Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening - The Perth carotid ultrasound disease assessment study (CUDAS)

Background-Hyperhomocysteinemia has been identified as a potential risk fac tor for atherosclerosis. This study examined whether a modest elevation of plasma total homocysteine (tHcy) was an independent risk factor for increas ed carotid artery intimal-medial wall thickness (IMT) and focal plaque form ation in a large, randomly selected community population. We also examined whether vitamin cofactors and the C677T genetic mutation of the methylenete trahydrofolate reductase (MTHFR) enzyme were major contributors to elevated plasma tHcy and carotid vascular disease. Methods and Results-In 1111 subjects (558 men, 553 women) 52+/-13 years old (mean+/-SD; range, 27 to 77 years) recruited from a random electoral roll survey, we measured fasting tHcy and performed bilateral carotid B-mode ult rasound. For the total population, mean tHcy was 12.1+/-4.0 mu mol/L. Plasm a tHcy levels were correlated with IMT (Spearman rank r(s)=0.31, P=0.0001). After adjustment for age, sex, and other conventional risk factors, subjec ts in the highest versus the lowest quartile of tHcy had an odds ratio of 2 .60 (95% CI, 1.51 to 4.45) for increased IMT and 1.76 (95% CI, 1.10 to 2.82 ) for plaque. Serum and dietary folate levels and the C677T mutation in MTH FR were independent determinants of tHcy (all P=0.0001). The mutant homozyg otes (10% of the population) had higher mean tHcy than heterozygotes or tho se without the mutation (14.2 versus 12.3 Versus 11.6 mu mol/L, respectivel y, P=0.0001), The inverse association of folate levels with tHcy was steepe r in the mutant homozygotes. Despite this, the C677T MTHFR mutation was not independently predictive of increased carotid IMT or plaque formation. Conclusions-Mild hyperhomocysteinemia is an independent risk factor for inc reased carotid artery wall thickness and plaque formation in a general popu lation. Lower levels of dietary folate intake and the C677T mutation in MTH FR are important causes of mild hyperhomocysteinemia and may therefore cont ribute to vascular disease in the community.