Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS One. 2011 Jan 24;6(1):e14581. doi: 10.1371/journal.pone.0014581.
Lipoprotein(a) (Lp(a)) is an important causal cardiovascular risk factor, with serum Lp(a) levels predicting atherosclerotic heart disease and genetic determinants of Lp(a) levels showing association with myocardial infarction. Lp(a) levels vary widely between populations, with African-derived populations having nearly 2-fold higher Lp(a) levels than European Americans. We investigated the genetic basis of this difference in 4464 African Americans from the Jackson Heart Study (JHS) using a panel of up to 1447 ancestry informative markers, allowing us to accurately estimate the African ancestry proportion of each individual at each position in the genome. In an unbiased genome-wide admixture scan for frequency-differentiated genetic determinants of Lp(a) level, we found a convincing peak (LOD = 13.6) at 6q25.3, which spans the LPA locus. Dense fine-mapping of the LPA locus identified a number of strongly associated, common biallelic SNPs, a subset of which can account for up to 7% of the variation in Lp(a) level, as well as >70% of the African-European population differences in Lp(a) level. We replicated the association of the most strongly associated SNP, rs9457951 (p = 6 × 10(-22), 27% change in Lp(a) per allele, ∼5% of Lp(a) variance explained in JHS), in 1,726 African Americans from the Dallas Heart Study and found an even stronger association after adjustment for the kringle(IV) repeat copy number. Despite the strong association with Lp(a) levels, we find no association of any LPA SNP with incident coronary heart disease in 3,225 African Americans from the Atherosclerosis Risk in Communities Study.
脂蛋白(a)(Lp(a))是一个重要的心血管疾病致病风险因素,血清 Lp(a)水平可预测动脉粥样硬化性心脏病,而 Lp(a)水平的遗传决定因素也与心肌梗死相关。Lp(a)水平在不同人群中差异很大,非洲裔人群的 Lp(a)水平比欧洲裔美国人高近 2 倍。我们使用多达 1447 个遗传标记物的面板,对来自杰克逊心脏研究(JHS)的 4464 名非裔美国人进行了遗传基础研究,这使我们能够准确估计每个个体在基因组中每个位置的非洲裔遗传比例。在对 Lp(a)水平的频率分化遗传决定因素进行无偏的全基因组混合扫描中,我们在 6q25.3 发现了一个令人信服的峰(LOD = 13.6),该峰跨越 LPA 基因座。对 LPA 基因座的密集精细定位确定了许多强烈相关的常见双等位基因 SNPs,其中一些可以解释高达 7%的 Lp(a)水平变异,以及超过 70%的非洲裔和欧洲裔人群 Lp(a)水平差异。我们在来自达拉斯心脏研究的 1726 名非裔美国人中复制了与最强相关 SNP(rs9457951,p = 6 × 10(-22),每个等位基因 Lp(a)水平变化 27%,JHS 中解释 Lp(a)变异的约 5%)的关联,并在调整 kringle(IV)重复拷贝数后发现了更强的关联。尽管与 Lp(a)水平的强烈关联,但我们在来自社区动脉粥样硬化风险研究的 3225 名非裔美国人中没有发现任何 LPA SNP 与冠心病发病的关联。
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