Interaction of homocysteine and conventional predisposing factors on risk of ischaemic stroke in young people: consistency in phenotype-disease analysis and genotype-disease analysis.
OBJECTIVE
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 micromol/l, range 2.0-94.0) than in controls (median 9.8 micromol/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.
Pezzini
A
A
Clinica Neurologica, Università degli Studi di Brescia, Ple Spedali Civili, 1, 25100 Brescia, Italy. ale_pezzini@hotmail.com
Grassi
M
M
Del Zotto
E
E
Assanelli
D
D
Archetti
S
S
Negrini
R
R
Caimi
L
L
Padovani
A
A
D000293:Adolescent; D000328:Adult; D002545:Brain Ischemia / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D015984:Causality; D004777:Environment; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006711:Homocystine; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D012042:Registries / Q000706:statistics & numerical data; D012044:Regression Analysis; D012307:Risk Factors; D020521:Stroke / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology
D006711:Homocystine; D042965:Methylenetetrahydrofolate Reductase (NADPH2)