Interactions of 5'-UTR Thymidylate Synthase Polymorphism with 677C→ T Methylene Tetrahydrofolate Reductase and 66A→ G Methyltetrahydrofolate Homocysteine Methyl-transferase Reductase Polymorphisms Determine Susceptibility to Coronary Artery Disease

Lakshmi, Sana Venkata Vijaya; Naushad, Shaik Mohammad; Rupasree, Yedluri; Rao, D. Seshagiri; Kutala, Vijay Kumar

doi:10.5551/jat.5702

Cited by 41 publications

(27 citation statements)

References 27 publications

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“…MTHFR 1298AC/TYMS 2R/2R genotypic combination is associated with reduced risk factor for DS in Italian population [8]. In another study, the 2R/2R genotype has been reported to be protective for coronary artery disease [35] and in drug response for certain cancer treatment [27,36,37] via interaction with folate intake. Further in a study of Artificial neural network analysis by Coppede et al, revealed TYMS 2R/3R genotype is closely connected with a condition of being mothers of DS and TYMS 3R/3R genotype connected with control mothers [38].…”

Section: Discussionmentioning

confidence: 99%

Association of Genetic Polymorphisms in Genes Involved at the Branch Point of Nucleotide Biosynthesis and Remethylation with Down Syndrome Birth Risk: A Case-Control Study

Jaiswal¹,

Sukla²,

Mishra³

et al. 2016

J Mol Genet Med

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DNA methylation and nucleic acid biosynthesis are two crucial phenomena for normal chromosomes segregation. From our earlier studies, MTHFR 677T individually and in combination with other gene polymorphisms, micronutrient deficiency, hyperhomocysteinemia was shown to be associated with risk in Down syndrome (DS) mothers. Remethylation and nucleic acid biosynthesis pathways are dependent on the activity of Methylenetetrahydrofolate reductase (MTHFR) and Thymidylate synthase (TYMS) respectively, competing for common substrate molecule 5,10-methelenetetrahydrofolate (5,10-MTHF). The role of MTHFD1 1958 G>A (affecting synthesis of 5,10-MTHF), MTHFR 677 C>T (affecting methylation), TYMS 5'UTR 28 bp repeat polymorphism and TYMS 3'UTR 6bp deletion polymorphism (affecting nucleic acid biosynthesis) in a cohort of 200 case mothers and 187 control mothers (also 146 case triads: mother, father, and child) were studied in the present study. We observed a significant association of MTHFR 677 C>T in a co-dominant model (p=0.0428) and dominant model (0.0194) as well as TYMS 5'UTR 28 bp repeat polymorphism in a recessive model (p=0.0005) and dominant model (0.0161). The genotypic combination analysis revealed a significant additive effect of certain genotypic combinations (especially combination of MTHFR 677T and TYMS 2R alleles with other alleles or genotypes) in increasing risk. Weak linkage disequilibrium (LD) was observed between TYMS 5' and 3' UTR regions polymorphism in LD analysis. Transmission disequilibrium test (TDT) analysis revealed a consistent trend of preferential allele's transmission from parents. We concluded that genetic interaction of remethylation pathway and the nucleic acid metabolic pathway was significantly associated with risk factors for DS childbirth. However, replication studies are required to validate our observation in the population.

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Section: Discussionmentioning

confidence: 99%

Association of Genetic Polymorphisms in Genes Involved at the Branch Point of Nucleotide Biosynthesis and Remethylation with Down Syndrome Birth Risk: A Case-Control Study

Jaiswal¹,

Sukla²,

Mishra³

et al. 2016

J Mol Genet Med

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“…4A. Disruption of cysteine and methionine metabolism also influences oxidative stress through involvement of metabolic intermediates causing endothelial cell damage or inflammation (29). NAD metabolism is a major consequence of reactive oxygen species (ROS) generation, which has been associated with androgenic effects on prostate tissue (30).…”

Section: Metabolic Pathway Alterations In Pct-mentioning

confidence: 99%

Integration of Metabolomics and Transcriptomics Reveals Major Metabolic Pathways and Potential Biomarker Involved in Prostate Cancer

Ren

Shao

Zhao

et al. 2016

Molecular & Cellular Proteomics

163

130

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Prostate cancer is a highly prevalent tumor affecting millions of men worldwide, but poor understanding of its pathogenesis has limited effective clinical management of patients. In addition to transcriptional profiling or transcriptomics, metabolomics is being increasingly utilized to discover key molecular changes underlying tumorigenesis. In this study, we integrated transcriptomics and metabolomics to analyze 25 paired human prostate cancer tissues and adjacent noncancerous tissues, followed by further validation of our findings in an additional cohort of 51 prostate cancer patients and 16 benign prostatic hyperplasia patients. We found several altered pathways aberrantly expressed at both metabolic and transcriptional levels, including cysteine and methionine metabolism, nicotinamide adenine dinucleotide metabolism, and hexosamine biosynthesis. Additionally, the metabolite sphingosine demonstrated high specificity and sensitivity for distinguishing prostate cancer from benign prostatic hyperplasia, particularly for patients with low prostate specific antigen level (0 -10 ng/ml). We also found impaired sphingosine-1-phosphate receptor 2 signaling, downstream of sphingosine, representing a loss of tumor suppressor gene and a potential key oncogenic pathway for therapeutic targeting. By integrating metabolomics and transcriptomics, we have provided both a broad picture of the molecular perturbations underlying prostate cancer and a preliminary study of a novel metabolic signature, which may help to discriminate prostate cancer from normal tissue and benign prostatic hyperplasia. Molecular & Cellular Proteomics

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“…COMT supports the production of homocysteine 9) , predisposing subjects to coronary artery disease 15) , internal carotid artery stenosis and occlusion 16) , by thickening the arterial wall and narrowing the vascular radius 17) . Thus, it is conceivable that higher levels of COMT activity may result in higher total plasma homocysteine (tHcy) levels.…”

Section: Discussionmentioning

confidence: 96%

Association of COMT Gene Polymorphisms with Systemic Atherosclerosis in Elderly Japanese

Ikeda

Mieno-Naka

et al. 2012

JAT

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Aim: Atherosclerotic disease is a major health problem among the elderly, which arises from a complex interaction between genetic and environmental factors. The catechol-O-methyltransferase (COMT) gene encodes an enzyme that degrades catecholamines and estrogens to less active metabolites. The objective of this study was to examine whether polymorphisms of the COMT gene affected the severity of atherosclerotic disease in a Japanese elderly population. Method: A total of 1536 autopsy cases of hospital deaths were assessed for the degree of pathological atherosclerotic index (PAI), coronary stenotic index (CSI) and intracranial stenotic index (ICAI), which were obtained by macroscopic examination of the luminal surface of formalin-fixed arteries. Two single nucleotide polymorphisms (SNPs) in the COMT gene, rs4633 (C/T) and rs4680 (G/A) were genotyped. The rs4680 (G/A) corresponds to a functional SNP with the substitution of valine to methionine. Result: The CC genotype of rs4633 (C/T) and the GG genotype of rs4680 (G/A) showed a significantly higher degree of PAI and the association remained positive after adjustment for age, hypertension, diabetes, smoking and drinking (p=0.035 and p= 0.031, respectively). There were no significant associations between COMT genotypes and CSI or ICAI. When male and female subjects were analyzed separately, the association was observed only in female subjects (p = 0.012 and p= 0.027) after adjustment for age, hypertension, diabetes, smoking and drinking. Conclusion: The functional SNP in the COMT gene associated with the severity of atherosclerosis in a Japanese elderly population, whereby the influence of the genotype appears to be stronger in females than in males.

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Interactions of 5'-UTR Thymidylate Synthase Polymorphism with 677C→ T Methylene Tetrahydrofolate Reductase and 66A→ G Methyltetrahydrofolate Homocysteine Methyl-transferase Reductase Polymorphisms Determine Susceptibility to Coronary Artery Disease

Abstract: Dietary folate status and TYMS 5'-UTR 28bp tandem repeat polymorphism are important effect modifiers of CAD risk associated with genetic variants in remethylating genes.

Cited by 41 publications

References 27 publications

Association of Genetic Polymorphisms in Genes Involved at the Branch Point of Nucleotide Biosynthesis and Remethylation with Down Syndrome Birth Risk: A Case-Control Study

Association of Genetic Polymorphisms in Genes Involved at the Branch Point of Nucleotide Biosynthesis and Remethylation with Down Syndrome Birth Risk: A Case-Control Study

Integration of Metabolomics and Transcriptomics Reveals Major Metabolic Pathways and Potential Biomarker Involved in Prostate Cancer

Association of COMT Gene Polymorphisms with Systemic Atherosclerosis in Elderly Japanese

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