Genome-wide linkage and association analyses to identify genes influencing adiponectin levels: the GEMS Study.
Genome-wide linkage and association analyses to identify genes influencing adiponectin levels: the GEMS Study.
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DOI：
10.1038/oby.2008.625
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发表时间：
2009-04
期刊：
影响因子：
6.9
通讯作者：
Mitchell, Braxton D.
中科院分区：
文献类型：
--
作者：
Ling, Hua;Waterworth, Dawn M.;Stirnadel, Heide A.;Pollin, Toni I.;Barter, Philip J.;Kesaniemi, Y. Antero;Mahley, Robert W.;McPherson, Ruth;Waeber, Gerard;Bersot, Thomas P.;Cohen, Jonathan C.;Grundy, Scott M.;Mooser, Vincent E.;Mitchell, Braxton D.
脂联素对肥胖、胰岛素敏感性和动脉粥样硬化有多种代谢作用。为了确定影响血浆脂联素水平变化的基因，我们在代谢综合征遗传流行病学研究中招募的两组受试者中进行了脂联素的全基因组连锁和关联扫描。全基因组连锁扫描是在起源于土耳其和南欧(TSE，n=789)和北欧和西欧(NWE，N=2280)的家庭中进行的。全基因组关联(WGA)分析(500K Affymetrix平台)在一组无关的NWE受试者中进行，这些受试者包括大约1000名血脂异常的受试者和1000名血脂正常的超重受试者。在NWE患者(LOD=3.10)和TSE患者(LOD=1.70)中，连锁高峰出现在染色体8p23(LOD=3.10)和3q28(靠近脂联素结构基因ADIPOQ)。在WGA分析中，与脂联素关联最强的单核苷酸多态(SNP)是rs3774261和rs6773957(P<；10−7)。这两个SNP处于高度连锁不平衡状态(R2=0.98)，位于ADIPOQ内。有趣的是，我们的第四个最强的结合区域(P<；2×10−5)是与CDH13中的一个单核苷酸多态结合的，其蛋白产物是新发现的高相对分子质量脂联素的受体。通过WGA分析，我们证实了先前的研究表明ADIPOQ中的SNPs与脂联素水平的变化密切相关，并进一步观察到这些SNPs对整个基因组中的脂联素水平具有最强的影响。此外，我们还发现了第二个基因(CDH13)，可能会影响脂联素水平的变化。这些单核苷酸多态对健康和疾病的影响尚未确定。
Adiponectin has a variety of metabolic effects on obesity, insulin sensitivity, and atherosclerosis. To identify genes influencing variation in plasma adiponectin levels, we performed genome-wide linkage and association scans of adiponectin in two cohorts of subjects recruited in the Genetic Epidemiology of Metabolic Syndrome Study. The genome-wide linkage scan was conducted in families of Turkish and southern European (TSE, n = 789) and Northern and Western European (NWE, N = 2,280) origin. A whole genome association (WGA) analysis (500K Affymetrix platform) was carried out in a set of unrelated NWE subjects consisting of approximately 1,000 subjects with dyslipidemia and 1,000 overweight subjects with normal lipids. Peak evidence for linkage occurred at chromosome 8p23 in NWE subjects (lod = 3.10) and at chromosome 3q28 near ADIPOQ, the adiponectin structural gene, in TSE subjects (lod = 1.70). In the WGA analysis, the single-nucleotide polymorphisms (SNPs) most strongly associated with adiponectin were rs3774261 and rs6773957 (P < 10−7). These two SNPs were in high linkage disequilibrium (r2 = 0.98) and located within ADIPOQ. Interestingly, our fourth strongest region of association (P < 2 × 10−5) was to an SNP within CDH13, whose protein product is a newly identified receptor for high-molecular-weight species of adiponectin. Through WGA analysis, we confirmed previous studies showing SNPs within ADIPOQ to be strongly associated with variation in adiponectin levels and further observed these to have the strongest effects on adiponectin levels throughout the genome. We additionally identified a second gene (CDH13) possibly influencing variation in adiponectin levels. The impact of these SNPs on health and disease has yet to be determined.
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