The Frequency of a Common Mutation of the Methionine Synthase Gene in the Australian Population and its Relation to Smoking and Coronary Artery Disease

Abstract

Modest elevations in levels of circulating homocysteine are common in patients with vascular disease. Methionine synthase is a vitamin B12-dependent enzyme catalysing the re-methylation of homocysteine to methionine; reduced methionine synthase activity results in elevated level of homocysteine. A case-control study. We explored the frequency and distribution of a 2756A-->G (D919G) mutation of the methionine synthase gene, detected by polymerase chain reaction genotyping, in 745 Australian Caucasian patients aged < or = 65 years (550 men and 195 women) with and without angiographically documented coronary artery disease (CAD). The frequency distributions of AA, AG and GG genotypes were 61.9%, 33.8% and 4.3%, respectively, and were in Hardy-Weinberg equilibrium. There was no correlation between the methionine synthase mutation and CAD from simple chi2 comparison. However, the interactive term of life-time smoking dose with methionine synthase genotypes was predictive of both the number of significantly diseased vessels (> or =50% luminal obstruction; chi2 = 12.518, P=0.0019), and the presence or absence of significant CAD (chi2=7.045, P=0.027). A stepwise logistic regression analysis showed that smokers who were also GG homozygotes had more severe CAD compared with smokers of other genotypes. The methionine synthase genotypes were not associated with any of the other established CAD risk factors assessed in our study. We conclude that the methionine synthase 2756A-->G mutation is common, with homozygosity occurring in approximately 4% of white Australians, and that it has an interactive effect with life-time smoking dose to increase the severity of CAD. Smokers who are also GG homozygotes have additionally elevated CAD risk.