Changes in whole blood DNA methylation levels at several CpG sites have been associated with circulating blood lipids, specifically high-density lipoprotein and triglycerides. This study performs a discovery and validation epigenome-wide association study (EWAS) for circulating lipoprotein(a) [Lp(a)], an independent risk factor for cardiovascular diseases. Whole-blood DNA methylation profiles were assessed in a cohort of 1020 elderly individuals using the Illumina EPIC array and independent validation in 359 elderly males using the Illumina 450 k array. Plasma Lp(a) was measured using an apolipoprotein(a)-size-independent ELISA. Epigenome-wide rank regression analysis identified and validated a single CpG site, cg17028067 located in intron 1 of the LPA gene, that was significantly associated with plasma Lp(a) levels after correction for multiple testing. Genotyping of the site identified a relatively uncommon SNP (rs76735376, MAF <0.02) at the CpG site that largely explained the observed methylation effect. Rs76735376 is an expression quantitative trait loci for the LPA gene and could affect expression by altering enhancer activity. This EWAS for plasma Lp(a) identified a single CpG site within LPA. This association is due to an uncommon, but highly effective genetic variant, which was not in significant linkage disequilibrium with other variants known to influence Lp(a) levels or apo(a) isoform size. This study highlights the utility of CpG site methylation to identify potentially important genetic associations that would not be readily apparent in a comparable size genetic association study.

几个CpG位点的全血DNA甲基化水平的变化与循环血脂有关，特别是高密度脂蛋白和甘油三酸酯。这项研究针对循环脂蛋白（a）[Lp（a）]（一种心血管疾病的独立危险因素）进行了一项发现和验证表观基因组范围的关联研究（EWAS）。使用Illumina EPIC阵列对1020名老年个体的全血DNA甲基化谱进行了评估，并使用Illumina 450 k阵列对359名老年男性进行了独立验证。使用载脂蛋白（a）大小独立的ELISA测量血浆Lp（a）。整个表观基因组秩回归分析确定并验证了位于LPA基因内含子1的单个CpG位点cg17028067，经过多次测试校正后，这与血浆Lp（a）水平显着相关。该位点的基因分型在CpG位点鉴定出相对罕见的SNP（rs76735376，MAF <0.02），这在很大程度上解释了所观察到的甲基化作用。Rs76735376是LPA基因的表达定量性状基因座，可通过改变增强子活性来影响表达。该血浆Lp（a）的EWAS识别LPA中的单个CpG位点。这种关联是由于罕见但高效的遗传变异，与已知影响Lp（a）水平或apo（a）同工型大小的其他变异没有明显的连锁不平衡。这项研究强调了CpG位点甲基化在鉴定潜在重要的遗传关联中的作用，而这种潜在的遗传关联在类似规模的遗传关联研究中不容易发现。