Both the health burden and genetic heritability of blood pressure are well-established, yet only a fraction of blood pressure genes have been identified. Epigenetic changes in or near genes related to blood pressure may explain part of its variance and provide new insights into the biological mechanisms involved in blood pressure regulation.
DNA methylation measured on the Infinium HumanMethylation450 BeadChip was tested for association with systolic and diastolic blood pressure in individuals of European (EA) and African ancestry (AA) in the ARIC, CHS, FHS, GENOA, GOLDN, NAS, LBC1936, RS-III, and TwinsUK cohorts (N-total=9,828; N-EA=6,650, N-AA=3,178). In each cohort, linear mixed models were used to estimate associations adjusting for age, sex, blood cell counts, BMI, smoking, and ancestry, as well as surrogate variables and technical covariates to control for batch effects. Effect estimates from all cohorts were combined using inverse variance fixed effects meta-analysis; heterogeneity of effects in race- and sex-stratified analyses was not observed.
Thirty-one methylation probes were found to be significantly associated with blood pressure after Bonferroni correction (p<1E-7) and eight of these probes replicated with p <0.05 in meta-analyses of EA, AA, and Hispanic/Latino individuals in the MESA cohort (N-total=1,183). Replicated probes tended to be enriched for location in gene enhancer regions and DNase I hypersensitivity sites. ENCODE annotation of these probes revealed two probes to be in enhancer regions for genes involved in angiogenesis, vasoconstriction/vasodilation, and the renin-angiotensin system, including SRF and VEGFA (cg18120259) and PTPN6 and SCNN1A (cg10601624). Additionally, SNPs in these probe-enhanced genes have not been reported to associate with blood pressure or hypertension in prior genetic studies of EA or AA populations, suggesting a novel epigenetic determinant of these traits. Additional replicated probes are located in PHGDH (cg14476101), TXNIP (cg19693031), SLC7A11 (cg06690548), and ZMIZ1 (cg00533891). Previous associations of these probes have been reported with BMI (PHGDH cg14476101); type II diabetes and related traits (TXNIP cg19693031); and IgE and A-diol levels (SLC7A11 cg06690548). SNPs in TXNIP have previously shown associations with blood pressure-related phenotypes, including type II diabetes, and the TXNIP protein has a biological role in the function of calcium channel blockers used to treat hypertension. The association of TXNIP with systolic blood pressure is also supported by gene expression results in FHS. Narrow-sense heritability of the eight replicated probes ranged from 30-65% in whole blood samples from FHS family data, whereas epigenome-wide heritability averaged 12%.
Our findings suggest a novel genetic regulation of known blood pressure systems through heritable DNA methylation.