Some methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms are associated with hyperhomocysteinemia. Trials have shown a plasma homocysteine raising effect of coffee. We determined the effect of a daily intake of 600 ml coffee and a supplementation of 200 µg folic acid or placebo on plasma homocysteine (tHcy) with respect to the MTHFR C677T and A1298C polymorphisms. Onehundred and twenty healthy, non-smoking men (22%) and women (78%) aged 29-65 years, took part in a controlled, randomized, blinded study with two intervention periods: i) a coffee-free period of three weeks, ii) 600 ml coffee/day and a supplement of 200 µg folic acid/d or placebo for four weeks. The results showed that tHcy at baseline was significantly higher for the 677TT genotype group compared to the 677CC genotype group (p=0.0045) and that this group responded with significantly larger increase in tHcy upon coffee exposure than the 677CC and 677CT genotype groups (p=0.0045 and p=0.0041, respectively). Supplementation with 200 µg folic acid compared to placebo reduced the tHcy increasing effect of coffee in the 677TT genotype group. The A1298C polymorphism did not affect tHcy concentration significantly at any stage in the study. In conclusion, the homocysteine increasing effect of coffee is particularly seen in individuals with the homozygous 677TT genotype. Supplementation with 200 µg folic acid/d decreases this tHcy increment.

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