Association between high homocyst(e)ine and ischemic stroke due to large- and small-artery disease but not other etiologic subtypes of ischemic stroke

Background and Purpose-Elevated plasma homocyst(e)ine may be a causal and m odifiable risk factor for ischemic stroke, but the results of previous stud ies have been conflicting. One possible explanation is that homocyst(e)ine may only be associated with certain pathophysiological subtypes of ischemic stroke. Methods-We conducted a case-control study of 219 hospital cases with a firs t-ever ischemic stroke and 205 randomly selected community control subjects stratified by age, sex, and postal code. With the use of established crite ria, cases of stroke were classified by etiologic subtype in a blinded fash ion. The prevalence of conventional vascular risk factors, fasting plasma h omocyst(e)ine levels, vitamin levels, and nucleotide 677 methylene tetrahyd rofolate reductase (MTHFR) genotypes were determined in cases and controls. Results-Increasing homocyst(e)ine was a strong and independent risk factor for ischemic stroke (adjusted OR 2.7, 95% CI 1.4 to 5.1 for a 5-mu mol/L in crease in fasting plasma homocyst(e)ine from 10 to 15 mu mol/L). Compared w ith the lowest quartile, the highest quartile of homocyst(e)ine was associa ted with an adjusted OR of ischemic stroke of 2.2 (95% CI 1.1 to 4.2), Mean plasma homocyst(e)ine was significantly higher in cases of ischemic stroke due to large-artery disease (14.1 mu mol/L, 95% CI 12.5 to 15.9, P<0.001) and small-artery disease (12.7 mu mol/L, 95% CI 11.4 to 14.1, P=0.004) comp ared with control subjects (10.5 mu mol/L; 95% CI 10.0 to 11.0) but not in cardioembolic or other etiologic subtypes of ischemic stroke. Compared with the lowest quartile of homocyst(e)ine, the upper 3 quartiles were associat ed with an adjusted OR of ischemic stroke due to large-artery disease of 3. 0 (95% CI 0.8 to 10.8) for the second quartile, 5.6 (95% CI 1.6 to 20) for the third quartile, and 8.7 (95% CI 2.4 to 32) for the fourth quartile (P f or trend=0.0005). However, despite a clear association between the TT MTHFR genotype and elevated fasting plasma homocyst(e)ine. there was no associat ion between MTHFR genotype and ischemic stroke or subtype of ischemic strok e. Conclusions-There is a strong, graded association between increasing plasma homocyst(e)ine and ischemic stroke caused by large-artery atherosclerosis and, to a much lesser extent, small-artery disease, but not cardioembolic o r other etiologic subtypes of ischemic stroke. Our results are consistent w ith the hypothesis that the deleterious effect of high homocyst(e)ine is me diated primarily via a proatherogenic effect.