全基因组关联研究确定了非洲裔人群中代谢综合征的特异性变异。
Genome-wide association study identifies African-ancestry specific variants for metabolic syndrome.
作者信息
Tekola-Ayele Fasil, Doumatey Ayo P, Shriner Daniel, Bentley Amy R, Chen Guanjie, Zhou Jie, Fasanmade Olufemi, Johnson Thomas, Oli Johnnie, Okafor Godfrey, Eghan Benjami A, Agyenim-Boateng Kofi, Adebamowo Clement, Amoah Albert, Acheampong Joseph, Adeyemo Adebowale, Rotimi Charles N
机构信息
Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
出版信息
Mol Genet Metab. 2015 Dec;116(4):305-13. doi: 10.1016/j.ymgme.2015.10.008. Epub 2015 Oct 23.
The metabolic syndrome (MetS) is a constellation of metabolic disorders that increase the risk of developing several diseases including type 2 diabetes and cardiovascular diseases. Although genome-wide association studies (GWAS) have successfully identified variants associated with individual traits comprising MetS, the genetic basis and pathophysiological mechanisms underlying the clustering of these traits remain unclear. We conducted GWAS of MetS in 1427 Africans from Ghana and Nigeria followed by replication testing and meta-analysis in another continental African sample from Kenya. Further replication testing was performed in an African American sample from the Atherosclerosis Risk in Communities (ARIC) study. We found two African-ancestry specific variants that were significantly associated with MetS: SNP rs73989312[A] near CA10 that conferred increased risk (P=3.86 × 10(-8), OR=6.80) and SNP rs77244975[C] in CTNNA3 that conferred protection against MetS (P=1.63 × 10(-8), OR=0.15). Given the exclusive expression of CA10 in the brain, our CA10 finding strengthens previously reported link between brain function and MetS. We also identified two variants that are not African specific: rs76822696[A] near RALYL associated with increased MetS risk (P=7.37 × 10(-9), OR=1.59) and rs7964157[T] near KSR2 associated with reduced MetS risk (P=4.52 × 10(-8), Pmeta=7.82 × 10(-9), OR=0.53). The KSR2 locus displayed pleiotropic associations with triglyceride and measures of blood pressure. Rare KSR2 mutations have been reported to be associated with early onset obesity and insulin resistance. Finally, we replicated the LPL and CETP loci previously found to be associated with MetS in Europeans. These findings provide novel insights into the genetics of MetS in Africans and demonstrate the utility of conducting trans-ethnic disease gene mapping studies for testing the cosmopolitan significance of GWAS signals of cardio-metabolic traits.
代谢综合征（MetS）是一组代谢紊乱症候群，会增加患包括2型糖尿病和心血管疾病在内的多种疾病的风险。尽管全基因组关联研究（GWAS）已成功鉴定出与构成MetS的个体特征相关的变异，但这些特征聚集背后的遗传基础和病理生理机制仍不清楚。我们对来自加纳和尼日利亚的1427名非洲人进行了MetS的GWAS研究，随后在另一个来自肯尼亚的非洲大陆样本中进行了重复测试和荟萃分析。在社区动脉粥样硬化风险（ARIC）研究中的一个非裔美国人样本中进行了进一步的重复测试。我们发现了两个与MetS显著相关的非洲血统特异性变异：CA10附近的SNP rs73989312[A]，其增加了患病风险（P = 3.86×10(-8)，OR = 6.80），以及CTNNA3中的SNP rs77244975[C]，其对MetS具有保护作用（P = 1.63×10(-8)，OR = 0.15）。鉴于CA10仅在大脑中表达，我们关于CA10的发现强化了先前报道的脑功能与MetS之间的联系。我们还鉴定出两个非非洲特异性变异：RALYL附近的rs76822696[A]与MetS风险增加相关（P = 7.37×10(-9)，OR = 1.59），以及KSR2附近的rs7964157[T]与MetS风险降低相关（P = 4.52×10(-8)，Pmeta = 7.82×10(-9)，OR = 0.53）。KSR2基因座与甘油三酯和血压测量值存在多效性关联。据报道，罕见的KSR2突变与早发性肥胖和胰岛素抵抗有关。最后，我们重复了先前在欧洲人中发现的与MetS相关的LPL和CETP基因座。这些发现为非洲人MetS的遗传学提供了新的见解，并证明了进行跨种族疾病基因图谱研究以测试心血管代谢特征GWAS信号的全球意义的实用性。
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