C677T (THERMOLABILE ALANINE VALINE) POLYMORPHISM IN METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) - ITS FREQUENCY AND IMPACT ON PLASMA HOMOCYSTEINE CONCENTRATION IN DIFFERENT EUROPEAN POPULATIONS/

A common polymorphism has been described in the methylenetetrahydrofol ate reductase (MTHFR) gene, substituting an alanine (A) for a valine ( V), where the V allele results in a thermolabile enzyme with reduced a ctivity. This polymorphism is easily detectable by PCR amplification a nd digestion with HinfI restriction enzyme. We describe the use of the MADGE high throughput genotyping system for rapid typing of this poly morphism. Seven hundred and eighty five individuals participating in t he European Atherosclerosis Research Study II (EARS II), aged 22-25 fr om 14 universities in 12 countries across Europe were genotyped for th is polymorphism. The frequency of the V allele was 0.32 overall (95% C I; 0.30-0.35), but was significantly lower in the Baltic countries (0. 23; 95% CI; 0.19-0.28) compared with the other regions of Europe (0.37 ; 95% CI; 0.32-0.38) (P < 0.001). Individuals homozygous for the V all ele had statistically significant (P < 0.001) higher plasma homocystei ne (16.5 mu mol/l) compared with those heterozygous for an A allele (1 0.4 mu mol/l) or homozygous for an A allele (10.0 mu mol/l). This effe ct was seen in all countries and regions of Europe. Mean plasma homocy steine levels were significantly higher in the South compared to the B altic, UK and Middle regions (P = 0.001), but this difference was not explained by the difference in the frequency of the V allele in the sa mples. This polymorphism explained 12.3% of the total sample variance in plasma homocysteine, other measured factors (smoking, alcohol consu mption, systolic blood pressure, physical activity) explained 0.7%. Th is study demonstrates the large and consistent impact of the thermolab ile MTHFR Variant on plasma homocysteine levels in different European populations, and shows a regional difference in the levels of homocyst eine that must be explained by other genetic or environmental factors. (C) 1998 Elsevier Science Ireland Ltd.