Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA.
BMC Med Genet. 2013 Jul 19;14:75. doi: 10.1186/1471-2350-14-75.
Coronary heart disease (CHD) is the major cause of death in the United States. Coronary artery calcification (CAC) scores are independent predictors of CHD. African Americans (AA) have higher rates of CHD but are less well-studied in genomic studies. We assembled the largest AA data resource currently available with measured CAC to identify associated genetic variants.
We analyzed log transformed CAC quantity (ln(CAC + 1)), for association with ~2.5 million single nucleotide polymorphisms (SNPs) and performed an inverse-variance weighted meta-analysis on results for 5,823 AA from 8 studies. Heritability was calculated using family studies. The most significant SNPs among AAs were evaluated in European Ancestry (EA) CAC data; conversely, the significance of published SNPs for CAC/CHD in EA was queried within our AA meta-analysis.
Heritability of CAC was lower in AA (30%) than previously reported for EA (50%). No SNP reached genome wide significance (p < 5E-08). Of 67 SNPs with p < 1E-05 in AA there was no evidence of association in EA CAC data. Four SNPs in regions previously implicated in CAC/CHD (at 9p21 and PHACTR1) in EA reached nominal significance for CAC in AA, with concordant direction. Among AA, rs16905644 (p = 4.08E-05) had the strongest association in the 9p21 region.
While we observed substantial heritability for CAC in AA, we failed to identify loci for CAC at genome-wide significant levels despite having adequate power to detect alleles with moderate to large effects. Although suggestive signals in AA were apparent at 9p21 and additional CAC and CAD EA loci, overall the data suggest that even larger samples and an ethnic specific focus will be required for GWAS discoveries for CAC in AA populations.
冠心病（CHD）是美国的主要死亡原因。冠状动脉钙化（CAC）评分是 CHD 的独立预测因子。非裔美国人（AA）的 CHD 发病率较高，但在基因组研究中研究较少。我们汇集了目前可用的具有测量 CAC 的最大 AA 数据资源，以确定相关的遗传变异。
我们分析了 CAC 数量的对数转换值（ln(CAC+1)）与~250 万个单核苷酸多态性（SNP）的关联，并对来自 8 项研究的 5823 名 AA 进行了逆方差加权荟萃分析。使用家系研究计算 CAC 的遗传率。在 EA CAC 数据中评估了 AA 中最显著的 SNP；相反，在我们的 AA 荟萃分析中，查询了已发表的 SNP 对 EA 中 CAC/CHD 的意义。
AA 中的 CAC 遗传率（30%）低于之前报道的 EA（50%）。没有 SNP 达到全基因组显著性（p<5E-08）。在 AA 中 p<1E-05 的 67 个 SNP 中，在 EA 的 CAC 数据中没有关联的证据。在 EA 中与 CAC/CHD 相关的先前已确定的区域（9p21 和 PHACTR1）的四个 SNP 在 AA 中达到 CAC 的名义显著性，方向一致。在 AA 中，rs16905644（p=4.08E-05）在 9p21 区域的关联最强。
虽然我们观察到 AA 中 CAC 具有很大的遗传率，但尽管有足够的检测能力来检测中等至较大效应的等位基因，我们仍未能在全基因组显著水平上确定 CAC 的位点。尽管在 AA 中的 9p21 区域和其他 CAC 和 CAD EA 位点出现了明显的提示信号，但总体而言，数据表明，即使在 AA 人群中进行 CAC 的 GWAS 发现，也需要更大的样本和特定种族的重点。
