Evaluation of A2BP1 as an obesity gene.
Evaluation of A2BP1 as an obesity gene.
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作者：
Ma L;Hanson RL;Traurig MT;Muller YL;Kaur BP;Perez JM;Meyre D;Fu M;Körner A;Franks PW;Kiess W;Kobes S;Knowler WC;Kovacs P;Froguel P;Shuldiner AR;Bogardus C;Baier LJ
一项针对皮马印第安人（n = 413）的全基因组关联研究（GWAS）发现了与体脂率相关的ataxin-2结合蛋白1基因（A2BP1）的变异。基于这种关联和ataxin-2敲除小鼠的肥胖表型，我们对A2BP1进行了遗传和功能分析，以评估其在人类肥胖中的潜在作用。跨越A2BP1的变异在3234个全血统皮马印第安人的群体样本中进行了基因分型，其中2843人不是最初GWAS研究的一部分，因此可以作为评估复制的样本。此外，还分析了法国成人（n = 1426）和儿童病例/对照受试者（n = 1392）的A2BP1已发表的GWAS数据（Meyre等）。生物医学学报，2009;41(1):157 - 159。在另外两个白种人样本（阿米什人，n = 1149，德国儿童病例/对照，n = 998）和另外一个印第安人样本（n = 2531）中选择变异进行基因分型。小干扰RNA被用来敲低小鼠胚胎下丘脑细胞中的A2bp1信息水平。在不同的人群中，没有单一的A2BP1变异与肥胖有可重复性的联系。然而，A2BP1内含子1内的不同变异与全遗传皮马印第安人（rs10500331, P = 1.9 × 10−7）的BMI和法国白种人成人（rs4786847, P = 1.9 × 10−10）和儿童（rs8054147, P = 9.2 × 10−6）的肥胖相关。小鼠胚胎下丘脑细胞中A2bp1的减少降低了Atxn2、Insr和Mc4r的表达。关联分析表明，A2BP1的变异影响肥胖，功能研究表明，A2BP1可能通过下丘脑MC4R通路影响肥胖。
A genome-wide association study (GWAS) in Pima Indians (n = 413) identified variation in the ataxin-2 binding protein 1 gene (A2BP1) that was associated with percent body fat. On the basis of this association and the obese phenotype of ataxin-2 knockout mice, A2BP1 was genetically and functionally analyzed to assess its potential role in human obesity. Variants spanning A2BP1 were genotyped in a population-based sample of 3,234 full-heritage Pima Indians, 2,843 of whom were not part of the initial GWAS study and therefore could serve as a sample to assess replication. Published GWAS data across A2BP1 were additionally analyzed in French adult (n = 1,426) and children case/control subjects (n = 1,392) (Meyre et al. Nat Genet 2009;41:157–159). Selected variants were genotyped in two additional samples of Caucasians (Amish, n = 1,149, and German children case/control subjects, n = 998) and one additional Native American (n = 2,531) sample. Small interfering RNA was used to knockdown A2bp1 message levels in mouse embryonic hypothalamus cells. No single variant in A2BP1 was reproducibly associated with obesity across the different populations. However, different variants within intron 1 of A2BP1 were associated with BMI in full-heritage Pima Indians (rs10500331, P = 1.9 × 10−7) and obesity in French Caucasian adult (rs4786847, P = 1.9 × 10−10) and children (rs8054147, P = 9.2 × 10−6) case/control subjects. Reduction of A2bp1 in mouse embryonic hypothalamus cells decreased expression of Atxn2, Insr, and Mc4r. Association analysis suggests that variation in A2BP1 influences obesity, and functional studies suggest that A2BP1 could potentially affect adiposity via the hypothalamic MC4R pathway.