Catechol-O-methyltransferase promoter hypomethylation is associated with the risk of coronary heart disease.
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ABSTRACT:
SUBMITTER: Zhong J
PROVIDER: S-EPMC5103840 | biostudies-other | 2016 Nov
REPOSITORIES: biostudies-other
Publications
Catechol-O-methyltransferase promoter hypomethylation is associated with the risk of coronary heart disease.
Zhong Jinyan J Chen Xiaoying X Wu Nan N Shen Caijie C Cui Hanbin H Du Weiping W Zhang Zhaoxia Z Feng Mingjun M Liu Junsong J Lin Shaoyi S Zhang Lulu L Wang Jian J Chen Xiaomin X Duan Shiwei S
Experimental and therapeutic medicine 20160928 5
Catechol-O-methyltransferase (COMT) gene variation is known to be associated with the risk of acute coronary events. The purpose of the present study was to investigate the contribution of COMT promoter methylation towards the risk of coronary heart disease (CHD). COMT methylation was evaluated in 48 CHD cases and 48 well-matched non-CHD controls using bisulfite pyrosequencing technology. The results demonstrated that CHD cases had a significantly lower level of methylation at COMT CpG3 sites co ...[more]
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Project description:BackgroundInterleukin-6 (IL-6) is implicated in the pathogenesis of coronary heart disease (CHD), and IL-6 expression has associated with reduced DNA methylation of its gene promoter. However, there are no data on IL-6 promoter methylation and the risk of CHD.ObjectiveTo examine whether IL-6 promoter methylation measured in blood leukocyte DNA is associated with CHD risk.MethodsA total of 212 cases with CHD and 218 controls were enrolled. Methylation at two CpG sites in IL-6 promoter was measured by bisulfite pyrosequencing, and the mean IL-6 methylation was calculated by averaging the methylation measures of the two CpGs.ResultsMean methylation level in IL-6 promoter in CHD cases was significantly lower than that in controls (p = 0.023). Logistic regression analysis showed that IL-6 methylation was inversely associated with the risk of CHD. The odds ratios (ORs) of CHD for subjects in the second and first (lowest) tertile of IL-6 methylation were 1.87 (95% CI = 1.10‑3.20) and 2.01 (95% CI = 1.19-3.38) (ptrend = 0.013), respectively, compared to subjects in the third (highest) tertile. The IL-6 hypomethylation-related risk estimates tended to be stronger for acute myocardial infarction (ptrend = 0.006). CpG position-specific analysis showed that hypomethylation of position 1 conferred a more pronounced increase in CHD risk than that of position 2.ConclusionThese findings suggest that DNA hypomethylation of IL-6 promoter is associated with the increased risk for CHD, especially for acute myocardial infarction. The two distinct CpGs in IL-6 may contribute differently to the development of CHD.
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Project description:ObjectivesGlucokinase 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 methods36 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.ResultsOur 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).ConclusionsOur 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.
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Project description:Background Genetic variation in catechol-O-methyltransferase (COMT), a key enzyme in estrogen and catecholamine metabolism, has plausible physiological links to cardiovascular disease (CVD) and its risk factors. In WHS (Women's Health Study), COMT variants rs4818 and rs4680 were associated with a lower risk of CVD among women receiving placebo but not aspirin, suggesting a possible role of COMT in thrombosis. Methods and Results To evaluate potential pathways linking COMT with CVD, and COMT effect modification of aspirin in prevention, we examined COMT association with CVD risk and subclinical measures, coronary artery calcium, and carotid intima-media thickness in MESA (Multi-Ethnic Study of Atherosclerosis). In 65 957 person-years of follow-up, during which 498 events occurred, COMT rs4818 was associated with lower CVD risk (hazard ratio, 0.85; 95% CI, 0.74-0.97 [P=0.02]). This association remained virtually unchanged after adjusting for common CVD risk factors. Fibrinogen was the only risk factor associated with rs4818 (β, -3.65; SE, 1.35 mg/dL [P=0.007]). Results were directionally similar but not significant for rs4680. Adjusted hazard ratios for COMT rs4818 CVD association were 0.79 (95% CI, 0.65-0.95; P=0.02) among individuals who used aspirin <3 days per week and 0.89 (95% CI, 0.71-1.13; P=0.34) among more frequent users (Pinteraction=0.39). Neither intima-media thickness nor coronary artery calcium was associated with COMT. Conclusions In a multiethnic prospective cohort of men and women, the COMT rs4818G allele was associated with lower CVD risk and lower fibrinogen levels but not with radiographic measures of subclinical atherosclerosis. These results suggest a plausible role of COMT in the latter stages of CVD.
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Project description:ObjectivesCatechol O-methyltransferase (COMT) is expressed as both soluble (S) and membrane-bound (MB) isoforms, with S-COMT predominantly expressed in the liver. A common nonsynonymous single nucleotide polymorphism (SNP), 472G > A (108/158Val > Met, S/MB), has been associated with variation in levels of COMT enzyme activity and thermal stability. We set out to test the hypothesis that additional COMT polymorphisms might also be associated with phenotypic variation.MethodsWe phenotyped 268 liver biopsy samples for S-COMT activity and thermal stability, resequenced a portion of the gene that had not been resequenced earlier, and genotyped DNA from these same samples for 16 COMT polymorphisms.ResultsThere was a significant association between the two COMT phenotypes and genotype at the codon 108 SNP. A haplotype-based approach was then used to assess the possible association of other polymorphisms with phenotype. Specifically, the codon 108 SNP explained 20.4% of variance in enzyme activity (P < 10), and 59% of variance in thermal stability (P < 10). Haplotypes that included SNPs at cDNA nucleotides 408 and 472 explained additional variance in enzyme activity (up to 24.4%), and the addition to the haplotype of a SNP at intron 2 (51) explained a total of 27.5% of the variance. However, no SNPs beyond that at the nucleotide 472G > A polymorphism were associated with variation in thermal stability. We also observed a three-fold variation in the ability of reporter gene constructs for 'proximal promoter' haplotypes to drive transcription.ConclusionThe common COMT 108Val > Met polymorphism is associated with human liver S-COMT activity and thermal stability, but additional COMT SNPs also contribute to variation in activity.
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Project description:There is large inter-individual heterogeneity in risk of coronary heart disease (CHD). Risk factors traditionally used in primary risk assessment only partially explain this heterogeneity. Residual, unobserved heterogeneity leads to age-related attenuation of hazard rates and underestimation of hazard ratios. Its magnitude is unknown. Therefore, we aimed to estimate a lower and an approximate upper bound. Heterogeneity was parametrized by a log-normal distribution with shape parameter σ. Analysis was based on published data. From concordance indices of studies including traditional risk factors and additional diagnostic imaging data, we calculated the part of heterogeneity explained by imaging data. For traditional risk assessment, this part typically remains unexplained, thus constituting a lower bound on unobserved heterogeneity. Next, the potential impact of heterogeneity on CHD hazard rates in several large countries was investigated. CHD rates increase with age but the increase attenuates with age. Presuming this attenuation to be largely caused by heterogeneity, an approximate upper bound on σ was derived. Taking together both bounds, unobserved heterogeneity in studies without imaging information can be described by a shape parameter in the range σ = 1-2. It substantially contributes to observed age-dependences of hazard ratios and may lead to underestimation of hazard ratios by a factor of about two. Therefore, analysis of studies for primary CHD risk assessment should account for unobserved heterogeneity.
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Project description:ObjectiveCatechol-O-methyltransferase (COMT), a key enzyme in catecholamine metabolism, is implicated in cardiovascular, sympathetic, and endocrine pathways. This study aimed to confirm preliminary association of COMT genetic variation with incident cardiovascular disease (CVD). It further aimed to evaluate whether aspirin, a commonly used CVD prevention agent, modified the potential association of COMT with incident CVD.Approach and resultsWe examined COMT polymorphism rs4680 (MAF [minor allele frequency], 0.47), encoding a nonsynonymous methionine-to-valine substitution, in the Women's Genome Health Study (WGHS), a large population-based cohort of women with randomized allocation to aspirin or vitamin E when compared with placebo and 10-year follow-up. Rs4680 effects were confirmed with COMT polymorphism rs4818 and also examined in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis/The Coronary Artery Disease Genetics Consortium, consortia for genome-wide association studies of coronary artery disease. Among WGHS women allocated to placebo (135 events/n=5811), the rs4680 valine allele was protective against incident CVD relative to the methionine (hazard ratio [HR; 95% confidence interval {CI}], 0.66 [0.51-0.84]; P=0.0007); an association also observed in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis and The Coronary Artery Disease Genetics Consortium (combined P=2.4×10(-5)). In the WGHS, the rs4680 association was abolished by randomized allocation to aspirin, such that valine/valine women experienced higher CVD rates with aspirin allocation when compared with placebo (HR [95% CI], 1.85 [1.05-3.25]; P=0.033), whereas methionine/methionine women experienced lower rates (HR [95% CI], 0.60 [0.39-0.93]; P=0.023). Allocation to vitamin E also conferred higher but nonsignificant CVD rates on valine/valine (HR [95% CI], 1.50 [0.83-2.70]; P=0.180) when compared with significantly lower rates on methionine/methionine (HR [95% CI], 0.53 [0.34-0.84]; P=0.006) women. Rs4818 results were similar.ConclusionsCommon COMT polymorphisms were associated with incident CVD, and this association was modified by randomized allocation to aspirin or vitamin E. Replication of these findings is required.
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Project description:Pain is a distressing symptom of Parkinson disease (PD). We aim to determine whether the genetic variants of chronic pain-related genes contribute to pain in PD patients. We included 418 PD patients and evaluated pain severity on King's PD pain scale. We genotyped rs6267, rs6269, rs4633, rs4818 and rs4680 of COMT, rs6746030 of SCN9A, and rs1799971 of OPRM1. In total, 193 participants (46.2%) experienced pain. Compared to pain-free PD patients, PD patients with pain had an earlier age of onset, longer disease duration, and higher depression and motor severity (P < 0.01). The frequencies of COMT rs4680 "A" allele were higher in PD patients with pain than those without pain (46.1% vs. 31.1%, P < 0.01). Pain severity was significantly associated with disease duration (P = 0.02), and COMT rs6267 T allele (P < 0.01). We stratified PD by status of depression and the association between COMT rs6267 "GT" genotype and pain severity remained significant (P < 0.01). Furthermore, pain severity was significantly higher in participants having COMT rs4680 "GG" and "GA" genpotypes than those having "AA" genotype (P = 0.04). We concluded that depression and COMT rs4680 "GG" and "GA" genotypes and COMT rs6267 "GT" genotype contribute to pain in PD patients.
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