Key result
Blood pressure-related DNA methylation at 10 CpG sites is linked to hypertension-mediated organ damage.
Why the study?
It is unknown whether DNA methylation at blood pressure-associated CpG sites is also associated with hypertensive target organ damage in African Americans.
Is DNA methylation at blood pressure-associated CpG sites associated with target organ damage in hypertensive African Americans?
Cohort (n=1,218)
Yes
Is DNA methylation at blood pressure-associated CpG sites associated with target organ damage in hypertensive African Americans?
p-value: p=FDR q < 0.1
DNA methylation at previously identified blood pressure-associated loci is significantly associated with target organ damage in the kidneys and heart among older African Americans, partially mediated by blood pressure.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Kho et al. (2020) conducted a cohort in Hypertension and Target Organ Damage (n=1,218). DNA methylation at 13 blood pressure-associated CpG sites vs. Unexposed/reference methylation levels was evaluated on Target organ damage traits (eGFR, UACR, LVMI, RWT, ABI) (p=FDR q < 0.1). DNA methylation at 10 previously identified blood pressure-associated CpG sites was significantly associated with target organ damage measures including eGFR, UACR, and LVMI in older African Americans.
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