Mortality risk in men is associated with a common mutation in the methylene-tetrahydrofolate reductase gene (MTHFR)

An elevated level of homocysteine in plasma is associated with the occurren ce of cardiovascular disease. A common ala-to-val mutation in the methylene tetrahydrofolate reductase gene (MTHFR) is associated with an elevated leve l of plasma homocysteine, We studied the possible detrimental effects of th e MTHFR mutation on mortality. Within a population-based study in the city of Leiden, the Netherlands, we first compared the MTHFR genotype distributi on among 365 elderly subjects aged 85 years and over born in Leiden, and 25 0 young subjects aged 18 to 40 years whose families originated from the sam e geographical region. Second, the complete cohort of 666 subjects aged 85 years and over was followed over a period of 10 years for all-cause and cau se-specific mortality and stratified according to MTHFR genotype, The frequ ency of the MTHFR mutation was significantly lower in the elderly than in t he young (0.30 and 0.36, respectively; P = 0.03). The difference in genotyp e distribution was only present in men. The estimated mortality risk up to 85 years in men carrying the val/val genotype was 3.7 (95% confidence inter val (CI), 1.3-10.9). Over the age of 85, mortality in men with the val/val genotype was increased 2.0-fold (95% CI, 1.1-3.9) and appeared to be attrib utable to cancer rather than cardiovascular causes of death. Among women ag ed 85 years and over, no deleterious effect of the MTHFR mutation was obser ved. In conclusion, the MTHFR mutation is associated with increased mortali ty in men in middle and old age, but not in women.