Association of single-nucleotide polymorphisms in MTMR9 gene with obesity
Association of single-nucleotide polymorphisms in MTMR9 gene with obesity
复制标题
DOI：
10.1093/hmg/ddm260
复制
发表时间：
2007-12-15
影响因子：
3.5
通讯作者：
Hotta, Kikuko
中科院分区：
文献类型：
--
作者：
Yanagiya, Takahiro;Tanabe, Atsushi;Hotta, Kikuko
遗传因素显然与肥胖的发生有关，但肥胖的遗传背景仍不清楚。从三项连续病例对照关联研究中的 62 663 个基于基因的单核苷酸多态性 (SNP) 开始，我们确定了肥胖表型 (BMI >= 30 kg/m(2)) 与位于染色体片段肌管蛋白相关蛋白 9 (MTMR9) 基因中的 SNP (rs2293855) 之间的重复关联 8p23-p22。第一组（93 例病例对比 649 例对照）和第二组（564 例病例对比 562 例对照）的 P 值（次要等位基因显性模型）分别为 0.008 和 0.0002。这种关联在第三组中得到了重复[394 例病例与 958 例对照，P=0.005，比值比 (95% CI) =1.40 (1.11-1.78)]。全局 P= 值为 0.0000005。多元回归分析显示，性别、年龄BMI和rs2293855基因型（次要等位基因显性模型）与收缩压和舒张压显着相关。 MTMR9 被证明是单倍型块中唯一包含与肥胖相关的 SNP 的基因。在啮齿动物下丘脑外侧区和弓状核中均检测到MTMR9的转录本和蛋白，该蛋白与食欲素、黑色素浓缩激素、神经肽Y和阿片黑皮素原共存。小鼠下丘脑区域的 MTMR9 转录物水平在禁食后增加，并因高脂肪饮食而降低。我们的数据表明，MTMR9 的遗传变异可能通过调节下丘脑神经肽而赋予肥胖和高血压的倾向。
Genetic factors are clearly involved in the development of obesity, but the genetic background of obesity remains largely unclear. Starting from 62 663 gene-based single-nucleotide polymorphisms (SNPs) in three sequential case-control association studies, we identified a replicated association between the obesity phenotype (BMI >= 30 kg/m(2)) and a SNP (rs2293855) located in the myotublarin-related protein 9 (MTMR9) gene in the chromosomal segment 8p23-p22. P-values (minor allele dominant model) of the first set (93 cases versus 649 controls) and the second set (564 cases versus 562 controls) were 0.008 and 0.0002, respectively. The association was replicated in the third set [394 cases versus 958 controls, P=0.005, odds ratio (95% CI) =1.40 (1.11-1.78)]. The global P= value was 0.0000005. A multiple regression analysis revealed that gender, age BMI and rs2293855 genotype (minor allele dominant model) were significantly associated with both systolic and diastolic blood pressures. MTMR9 was shown to be the only gene within the haplotype block that contained SNPs associated with obesity. Both the transcript and protein of MTMR9 were detected in the rodent lateral hypothalamic area as well as in the arcuate nucleus, and the protein co-existed with orexin, melanin concentrating hormone, neuropeptide Y and proopiomelanocortin. The levels of MTMR9 transcript in the murine hypothalamic region increased after fasting and were decreased by a high-fat diet. Our data suggested that genetic variations in MTMR9 may confer a predisposition towards obesity and hypertension through regulation of hypothalamic neuropeptides.