Identification and functional characterisation of DNA methylation differences between East- and West-originating Finns

Eastern and Western Finns show a striking difference in coronary heart disease-related mortality; genetics is a known contributor for this discrepancy. Here, we discuss the potential role of DNA methylation in mediating the discrepancy in cardiometabolic disease-risk phenotypes between the sub-populations. We used data from the Young Finns Study (<i>n</i> = 969) to compare the genome-wide DNA methylation levels of East- and West-originating Finns. We identified 21 differentially methylated loci (FDR &lt; 0.05; Δβ &gt;2.5%) and 7 regions (smoothed FDR &lt; 0.05; CpGs ≥ 5). Methylation at all loci and regions associates with genetic variants (<i>p</i> &lt; 5 × 10⁻⁸). Independently of genetics, methylation at 11 loci and 4 regions associates with transcript expression, including genes encoding zinc finger proteins. Similarly, methylation at 5 loci and 4 regions associates with cardiometabolic disease-risk phenotypes including triglycerides, glucose, cholesterol, as well as insulin treatment. This analysis was also performed in LURIC (<i>n</i> = 2371), a German cardiovascular patient cohort, and results replicated for the association of methylation at cg26740318 and DMR_11p15 with diabetes-related phenotypes and methylation at DMR_22q13 with triglyceride levels. Our results indicate that DNA methylation differences between East and West Finns may have a functional role in mediating the cardiometabolic disease discrepancy between the sub-populations.

芬兰东部与西部人群在冠心病相关死亡率上存在显著差异，遗传因素是该差异的已知成因之一。本文探讨了DNA甲基化（DNA methylation）在介导这两个亚群心血管代谢疾病风险表型差异中的潜在作用。本研究使用青年芬兰人群研究（Young Finns Study，n=969）的数据，对比了东、西起源芬兰人群的全基因组DNA甲基化水平，共鉴定出21个差异甲基化位点（错误发现率FDR < 0.05；Δβ >2.5%）以及7个差异甲基化区域（平滑后错误发现率smoothed FDR < 0.05；CpG位点数量≥5）。所有位点与区域的甲基化水平均与遗传变异显著相关（p < 5 × 10^−8）。在独立于遗传因素的前提下，11个位点与4个区域的甲基化水平与转录本表达量相关，其中包括编码锌指蛋白的基因；类似地，5个位点与4个区域的甲基化水平与心血管代谢疾病风险表型相关，这些表型包括甘油三酯、血糖、胆固醇水平以及胰岛素治疗相关指标。本分析同时在德国心血管患者队列LURIC（n=2371）中开展，cg26740318位点与DMR_11p15的甲基化水平与糖尿病相关表型的关联、以及DMR_22q13的甲基化水平与甘油三酯水平的关联均得到了重复验证。本研究结果表明，芬兰东部与西部人群之间的DNA甲基化差异，可能在介导两个亚群心血管代谢疾病差异中发挥功能性作用。