Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom
N Engl J Med. 2009 Dec 24;361(26):2518-28. doi: 10.1056/NEJMoa0902604.
An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level and their relevance for the risk of coronary disease are incompletely understood.
We used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for associations in 3145 case subjects with coronary disease and 3352 control subjects. Replication was tested in three independent populations involving 4846 additional case subjects with coronary disease and 4594 control subjects.
Three chromosomal regions (6q26-27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26-27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV-type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished.
We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease.
脂蛋白(a)[Lp(a)]水平升高已被确定为冠心病的一个高度遗传性危险因素。Lp(a)脂蛋白水平的遗传决定因素及其与冠心病风险的相关性尚不完全清楚。
我们使用一种包含 2100 个候选基因 48742 个单核苷酸多态性(SNP)的新型基因芯片，在 3145 名冠心病病例和 3352 名对照中检测关联。在涉及 4846 名冠心病附加病例和 4594 名对照的三个独立人群中进行了复制测试。
三个染色体区域（6q26-27、9p21 和 1p13）与冠心病风险强烈相关。编码 Lp(a)脂蛋白的 6q26-27 上的 LPA 基因座具有最强的相关性。我们在 LPA 基因座上发现了一个常见的变体(rs10455872)，其冠心病的比值比为 1.70(95%置信区间[CI]，1.49 至 1.95)，另一个独立的变体(rs3798220)的比值比为 1.92(95%CI，1.48 至 2.49)。这两个变体都与 Lp(a)脂蛋白水平升高、LPA 拷贝数减少(决定 4 型 2 重复环的数量)和 Lp(a)脂蛋白小尺寸强烈相关。复制研究证实了这两种变体对 Lp(a)脂蛋白水平和冠心病风险的影响。荟萃分析表明，对于涉及两种 LPA SNP 的基因型评分，一种变体的冠心病比值比为 1.51(95%CI，1.38 至 1.66)，两种或更多变体的比值比为 2.57(95%CI，1.80 至 3.67)。在调整 Lp(a)脂蛋白水平后，LPA 基因型评分与冠心病风险之间的关联被消除。
我们发现了两种与 Lp(a)脂蛋白水平升高和冠心病风险增加都强烈相关的 LPA 变体。我们的研究结果为 Lp(a)脂蛋白在冠心病中的因果作用提供了支持。
