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GCK gene-body hypomethylation is associated with the risk of coronary heart disease.

ABSTRACT: OBJECTIVES: Glucokinase encoded by GCK is a key enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Variants of GCK gene were shown to be associated with type 2 diabetes (T2D) and coronary heart disease (CHD). The goal of this study was to investigate the contribution of GCK gene-body methylation to the risk of CHD. DESIGN AND METHODS: 36 patients (18 males and 18 females) and 36 age- and sex-matched controls were collected for the current methylation research. DNA methylation level of the CpG island (CGI) region on the GCK gene-body was measured through the sodium bisulfite DNA conversion and pyrosequencing technology. RESULTS: Our results indicated that CHD cases have a much lower methylation level (49.77 ± 6.43%) compared with controls (54.47 ± 7.65%, P = 0.018). In addition, GCK gene-body methylation was found to be positively associated with aging in controls (r = 0.443, P = 0.010). CONCLUSIONS: Our study indicated that the hypomethylation of GCK gene-body was significantly associated with the risk of CHD. Aging correlates with an elevation of GCK methylation in healthy controls.

SUBMITTER: Xu L

PROVIDER: S-EPMC3947703 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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GCK gene-body hypomethylation is associated with the risk of coronary heart disease.

Xu Limin L Zheng Dawei D Wang Lingyan L Jiang Danjie D Liu Haibo H Xu Leiting L Liao Qi Q Zhang Lina L Liu Panpan P Shi Xinbao X Wang Zhaoyang Z Sun Lebo L Zhou Qingyun Q Li Ni N Huang Yi Y Le Yanping Y Ye Meng M Shao Guofeng G Duan Shiwei S

BioMed research international 20140217

<h4>Objectives</h4>Glucokinase encoded by GCK is a key enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Variants of GCK gene were shown to be associated with type 2 diabetes (T2D) and coronary heart disease (CHD). The goal of this study was to investigate the contribution of GCK gene-body methylation to the risk of CHD.<h4>Design and methods</h4>36 patients (18 males and 18 females) and 36 age- and sex-matched controls were collected for the current methylation research ...[more]

PMID: 24696842

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Project description:Genome-wide association studies have identified a coronary artery disease (CAD) risk locus in a non-coding region at 9p21.3, the nearest genes being CDKN2A and CDKN2B. To understand the pathways by which this locus might influence CAD susceptibility, we investigated associations between the 9p21.3 risk genotype and global gene expression in heart tissue from donors with no diagnosed heart disease (n?=?108, predominant cause of death, cerebral vascular accident) and in carotid plaque (n?=?106), aorta (n?=?104) and mammary artery (n?=?88) tissues from heart valve and carotid endarterectomy patients. Genotyping was performed with Taqman assays and Illumina arrays, and gene expression profiles generated with Affymetrix microarrays. Associations were analyzed with an additive genetic model. In heart tissue, 46 genes were putatively altered in association with the 9p21.3 risk allele (70% down-regulated, fold-change >1.1 per allele, p<0.05 adjusted for age, gender, ethnicity, cause of death). These genes were enriched for biomarkers of myocardial infarction (p?=?1.53×10(-9)), response to wounding (p?=?2.65×10(-10)) and inflammatory processes (p<1.97×10(-7)). Among the top 10 most down-regulated genes, 7 genes shared a set of transcription factor binding sites within conserved promoter regions (p<1.14×10(-5)), suggesting they may be co-regulated. Canonical pathway modelling of the most differentially expressed transcripts across all tissues (154 genes, 60% down-regulated, fold-change >1.1 per allele, p<0.01) showed that 75% of the genes could be transcriptionally regulated through the cell cycle G1 phase progression pathway (p<1.08×10(-258)), in which CDKN2A and CDKN2B play a regulatory role. These data suggest that the cell cycle G1 phase progression pathway is activated in individuals with the 9p21.3 risk allele. This may contribute to a proliferative phenotype that promotes adverse cardiac hypertrophy and vascular remodeling, leading to an increased CAD risk.

Dataset Information

GCK gene-body hypomethylation is associated with the risk of coronary heart disease.

Publications

GCK gene-body hypomethylation is associated with the risk of coronary heart disease.

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