Hypertension is a major modifiable risk factor for arteriosclerosis that can lead to target organ damage (TOD) of heart, kidneys, and peripheral arteries. A recent epigenome-wide association study for blood pressure (BP) identified 13 CpG sites, but it is not known whether DNA methylation at these sites is also associated with TOD. In 1218 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study, a cohort of hypertensive sibships, we evaluated the associations between methylation at these 13 CpG sites measured in peripheral blood leukocytes and five TOD traits assessed approximately 5 years later. Ten significant associations were found after adjustment for age, sex, blood cell counts, time difference between CpG and TOD measurement, and 10 genetic principal components (FDR q < 0.1): two with estimated glomerular filtration rate (eGFR, cg06690548, cg10601624), six with urinary albumin-to-creatinine ratio (UACR, cg16246545, cg14476101, cg19693031, cg06690548, cg00574958, cg22304262), and two with left ventricular mass indexed to height (LVMI, cg19693031, cg00574958). All associations with eGFR and four associations with UACR remained significant after further adjustment for body mass index (BMI), smoking status, and diabetes. We also found significant interactions between cg06690548 and BMI on UACR, and between 3 CpG sites (cg19693031, cg14476101, and cg06690548) and diabetes on UACR (FDR q < 0.1). Mediation analysis showed that 4.7% to 38.1% of the relationship between two CpG sites (cg19693031 and cg00574958) and two TOD measures (UACR and LVMI) was mediated by blood pressure (Bonferroni-corrected P < 0.05). Mendelian randomization analysis suggests that methylation at two sites (cg16246545 and cg14476101) in PHGDH may causally influence UACR. In conclusion, we found compelling evidence for associations between arteriosclerotic traits of kidney and heart and previously identified blood pressure-associated DNA methylation sites. This study may lend insight into the role of DNA methylation in pathological mechanisms underlying target organ damage from hypertension.

中文翻译：

---

根据动脉病遗传流行病学网络 (GENOA) 研究，血压的表观遗传位点与老年非裔美国人的高血压靶器官损伤相关。


高血压是动脉硬化的一个主要可改变危险因素，可导致心脏、肾脏和外周动脉的靶器官损伤 (TOD)。最近一项针对血压 (BP) 的全表观基因组关联研究确定了 13 个 CpG 位点，但尚不清楚这些位点的 DNA 甲基化是否也与 TOD 相关。在来自动脉病遗传流行病学网络 (GENOA) 研究的 1218 名非裔美国人（一组高血压同胞）中，我们评估了外周血白细胞中测量的这 13 个 CpG 位点的甲基化与大约 5 年后评估的 5 个 TOD 特征之间的关联。调整年龄、性别、血细胞计数、CpG 和 TOD 测量之间的时间差以及 10 个遗传主要成分 (FDR q < 0.1) 后发现 10 个显着关联：其中两个与估计肾小球滤过率 (eGFR、cg06690548、cg10601624) ，六个具有尿白蛋白与促丁宁的比率（UACR，CG16246545，CG14476101，CG19693031，CG06690548，CG00574958，CG00574958，CG222304262），CG222304262），CG222304262），左心室质量为高度（lvmi）cg 009969696996999999999999999999999939999999999999999990次CG1999999999993999990号境内CG1919999999999999999999999999909.在进一步调整体重指数 (BMI)、吸烟状况和糖尿病后，所有与 eGFR 的关联以及四种与 UACR 的关联仍然显着。我们还发现 UACR 上的 cg06690548 和 BMI 之间以及 UACR 上的 3 个 CpG 位点（cg19693031、cg14476101 和 cg06690548）与糖尿病之间存在显着的相互作用（FDR q < 0.1）。中介分析显示，两个 CpG 位点（cg19693031 和 cg00574958）和两个 TOD 测量值（UACR 和 LVMI）之间的关系有 4.7% 到 38.1% 由血压介导（Bonferroni 校正 P < 0.05）。 孟德尔随机化分析表明，PHGDH 中两个位点（cg16246545 和 cg14476101）的甲基化可能会因果影响 UACR。总之，我们发现了令人信服的证据，证明肾脏和心脏的动脉硬化特征与之前确定的血压相关 DNA 甲基化位点之间存在关联。这项研究可能有助于深入了解 DNA 甲基化在高血压靶器官损伤的病理机制中的作用。