C e l l & D e v e l o p m e n t a l B i o l o g y ISSN: 2168-9296 Cell & Developmental Biology Alam, Cell Dev Biol 2016, 5:2 http://dx.doi.org/10.4172/2168-9296.1000172 Volume 5 • Issue 2 • 1000172 Cell Dev Biol ISSN: 2168-9296 CDB, an open access journal Open Access Review Article Methylenetetrahydrofolate Reductase Gene Polymorphisms and Cardiovascular Diseases Mohammad Afaque Alam*, Ph.D Department of Pediatrics, College of Medicine, Drexel University, Philadelphia, PA, USA Abstract A growing body of evidence suggests that mutations in MTHFR gene are involved in cardiovascular diseases (CVD) - cardiac development, atherosclerosis, myocardial infarction, heart failure, hypertension, aneurysms- and several other disease- cancers, neurological and metabolic disorders. Genetic variations in other genes are added risk for CVD- a leading cause of morbidity and mortality around the globe. Accumulating data over the decade has enhanced our understanding of MTHFR defciency and diseases associated risk. The frequency of MTHFR 677 C→T and 1298 A→C gene mutations varies substantially in different regions of the world among different racial and ethnic groups. In particular, 677C→T and 1298 A→C variant are associated with clinical manifestation of almost all non- communicable diseases. This review describes the roles of MTHFR gene mutation in CVD and prospective therapies for heart disease treatment. *Corresponding author: Mohammad Afaque Alam, Department of Pediatrics, College of Medicine, Drexel University, 894 Union Ave, Memphis,, TN 38103, USA, Tel: +1-901-518-6443; E-mail: aafaqq@gmail.com Received May 09, 2016; Accepted May 13, 2016; Published May 21, 2016 Citation: Alam MA (2016) Methylenetetrahydrofolate Reductase Gene Polymorphisms and Cardiovascular Diseases. Cell Dev Biol 5: 172. doi:10.4172/2168-9296.1000172 Copyright: © 2016 Alam MA. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Keywords: Polymorphism; MTHFR gene; Mutations; Cardiac diseases Methylenetetrahydrofolate Reductase (MTHFR) Gene Methylenetetrahydrofolate reductase (MTHFR) is a cytosolic enzyme, which contains a non-covalently bound Flavin Adenine Dinucleotide (FAD) cofactor and uses NADPH as the reducing agent. Tis is an essential enzyme for folate and homocysteine (hcy) metabolisms and exhibits a risk factor for a number of heart diseases [1,2]. MTHFR is responsible for converting the circulating form of folate 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate in multistep processes that converts homocysteine- an amino acid to another amino acid, methionine and S-adenosyl methionine - the common methyl donor for the maintenance of several biological processes (Figure 1). Te body uses methionine to make proteins and other important compounds for growth and metabolism. On the other hand, appropriate methylation facilitates the clearance of harmful substances, metabolites and waste products more efciently. Over the decade researchers have enhanced our understanding of pathophysiological relation with common and rare MTHFR mutations, enzyme defciency, elevated hcy and low folate levels in circulation. Of note, it has been reported that compromised MTHFR enzyme activity leads to elevated levels of hcy. Homocysteine is a sulpher containing amino acid, is an oxidant, and play a vital role in oxidation of lipids and lipoproteins, hence augmenting CVD risk [3,4]. Mudd et al. [5] have discovered a severe form of MTHFR enzyme defciency, which leads to a very serious health conditions- homocysteinuria - in which hcy excretes out in urine. Since the discovery of the role of MTHFR gene mutation in human diseases, this enzyme has received much interest in establishing the association with increased concentration of hcy and heart diseases. Tere are several case control, retrospective and meta analyses that have demonstrated that MTHFR polymorphism is associated with increased blood hcy concentration and CVD [3,6-9]. Te MTHFR 677C→T and 1298 A→C homozygous genotype is associated with premature CAD and other cardiovascular disorders [1,2,10]. On the other hand in the mid-nineties a great piece of discovery - cDNA synthesis - has been published, which paved the way for functional analysis of the MTHFR gene [11]. Tis transformed the MTFHR research which followed by identifcation of several rare and common variants including missense variant of alanine to valine at nucleotide 677, which encodes the thermolabile form of the enzyme [3,12]. Te mutant TT genotype is linked to elevated circulating hcy levels and the individuals carrying this mutation exhibits low folate levels [13]. 677C→T variant is the most common and prevalent form of MTHFR genetic polymorphisms, which depicts mild to high level of hcy and associated disease manifestation [13-15]. Nonetheless, this variant located in the catalytic domain of the gene and thermolabile in nature afects hcy and folate metabolism. In 1998, another common polymorphism in the MTHFR gene was described, the 1298 A→C transition, which caused an amino acid substitution of glutamate by alanine [16,17]. Sibani et al. [18] reported 33 severe mutation and two common mutations, however Martin et al. [19] reported 65 mutations in MTHFR gene. MTHFR- as a central modulator of folate- hcy-methionine pathway, inspired investigators from all felds to identify and characterize novel mutations in relation to human health. Terefore hundreds (~ 109) of polymorphism - that includes mutations, deletions, duplications, and splicing variants- have been identifed [19] and investigations continue to establish the role in CVD risk [20]. Correspondingly, to explore the cause of diseases pathology as a consequence of MHFR gene mutation, scientists developed Mthfr knockout mice. Tey have exhibited a remarkably lower (>60%) enzyme activity in 677C→T variant, resulting in high hcy level among mutant group and also observed high lipid deposition in the major arteries [21]. Cascading efect of hyperhomocysteinemia is the causative factor for high cholesterol deposition in the vessel which initiates atherosclerosis generation and progression, that would lead to myocardial infarction and heart failure. MTHFR gene exists in dimeric form, consisting of 656 amino acid translating a protein that migrates at ~ 74-77 kDa. Tis is an evolutionary conserved gene throughout organisms from yeast to human. However, mouse depicts the highest homology (>90%). MTHFR gene is located at the short arm of chromosome 1 (1p36.3) and