Potential Impact of COMT-rs4680 G > A Gene Polymorphism in Coronary Artery Disease

Abstract

Purpose: Catechol-O-methyltransferase (COMT) plays a central role in DNA repair and estrogen-induced carcinogenesis. The nonsynonymous single nucleotide polymorphism (SNP) in exon 4 G > A or Val108 > 158Met or rs4680 G > A influences COMT enzyme activity. The three phenotypes of the COMT enzyme activities include COMT A/A with low enzyme activity, COMT A/G with medium enzyme activity and COMT G/G with high enzyme activity. The Met allele is associated with low enzymatic activity resulting in higher levels of prefrontal dopamine. Conversely, the Val allele is associated with high enzymatic activity and lower levels of prefrontal dopamine. The Met allele has been associated with several psychiatric disorders such as panic disorder. Many recent epidemiologic studies have investigated the association between the COMT Val158Met polymorphism and coronary artery diseases risk, but the results are inconclusive. Therefore our study was aimed to explore the association between COMT Val158Met polymorphism and the risk of coronary artery disease in India. Methology: This study was conducted on 100 clinically confirmed cases of coronary artery diseases and 100 healthy controls. COMT Val158Met genotyping was performed by allele-specific polymerase chain reaction (AS-PCR). Results: A significant correlation was observed in the COMT Val158Met genotype distribution between the coronary artery disease cases and healthy controls (p = 0.008). The frequencies of all three genotypes, GG, GA, AA, reported in the CAD patients were 10%, 70%, and 20%, and 30%, 60%, and 10% in the healthy controls respectively. An increased risk of coronary artery disease was observed in the codominant inheritance model for COMT-GA vs. GG genotype with an OR of 3.5, 95% CI (1.58–7.74) p = 0.002) and COMT-AA vs. GG genotype with an OR of 6.0 95% CI (2.11–17.3) p = 0.003). The higher risk of coronary artery disease was observed in the dominant inheritance model for COMT (GA + AA) vs. GG genotype (OR 3.85, 95% CI 1.76–8.4, p < 0.007), whereas a non-significant association was found in recessive model for COMT (GG + GA vs. AA) (OR = 2.01, 95% CI (0.86–4.7) p = 0.72). The results indicated that A allele significantly increased the risk of coronary artery disease compared to the G allele (OR = 1.8, 95% CI (1.20–2.67) p = 0.004). COMT Val158Met polymorphism leads to a 6.0, 3.5 and 1.8-fold increased risk of developing coronary artery disease in the Indian population and providing novel insights into the genetic etiology and underlying biology of coronary artery disease. Conclusions: It is concluded that COMT-AA genotype and A allele are significantly associated with an increased susceptibility to coronary artery disease in Indian population. A larger sample size can be the key to progress in establishing the genetic co-relationship of COMT polymorphism and cardiovascular disease.

Systems Pharmacogenomics – Gene, Disease, Drug and Placebo Interactions: A Case Study in COMT

“…COMT deficiency in mouse models resulted in glucose intolerance which was rescued by 2-methoxyestradiol (2-ME) [49]. The COMT association extends to cardiovascular disease, specifically to the risk of myocardial infarction and stroke where the rate of incident events is lower among val-allele than met-allele homozygotes [52,53,73]. Interestingly, among women diagnosed with depression, the val-allele was associated with increased risk of cardiovascular disease [74].…”

A Machine Learning Model Utilizing a Novel SNP Shows Enhanced Prediction of Coronary Artery Disease Severity

“…utilized the well-established CAD severity score (Gensini) [17] to determine if known GWAS variants could be associated with CAD severity and found that while the 9p21 variant was associated with CAD severity, others were not [17]. Moreover, gene variants, such as the ID3 SNP at rs11574, FREM1 SNP at rs10511596, LDLR SNP rs688, and COMT SNP rs4680 [18][19][20][21] associated with direct measures of vessel disease including increased carotid intima-medial thickness (cIMT), coronary artery calcium (CAC) and coronary artery plaque volume as measured by intravascular ultrasound (IVUS) [19,22] have not been identified in GWAS of larger more heterogeneous cohorts. Given our interest in developing a machine learning tool to help predict CAD severity at angiography and our prior work demonstrating that the ID3 SNP at rs11574 was associated with cIMT, CAC and plaque volume as measured by IVUS in three distinct clinical cohorts, we selected ID3 SNP at rs11574 as the genetic factor to add to our analysis.…”

The atorvastatin metabolic phenotype shift is influenced by interaction of drug-transporter polymorphisms in Mexican population: results of a randomized trial

“…The catechol-O-methyltransferase, encoded by the COMT gene, is an enzyme that helps to eliminate endogenous or toxic metabolites, as well as exogenous polycyclic compounds 42,43 . Due to its regulatory function of catecholamines, more is known about its role in pharmacodynamics than its role in pharmacokinetics 44 . The A allele related to susceptibility to coronary artery disease 44 .…”

“…Due to its regulatory function of catecholamines, more is known about its role in pharmacodynamics than its role in pharmacokinetics 44 . The A allele related to susceptibility to coronary artery disease 44 . We discovered a significant effect of the COMT-rs4680 polymorphism on the C max , AUC 0-∞ and Cl of ATV, although this effect was not supported by regression analysis.…”

“…We discovered a significant effect of the COMT-rs4680 polymorphism on the C max , AUC 0-∞ and Cl of ATV, although this effect was not supported by regression analysis. The rs4680 variant produces a non-synonymous amino acid change (p.V158M) causing impaired COMT activity 44,45 . As far as we know this is the first study that reports a possible effect of COMT-rs4680 on ATV pharmacokinetics.…”