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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 deficiency 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 noncommunicable diseases. This review describes the roles of MTHFR gene mutation in CVD and prospective therapies for heart disease treatment.