A common mutation in the methylenetetrahydrofolate reductase gene and risk of coronary heart disease: results among U.S. men

Objectives. We examined the risk of coronary heart disease associated with homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase gene.Background. The mutation increases plasma homocysteine levels by impairing its remethylation. Increased plasma homocysteine is an independent risk factor for cardiovascular disease.Methods. This was a case-control study nested within the Health Professionals Follow-up Study. In 1986, 44,940 U.S. male health professionals, aged 40 to 75 years and free from diagnosed cardiovascular disease, provided detailed information on usual dietary intake, including intake of folate, vitamins B₂, B₆and B₁₂, and methionine. Between 1993 and 1995, blood samples were provided by approximately 40% of the participants. We compared data from 500 men with nonfatal coronary heart disease, diagnosed between 1986 and 1992, with data from 500 age-matched control subjects who were free of diagnosed cardiovascular disease at the time of the matched case subject’s diagnosis.Results. Frequencies of homozygosity (+/+) and heterozygosity (+/−) for the mutation were 12.2% and 41.8% in case subjects and 14.4% and 40.0% in control subjects. With subjects homozygous (−/−) or heterozygous (+/−) for the wildtype allele as a reference and matched by age, the odds ratio of coronary heart disease was 0.83 (95% confidence interval, 0.57 to 1.19) for +/+ subjects. The odds ratio was unchanged after adjustment for smoking and other risk factors for coronary heart disease. Odds ratios were also calculated within strata for intake of vitamins involved in homocysteine metabolism or methionine, the metabolic precursor of homocysteine. The +/+ genotype was not directly associated with risk of coronary heart disease among men with low (that is, within the lowest quartile) intake (<301 μg/d) of folate, the substrate for methylenetetrahydrofolate reductase; low intake (<1.8 mg/d) of vitamin B₂, the cofactor for methylenetetrahydrofolate reductase; low intake (<8.0 μg/d) of vitamin B₁₂, the cofactor for remethylation; low intake (<2.1 mg/d) of vitamin B₆, the cofactor in the catabolic pathway of homocysteine; or high intake (>2.4 g/d) of methionine.Conclusions. In this generally well-nourished population, men with the +/+ genotype for the C677T mutation in the methylenetetrahydrofolate reductase gene have no increase in risk of coronary heart disease, even when intake of folate or other B vitamins is low.