Genome-Wide Association Study of Cardiac Structure and Systolic Function in African Americans The Candidate Gene Association Resource (CARe) Study
Genome-Wide Association Study of Cardiac Structure and Systolic Function in African Americans The Candidate Gene Association Resource (CARe) Study
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DOI：
10.1161/circgenetics.111.962365
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发表时间：
2013-02-01
影响因子：
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通讯作者：
Vasan, Ramachandran S.
中科院分区：
文献类型：
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作者：
Fox, Ervin R.;Musani, Solomon K.;Vasan, Ramachandran S.
背景：在候选基因关联资源研究中，我们使用来自4个社区非洲裔美国人队列的数据，测试了全基因组标记（单核苷酸多态性）与心脏表型之间的关联。方法和结果：在6765名非裔美国人中，我们将9种心脏表型（通过超声心动图或磁共振成像评估）的年龄、性别、身高和体重调整残差与使用全基因组Affymetrix Human SNP Array 6.0 （Affy6.0）进行基因分型的250万个单核苷酸多态性进行了关联，其余部分进行了估算。在队列中，进行全基因组关联分析，然后使用逆方差权进行跨队列的荟萃分析（全基因组显著性阈值=4.0 × 10(-7)）。进行补充通路分析。我们尝试在3个较小的非洲血统队列中进行复制，并在1个欧洲血统联盟（EchoGEN）中进行了查找测试。在9种表型中，4个基因位点的变异具有全基因组意义：UBE2V2中rs4552931 （P=1.43 × 10(-7)）的左心室质量，WIPI1中rs7213314 （P=1.68 × 10(-7)）的左心室舒张内径，PPAPDC1A中rs1571099 （P=2.57 × 10(-8)）的室间隔壁厚度，KLF5中rs9530176 （P=4.02 × 10(-7)）的射血分数。在参与心脏重塑的3个信号通路中富集了相关变异。在EchoGEN的查找中，在非洲血统队列中复制的4个位点中没有一个得到证实。结论：在迄今为止最大的非裔美国人心脏结构和功能的全基因组关联研究中，我们确定了4个与左心室质量、室间隔壁厚度、左心室舒张内径和射血分数相关的基因位点，这些基因位点具有全基因组意义。复制结果表明，这些基因座可能是非洲血统个体所独有的。这些复杂的表型需要进一步的大规模研究。（中国心血管病杂志，2013;6:37-46）
Background-Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study.Methods and Results-Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0x10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43x10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68x10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57x10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02x10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN.Conclusions-In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes. (Circ Cardiovasc Genet. 2013;6:37-46.)