Epigenome-wide association study in Chinese monozygotic twins identifies DNA methylation loci associated with blood pressure

Abstract

Background Hypertension is a crucial risk factor for developing cardiovascular disease and reducing life expectancy. We aimed to detect DNA methylation (DNAm) variants potentially related to systolic blood pressure (SBP) and diastolic blood pressure (DBP) by conducting epigenome-wide association studies in 60 and 59 Chinese monozygotic twin pairs, respectively. Methods Genome-wide DNA methylation profiling in whole blood of twins was performed using Reduced Representation Bisulfite Sequencing, yielding 551,447 raw CpGs. Association between DNAm of single CpG and blood pressure was tested by applying generalized estimation equation. Differentially methylated regions (DMRs) were identified by comb-P approach. Inference about Causation through Examination of Familial Confounding was utilized to perform the causal inference. Ontology enrichment analysis was performed using Genomic Regions Enrichment of Annotations Tool. Candidate CpGs were quantified using Sequenom MassARRAY platform in a community population. Weighted gene co-expression network analysis (WGCNA) was conducted using gene expression data. Results The median age of twins was 52 years (95% range 40, 66). For SBP, 31 top CpGs (p < 1 × 10–4) and 8 DMRs were identified, with several DMRs within NFATC1, CADM2, IRX1, COL5A1, and LRAT. For DBP, 43 top CpGs (p < 1 × 10–4) and 12 DMRs were identified, with several DMRs within WNT3A, CNOT10, and DAB2IP. Important pathways, such as Notch signaling pathway, p53 pathway by glucose deprivation, and Wnt signaling pathway, were significantly enriched for SBP and DBP. Causal inference analysis suggested that DNAm at top CpGs within NDE1, MYH11, SRRM1P2, and SMPD4 influenced SBP, while SBP influenced DNAm at CpGs within TNK2. DNAm at top CpGs within WNT3A influenced DBP, while DBP influenced DNAm at CpGs within GNA14. Three CpGs mapped to WNT3A and one CpG mapped to COL5A1 were validated in a community population, with a hypermethylated and hypomethylated direction in hypertension cases, respectively. Gene expression analysis by WGCNA further identified some common genes and enrichment terms. Conclusion We detect many DNAm variants that may be associated with blood pressure in whole blood, particularly the loci within WNT3A and COL5A1. Our findings provide new clues to the epigenetic modification underlying hypertension pathogenesis.

DNA Methylation Mediated the Association of Body Mass Index With Blood Pressure in Chinese Monozygotic Twins

“…The primary materials and methods of this study were in accord with those reported in our previously published studies (Wang, Li et al, 2023; Wang, Yao, Li et al, 2023; Wang, Yao, Tan et al, 2023).…”

“…All co-twin pairs completed a questionnaire and undertook a health examination after a 10−12 hour overnight fast. The twins’ zygosity was determined by a combination of sex, ABO blood types, and DNA testing (Wang, Yao, Li et al, 2023). The measurement of BMI and BP has been described in our previous studies (Z. Li et al, 2021; Wang, Yao, Li et al, 2023).…”

“…The twins’ zygosity was determined by a combination of sex, ABO blood types, and DNA testing (Wang, Yao, Li et al, 2023). The measurement of BMI and BP has been described in our previous studies (Z. Li et al, 2021; Wang, Yao, Li et al, 2023). The ethical principles of the Helsinki Declaration were followed, and prior written informed consent was achieved.…”

“…In recent years, increasing evidence has supported the significant role of epigenetic modification, such as DNA methylation (DNAm) variation underlying complex phenotypes. Currently, a functional role of DNAm variation in the development of hypertension or regulation of BP has gradually been demonstrated (Demura & Saijoh, 2017; Liang, 2018; Wang, Yao, Li et al, 2023). Moreover, the association of DNAm variation with obesity has also been widely studied (van Dijk et al, 2015).…”

Shared genetic architecture of Genitourinary Cancer and Heart Failure

“…These genes exhibit clear and consistent expression in adipose tissue, cardiovascular tissue, and brain tissue (Fig. 3), and are closely associated with both CVD and cancer [50][51][52][53] . The pleiotropy genes that are linked to these risk genes are enriched in various cancer-related pathways as well as cell cycle-related pathways ( gure S13-16).…”