in BMI and fat mass of 2.67 kg/m(2) and 5.96 kg, respectively, compared with the alternative allele G. We further genotyped the five most significant CTNNBL1 SNPs in a French case-control sample comprising 896 class III obese adults (BMI >= 40 kg/m(2)) and 2916 lean adults (BMI < 25 kg/m(2)). All five SNPs showed consistent associations with obesity (8.83 x 10(-3) < P < 6.96 x 10(-4)). Those subjects who were homozygous for the rs6013029 T allele had 1.42-fold increased odds of obesity compared with those without the T allele. The protein structure of CTNNBL1 is homologous to beta-catenin, a family of proteins containing armadillo repeats, suggesting similar biological functions. beta-Catenin is involved in the Wnt/beta-catenin-signaling pathway which appears to contribute to maintaining the undifferentiated state of pre-adipocytes by inhibiting adipogenic gene expression. Our study hence suggests a novel mechanism for the development of obesity, where CTNNBL1 may play an important role. Our study also provided supportive evidence for previously identified associations between obesity and INSIG2 and PFKP , but not FTO .