Aberrant methylation of the GCK gene body is associated with the risk of essential hypertension

Fan, Rui; Wang, Weijie; Zhong, Qilong; Duan, Shiwei; Xu, Xuting; Hao, Lingmei; Zhao, Jing; Zhang, Lina

doi:10.3892/mmr.2015.3631

Cited by 24 publications

(14 citation statements)

References 36 publications

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“…In previous studies, aberrant methylation levels of ACE, ADD1, GCK, and 11β-HSD-2 were shown to correlate with the onset and development of EH [Friso et al, 2008;Riviere et al, 2011;Zhang et al, 2013;Rangel et al, 2014;Fan et al, 2015].…”

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confidence: 99%

Association of AGTR1 Promoter Methylation Levels with Essential Hypertension Risk: A Matched Case-Control Study

Fan

Mao²,

Zhong³

et al. 2015

Cytogenet Genome Res

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The purpose of the present study was to investigate whether methylation of the angiotensin II type 1 receptor (AGTR1) promoter contributed to the risk of essential hypertension (EH). A total of 96 EH cases and 96 gender- and age-matched healthy controls were recruited. Methylation of 8 CpG dinucleotides (CpG1-8) in the AGTR1 promoter was examined using the bisulphite pyrosequencing technology. Three CpG dinucleotides (CpG6-8) could not be well sequenced, therefore only the remaining 5 CpG sites were analysed. A significantly lower CpG1 methylation level was identified in EH cases than in controls (cases vs. controls: 6.74 ± 4.32% vs. 9.66 ± 5.45%, p = 0.007), and no significant association was observed in the remaining analyses. In addition, significantly lower CpG1 (p = 0.028) and higher CpG2 (p = 0.032) methylation levels were observed in males than in females. In the breakdown association test by gender, a higher CpG1 methylation level was also identified in EH in both males (p = 0.034) and females (p = 0.020). Receiver operating characteristic curves showed that CpG1 methylation was a significant predictor of EH. Furthermore, CpG1 methylation was inversely correlated with uric acid levels in controls. The present study suggests that CpG1 hypomethylation in the AGTR1 promoter is likely associated with the risk of EH in the population assessed.

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confidence: 99%

Association of AGTR1 Promoter Methylation Levels with Essential Hypertension Risk: A Matched Case-Control Study

Fan

Mao²,

Zhong³

et al. 2015

Cytogenet Genome Res

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“…Age-dependent gene methylation may also contribute to the phenotypic changes associated with skin aging (34). A previous study demonstrated that age-related DNA methylation affected the essential hypertension status (25). For the CDKN2A gene, older patients were more likely to be unmethylated in the present study, even when assessed independent of blood cholesterol and gender.…”

Section: Discussionmentioning

confidence: 39%

“…DNA extraction and quantification was performed as described previously (25). DNA samples were converted using an EZ DNA Methylation-Gold Kit (Zymo Research, Irvine, CA, USA), according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

CDKN2A and CDKN2B methylation in coronary heart disease cases and controls

Zhong

Chen

et al. 2017

Exp Ther Med

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Abstract. The aim of the present study was to investigate the association between cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase inhibitor 2B (CDKN2B) methylation, and coronary heart disease (CHD), and to explore the interaction between methylation status and CHD clinical characteristics in Han Chinese patients. A total of 189 CHD (96 males, 93 females) and 190 well-matched non-CHD controls (96 males, 94 females) were recruited for the study. Methylation-specific polymerase chain reaction technology was used to examine gene promoter methylation status. Comparisons of methylation frequencies between CHD and non-CHD patients were carried out using the Chi-square test. Methylation levels of CDKN2A and CDKN2B genes were not found to be associated with the risk of CHD. However, the mean age of CDKN2A-hypermethylated participants was significantly lower than CDKN2A-unmethylated participants (58.73±5.88 vs. 62.62±5.36 years, adjusted P<0.001). Conversely, the mean age of CDKN2B-hypermethylated participants was significantly higher compared with CDKN2B-unmethylated participants (62.26±5.48 vs. 58.33±7.47 years, adjusted P=0.048). In addition, CDKN2B methylation frequencies were significantly increased in female participants compared with males (99.47 vs. 11.98%, P=0.032). In conclusion, the results indicated that CDKN2A and CDKN2B promoter methylation frequencies were significantly associated with age, and there was a gender dimorphism in CDKN2B methylation. IntroductionCoronary heart disease (CHD) is a complex chronic disease that is caused by an imbalance between blood supply and demand in myocardium. Various environmental and genetic factors are known to contribute to onset and development of CHD (1). As of 2010, CHD was the leading cause of mortality globally, resulting in over 7 million cases of mortality (2). Therefore, association studies for CHD biomarkers have been performed worldwide (3-5) for future forefront diagnostics for the early assessment of cardiac risks.The genetic locus at chromosome 9p21 has been demonstrated to be strongly associated with the risk of CHD (6,7). Cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase inhibitor 2B (CDKN2B) genes both encode putative regulators of cyclin-dependent kinases on chromosome 9p21. Genome-wide association studies have identified that some CDKN2A or CDKN2B genetic variants are susceptible to CHD (8-10). As recently reported, many human diseases, including cardiovascular disease, could be influenced by aberrant DNA methylation modification (11). Aberrant methylation of cytosine-phosphate-guanine (CpG) islands in gene promoters is associated with transcription silencing and activity (3). However, the exact role of CDKN2A and CDKN2B methylation in cardiovascular system has not yet been fully elucidated.CDKN2A gene is involved in the regulation of cell proliferation, cell aging and apoptosis (12). However, a bidirectional role of CDKN2A gene expression has been reported in previous studies. Knösel et al (13) reported...

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“…Briefly, unmethylated cytosine residues of the target sequences of the candidate gene are first converted to thymine, using sodium bisulfite (EpiTect Bisulfite Kit, Qiagen, Hilden, Germany). The converted DNA is then amplified by polymerase chain reaction (PCR) using Mastercycler Nexus Gradient (Eppendorf, Hamburg, Germany), followed by “sequencing by synthesis” of the target (PyroMark Gold Q96, Qiagen) [21, 22]. The PCR reaction mixture consisted of 12 μ L ZymoTaq™ Premix (Zymo Research Corporation, Irvine, CA, USA), 8 μ L DNase/RNase-free water, 2 μ L converted DNA, and 1.5 μ L of each of the forward and reverse primers.…”

Section: Methodsmentioning

confidence: 99%

Interactions betweenCYP11B2Promoter Methylation and Smoking Increase Risk of Essential Hypertension

Mao

Fan

et al. 2016

BioMed Research International

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Aldosterone synthase (CYP11B2) is closely linked to essential hypertension (EH). However, it remains unclear whether the methylation of the CYP11B2 promoter is involved in the development of EH in humans. Our study is aimed at evaluating the contribution of CYP11B2 promoter methylation to the risk of EH. Methylation levels were measured using pyrosequencing technology in 192 participants in a hospital-based case-control study. Logistic regression and multiple linear regression analyses were utilized to adjust for confounding factors and the GMDR method was applied to investigate high-order gene-environment interactions. Although no significant result was observed linking the four analyzed CpG sites to EH, GMDR detected significant interactions among CpG1, CpG3, CpG4, and smoking correlated with an increased risk of EH (OR = 4.62, adjusted P = 0.011). In addition, CpG2 (adjusted P = 0.013) and CpG3 (adjusted P = 0.039) methylation was significantly lower in healthy males than in healthy females. Likewise, after adjusting for confounding factors, CpG2 methylation (adjusted P = 0.007) still showed significant gender-specific differences among the participants of the study. CpG1 (P = 0.009) site was significantly positively correlated with age, and CpG3 (P = 0.007) and CpG4 (P = 0.006) were both inversely linked to smoking. Our findings suggest that gene-environment interactions are associated with the pathogenesis and progression of EH.

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Aberrant methylation of the GCK gene body is associated with the risk of essential hypertension

Cited by 24 publications

References 36 publications

Association of <b><i>AGTR1</i></b> Promoter Methylation Levels with Essential Hypertension Risk: A Matched Case-Control Study

Association of <b><i>AGTR1</i></b> Promoter Methylation Levels with Essential Hypertension Risk: A Matched Case-Control Study

CDKN2A and CDKN2B methylation in coronary heart disease cases and controls

Interactions betweenCYP11B2Promoter Methylation and Smoking Increase Risk of Essential Hypertension

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