Oxidative Stress is Associated with Genetic Polymorphisms in One-Carbon Metabolism in Coronary Artery Disease

Abstract

In view of growing body of evidence favouring the association of aberrations in one-carbon metabolism and oxidative stress in the aetiology of coronary artery disease (CAD), we investigated the risk associated with polymorphisms regulating the folate uptake and transport such as the glutamate carboxypeptidase II (GCPII) C1561T, reduced folate carrier 1 (RFC1) G80A and cytosolic serine hydroxymethyltransferase (cSHMT) C1420T. We further evaluated the impact of seven putatively functional polymorphisms of this pathway on oxidative stress markers. Genotyping was performed on 288 CAD cases and 266 healthy controls along with the dietary folate assessment. GCPII C1561T polymorphism was found to be an independent risk factor (OR 2.71, 95% CI 1.47-4.98) for CAD, whereas cSHMT C1420T conferred protection (OR 0.51, 95% CI 0.37-0.70). Oxidative stress markers like the plasma levels of malondialdehyde, protein carbonyls and 8-oxo-deoxyguanosine were significantly increased and total glutathione was significantly decreased in CAD cases. Elevated oxidative stress was observed in subjects carrying GCPII 1561T and MTRR 66A-variant alleles and low oxidative stress was observed in the subjects carrying cSHMT 1420T and TYMS 5'-UTR 2R allele. GCPII C1561T, MTHFR C677T and MTRR A66G polymorphisms were observed to influence the homocysteine levels (P < 0.05). SHMT and TYMS variants were found to decrease oxidative stress by increasing the folate pool (r = 0.38, P = 0.003) and also by increasing the antioxidant status (r = 0.28, P = 0.03). Influence of dietary folate status was not observed. Overall, this study revealed elevated oxidative stress that was associated with the aberrations in one-carbon metabolism which could possibly influence the CAD risk.

Multifactor dimensionality reduction analysis to elucidate the cross-talk between one-carbon and xenobiotic metabolic pathways in multi-disease models

“…In another study, we observed that GCPII 1561 C[T as a risk factor for CAD, while cSHMT 1420 C[T conferred protection [24]. GCPII 1561T and MTRR 66A-variant alleles were reported to contribute to increased oxidative stress while cSHMT 1420T and TYMS 5 0 -UTR 2R alleles reduce oxidative stress [24]. In the same cohort, we observed association of CYP1A1 m1, CYP1A1 m2 (rs1048943) and GSTT1 null with CAD risk [25].…”

“…Earlier, we reported MTHFR 677 C[T, MTRR 66 A[G (rs1801394) as risk factors for CAD and TYMS 5 0 -UTR 28 bp tandem repeat polymorphism as a protective factor [23]. In another study, we observed that GCPII 1561 C[T as a risk factor for CAD, while cSHMT 1420 C[T conferred protection [24]. GCPII 1561T and MTRR 66A-variant alleles were reported to contribute to increased oxidative stress while cSHMT 1420T and TYMS 5 0 -UTR 2R alleles reduce oxidative stress [24].…”

“…The case-control datasets of our ten published studies from the Nizam's Institute of Medical Sciences (NIMS), Hyderabad, India were chosen for the analysis [17][18][19][20][21][23][24][25][26][27]. For each of the four disease models, the subjects involved were identified individually and the case-control statistics differ between each of the disease.…”

Assessment of Oxidative Stress Markers and Carotid Artery Intima-Media Thickness in Elderly Patients Without and with Coronary Artery Disease

“…Our previous studies and others have shown that oxidative stress is involved in diabetes, hyperlipidemia, and smoking are the potential risk factors for CAD [40][41][42]. Oxidative DNA damage is directly or indirectly involved in the pathophysiology of CAD.…”

Genetic Variation in Glutamate Carboxypeptidase II and Interaction with Dietary Natural Vitamin C May Predict Risk for Adenomatous Polyp Occurrence

“…GCPII and its genetic variants are known to be associated with folate nutritional status and disease 1 susceptibility, as this is a critical locus for the absorption mechanism of methylfolate (Devlin et al, 2000). One particular mutation of this gene, C1561T in which histidine 475 is changed to tyrosine (rs61886492, H475Y), has been reported to be associated with risk for breast and prostate cancer, coronary artery disease and miscarriage (Divyya et al, 2012;Vijaya Lakshmi et al, 2013). This genetic variant may lead to a reduction in GCPII activity, and hence to a lower blood folate concentration and higher homocysteine (Hcy), potentially implicating this polymorphism in the pathoaetiology of these disorders (Devlin et al, 2000).…”