Interaction of homocysteine and conventional predisposing factors on risk of ischaemic stroke in young people: consistency in phenotype-disease analysis and genotype-disease analysis

Background and objectives: Whether the association between mild hyperhomocysteinaemia and ischaemic stroke is the consequence of a predisposing genetic background or is due to the confounding influence of established predisposing factors remains to be determined. Methods: Plasma total homocysteine (tHcy) concentration and the distribution of the C677T genotypes of the methylenetetrahydrofolate reductase gene (MTHFR) were compared in 174 consecutive patients with stroke aged < 45 years and 155 age and sex-matched controls. The effect of conventional risk factors on the relationship between phenotype-disease and genotype-disease was analysed by two-way and three-way interaction analysis and by the classification and regression trees (CART) model. Results: tHcy concentrations were markedly higher in patients with ischaemic stroke (median 11.9 mmol/l, range 2.0 - 94.0) than in controls (median 9.8 mmol/l, range 4.7 - 49.6). An increased risk was also associated with the TT677 genotype (odds ratio (OR) 1.98; 95% confidence interval (CI) 1.04 to 3.78) and with the T allele (1.40; 95% 1.03 to 1.92) of the MTHFR gene. A differential effect of Hcy levels on risk of stroke was observed according to the distribution of environmental-behavioural risk factors, with a stronger influence in the subcategory of people with hypertension and smokers (OR 24.8; 95% CI 3.15 to 196). A comparable environmental-dependent TT677 MTHFR genotype-stroke association was observed in the genotype-disease analysis. Conclusions: A consistency of phenotype- disease analysis and genotype-disease analysis is indicated by analysing specific subcategories of patients, defined by the distribution of established risk factors. The assumption that the Hcy - stroke relationship is unlikely due to a reverse-causality bias is indirectly supported by our data.