The 5,10-methylenetetrahydrofolate reductase C677T polymorphism interacts with smoking to increase homocysteine

Elevated homocysteine is a risk marker for several human pathologies. Risk factors for elevated homocysteine include low folate and homozygosity for the T allele of the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism. Because nitric oxide may inhibit folate catabolism and endothelial nitric oxide synthase activity is reduced in smokers, we postulated that smoking status might modify the impact of the MTHFR C677T polymorphism on homocysteine (tHcy) concentrations. We tested this hypothesis in a healthy young adult population for which MTHFR C677T genotypes and tHcy concentrations were previously reported. The MTHFR 677TT genotype was significantly associated with elevated tHcy concentrations in smokers (P=0.001) but not in non-smokers (P=0.36). Among smokers, the MTHFR 677TT genotype was significantly associated with high tHcy in heavy smokers (P=0.003) but not light smokers (P=0.09), in men (P=0.003) but not women (P=0.11), and in subjects from the lowest serum folate quartile (P=0.003) but not from folate quartiles 2-4 (P=0.49). After adjustment for nutritional variables, interactions between MTHFR C677T genotype and NOS3 G894T genotype, and between MTHFR genotype, smoking status and gender were statistically significant. We propose that hyperhomocysteinemia in MTHFR 677TT homozygote smokers is the consequence of mild intracellular folate deficiency caused by a smoking-related reduction of NOS3 activity that is exacerbated when serum folate is low.