A Genome-Wide Methylation Study on Essential Hypertension in Young African American Males

Xiaoling Wang,Bernard Gutin,Ashok Kumar Sharma,Frank Treiber,Xiaojing Xu,Yanbin Dong,Bonita Falkner,Gregory Harshfield,Huidong Shi,Haidong Zhu,Harold Snieder,Shaoyong Su

doi:10.1371/journal.pone.0053938

Abstract

ObjectiveThere is emerging evidence from animal studies suggesting a key role for methylation in the pathogenesis of essential hypertension. However, to date, very few studies have investigated the role of methylation in the development of human hypertension, and none has taken a genome-wide approach. Based on the recent studies that highlight the involvement of inflammation in the development of hypertension, we hypothesize that changes in DNA methylation of leukocytes are involved in the pathogenesis of hypertension.Method & ResultsWe conducted a genome-wide methylation analysis on 8 hypertensive cases and 8 normotensive age-matched controls aged 14–23 years and performed validation of the most significant CpG sites in 2 genes in an independent sample of 36 hypertensive cases and 60 normotensive controls aged 14–30 years. Validation of the CpG sites in the SULF1 gene was further conducted in a second replication sample of 36 hypertensive cases and 34 controls aged 15.8–40 years. A CpG site in the SULF1 gene showed higher methylation levels in cases than in healthy controls in the genome-wide step (p = 6.2×10−5), which was confirmed in the validation step (p = 0.011) for subjects ≤30 years old but was not significant for subjects of all ages combined (p = 0.095).ConclusionThe identification of a difference in a blood leukocyte DNA methylation site between hypertensive cases and normotensive controls suggests that changes in DNA methylation may play an important role in the pathogenesis of hypertension. The age dependency of the effect further suggests complexity of epigenetic regulation in this age-related disease.

Highlights

Essential hypertension (EH) is a major health problem worldwide with approximately one in three adults suffering from the disease
The identification of a difference in a blood leukocyte DNA methylation site between hypertensive cases and normotensive controls suggests that changes in DNA methylation may play an important role in the pathogenesis of hypertension
Twin and family studies highlight a clear inherited component to EH [1], the current purely sequence-based approach only accounts for a fraction of the genetic risk of the disease as evidenced by the recent genome-wide association studies in which the identified genetic variants explain less than 1% of the blood pressure (BP) variation in the population [2]

Summary

Introduction

Essential hypertension (EH) is a major health problem worldwide with approximately one in three adults suffering from the disease. Several epidemiological and clinical peculiarities of EH such as the incomplete concordance between monozygotic (MZ) twins (ranges from 38% to 52%) [3,4] and its late onset and progressive nature, are difficult to explain with traditional DNA sequence-based approaches. These observations may indicate the involvement of epigenetic factors in EH development. Based on recent studies [11,12] that highlight the involvement of inflammation in the development of EH, we hypothesized that changes in the DNA methylation of leukocytes are involved in the pathogenesis of EH. The goal of this study was to characterize the DNA methylation profile in peripheral blood leukocytes in EH cases versus normotensive controls using a 3stage genome-wide approach

Methods

Results

Conclusion