ABSTRACT

Target organ damage (TOD) manifests as vascular injuries in the body organ systems associated with long-standing hypertension. DNA methylation in peripheral blood leukocytes can capture inflammatory processes and gene expression changes underlying TOD. We investigated the association between epigenome-wide DNA methylation and five measures of TOD (estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), left ventricular mass index (LVMI), relative wall thickness (RWT), and white matter hyperintensity (WMH)) in 961 African Americans from hypertensive sibships. A multivariate (multi-trait) model of eGFR, UACR, LVMI, and RWT identified seven CpGs associated with at least one of the traits (cg21134922, cg04816311 near C7orf50, cg09155024, cg10254690 near OAT, cg07660512, cg12661888 near IFT43, and cg02264946 near CATSPERD) at FDR q < 0.1. Adjusting for blood pressure, body mass index, and type 2 diabetes attenuated the association for four CpGs. DNA methylation was associated with cis-gene expression for some CpGs, but no significant mediation by gene expression was detected. Mendelian randomization analyses suggested causality between three CpGs and eGFR (cg04816311, cg10254690, and cg07660512). We also assessed whether the identified CpGs were associated with TOD in 614 African Americans in the Hypertension Genetic Epidemiology Network (HyperGEN) study. Out of three CpGs available for replication, cg04816311 was significantly associated with eGFR (p = 0.0003), LVMI (p = 0.0003), and RWT (p = 0.002). This study found evidence of an association between DNA methylation and TOD in African Americans and highlights the utility of using a multivariate-based model that leverages information across related traits in epigenome-wide association studies.

摘要

靶器官损伤 (TOD) 表现为与长期高血压相关的身体器官系统中的血管损伤。外周血白细胞中的 DNA 甲基化可以捕获 TOD 的炎症过程和基因表达变化。我们调查了表观基因组范围内的 DNA 甲基化与 TOD 的五项指标（估计肾小球滤过率 (eGFR)、尿白蛋白肌酐比值 (UACR)、左心室质量指数 (LVMI)、相对壁厚 (RWT) 和白色961 名来自高血压同胞的非洲裔美国人的物质高强度 (WMH)）。eGFR、UACR、LVMI 和 RWT 的多变量（多性状）模型确定了与至少一种性状相关的七个 CpG（cg21134922、cg04816311 near C7orf50、cg09155024、cg10254690 near OAT，cg07660512，IFT43附近的 cg12661888和CATSPERD附近的 cg02264946 ）在 FDR q < 0.1。对血压、体重指数和 2 型糖尿病进行调整后，减弱了四种 CpG 的相关性。DNA甲基化与顺式相关- 一些 CpG 的基因表达，但未检测到基因表达的显着介导。孟德尔随机化分析表明三种 CpG 和 eGFR（cg04816311、cg10254690 和 cg07660512）之间存在因果关系。我们还在高血压遗传流行病学网络 (HyperGEN) 研究中评估了已鉴定的 CpG 是否与 614 名非洲裔美国人的 TOD 相关。在可用于复制的三个 CpG 中，cg04816311 与 eGFR (p = 0.0003)、LVMI (p = 0.0003) 和 RWT (p = 0.002) 显着相关。这项研究发现了非裔美国人 DNA 甲基化和 TOD 之间关联的证据，并强调了使用基于多变量的模型的效用，该模型利用表观基因组范围关联研究中相关特征的信息。