Abstract:
Genome-wide association studies have identified numerous genetic loci for blood pressure (BP). However, the relationships of functional elements inside these loci with BP are not fully understood. This study represented an effort to determine if promoter DNA methylations inside BP-associated loci were associated with BP.We conducted a cross-sectional study investigating the association between promoter DNA methylations of 10 candidate genes and BP in 1,241 Chinese individuals. Twenty-one genomic fragments in the CpG Islands were sequenced. The associations of methylation levels with BP and hypertension were assessed in regression models. Mendelian randomization (MR) analysis was then applied to find supporting evidence for the identified associations.A total of 413 DNA methylation sites were examined in an observational study. Methylation levels of 24 sites in PRDM6, IGFBP3, SYT7, PDE3A, TBX2 and C17orf82 were significantly associated with BP. Methylation levels of PRDM6 and SYT7 were significantly associated with hypertension. Methylation levels of five sites (including cg06713098) in IGFBP3 were significantly associated with DBP. MR analysis found associations between the methylation levels of six CpG sites (cg06713098, cg14228300, cg23193639, cg21268650, cg10677697 and cg04812164) around the IGFBP3 promoter and DBP. Methylation levels of cg14228300 and cg04812164 were associated with SBP. By further applying several MR methods we showed that the associations may not be due to pleiotropy. Association between IGFBP3 mRNA levels in blood cells and BP was also found in MR analysis. This study identified promoter methylation as potential functional element for BP. The identified methylations may be involved in the regulatory pathway linking genetic variants to BP.
摘要:
全基因组关联研究已经确定了许多血压(BP)的遗传基因座。然而,这些位点内的功能元件与BP的关系尚未完全了解。这项研究代表了确定BP相关基因座内部启动子DNA甲基化是否与BP相关的努力。我们进行了一项横断面研究,调查了1,241名中国人的10个候选基因的启动子DNA甲基化与BP之间的关联。对CpG群岛中的21个基因组片段进行了测序。在回归模型中评估甲基化水平与BP和高血压的关联。然后应用孟德尔随机化(MR)分析来寻找所识别关联的支持证据。在观察性研究中检查了总共413个DNA甲基化位点。PRDM6、IGFBP3、SYT7、PDE3A、TBX2和C17orf82与BP显著相关。PRDM6和SYT7的甲基化水平与高血压显著相关。IGFBP3中五个位点(包括cg06713098)的甲基化水平与DBP显著相关。MR分析发现IGFBP3启动子和DBP周围的六个CpG位点(cg06713098,cg14228300,cg23193639,cg21268650,cg10677697和cg04812164)的甲基化水平之间存在关联。cg14228300和cg04812164的甲基化水平与SBP相关。通过进一步应用几种MR方法,我们表明这些关联可能不是由于多效性。在MR分析中还发现了血细胞中IGFBP3mRNA水平与BP之间的关联。这项研究确定启动子甲基化是BP的潜在功能元件。鉴定的甲基化可能涉及将遗传变体与BP连接的调节途径。