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Genome-wide association studies have identified numerous genetic loci for blood pressure (BP). However, the relationships of functional elements inside these loci with BP are not fully understood. This study represented an effort to determine if promoter DNA methylations inside BP-associated loci were associated with BP.We conducted a cross-sectional study investigating the association between promoter DNA methylations of 10 candidate genes and BP in 1,241 Chinese individuals. Twenty-one genomic fragments in the CpG Islands were sequenced. The associations of methylation levels with BP and hypertension were assessed in regression models. Mendelian randomization (MR) analysis was then applied to find supporting evidence for the identified associations.A total of 413 DNA methylation sites were examined in an observational study. Methylation levels of 24 sites in  PRDM6 ,  IGFBP3 ,  SYT7 ,  PDE3A ,  TBX2  and  C17orf82  were significantly associated with BP. Methylation levels of  PRDM6  and  SYT7  were significantly associated with hypertension. Methylation levels of five sites (including cg06713098) in  IGFBP3  were significantly associated with DBP. MR analysis found associations between the methylation levels of six CpG sites (cg06713098, cg14228300, cg23193639, cg21268650, cg10677697 and cg04812164) around the  IGFBP3  promoter and DBP. Methylation levels of cg14228300 and cg04812164 were associated with SBP. By further applying several MR methods we showed that the associations may not be due to pleiotropy. Association between  IGFBP3  mRNA levels in blood cells and BP was also found in MR analysis. This study identified promoter methylation as potential functional element for BP. The identified methylations may be involved in the regulatory pathway linking genetic variants to BP.

frontiers in genetics

Promoter DNA Methylation in GWAS-Identified Genes as Potential Functional Elements for Blood Pressure: An Observational and Mendelian Randomization Study