The effect of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase gene on homocysteine levels in elderly men and women fromthe British regional heart study

Total blood levels of homocysteine (tHcy) have been shown to depend on both environmental and genetic factors, and to be associated with the risk of d eveloping atherosclerosis with its complications of coronary heart disease (CHD) and stroke. In this study. 408 men and 346 women from two towns, Dews bury and Maidstone were examined for tHcy levels and genotyped for the C677 T and the A1298C polymorphisms in the methylenetetrahydrofolate reductase ( MTHFR) gene. Blood tHcy was significantly higher in men from the CHD high r isk town of Dewsbury (12.7 mu mol/l) than in the low CHD risk town of Maids tone (11.5 mu mol/l) P < 0.001. but not in women (10.7 vs. 10.5 <mu>mol/l), with women in both towns. thus, showing significantly lower tHcy than men. There was no difference between towns in folate or vitamin B-12 levels but the conventional inverse relationship with tHcy was seen. Smoking men and women from both towns had significantly higher tHcy and lower folate levels than non-smoking individuals (P < 0.001). The frequency of the 677T allele in Dewsbury was 0.35 (95% CI; 0.32-0.39) compared with 0.29 (95% CI; 0.26- 0.32) in Maidstone (P < 0.01). Similar frequency difference of borderline s tatistical significance was seen both for men (P = 0.054) and women (P = 0. 048) in both the towns, suggesting a true regional frequency difference. Th e effect of the 677T on tHcy was highly significant in the group as a whole with the most profound effect seen in men (12.0 mu mol/l for CC vs. 14.1 m u mol/l for TT, P < 0.001). By contrast, there was no significant effect of the A1298C polymorphism on tHcy, folate: or vitamin B-12 levels, with no e vidence for an interaction with the C677T genotype. The regional difference s in tHcy levels were still present after the adjustment for folate and vit amin B-12 levels, smoking and the effect of the C677T polymorphism. This su ggests that there may be other unidentified factors, either environmental o r genetic, affecting tHcy levels, and thus potentially having an impact on the risk of developing hyperhomocysteinaemia and CHD. These observations ma y have a bearing on regional differences in tHcy levels and the variation i n CHD risk between regions in the UK. (C) 2001 Elsevier Science Ireland Ltd . All rights reserved.