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

¹ Clinica Neurologica, Università degli Studi di Brescia, Brescia, Italy
² Dipartimento di Scienze Sanitarie Applicate, Sezione di Statistica Medica ed Epidemiologia, Università degli Studi di Pavia, Pavia, Italy
³ Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi di Brescia
⁴ III Laboratorio di Analisi, Biotecnologie, Università degli Studi di Brescia
⁵ Laboratorio di Microbiologia, Università degli Studi di Brescia
⁶ Dipartimento di Biochimica, Università degli Studi di Brescia

Correspondence to:
Correspondence to:
Alessandro Pezzini
Clinica Neurologica, Università degli Studi di Brescia, Ple Spedali Civili, 1, 25100 Brescia, Italy; ale_pezzini{at}hotmail.com

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 µmol/l, range 2.0–94.0) than in controls (median 9.8 µmol/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.

Abbreviations: CART, classification and regression trees; MTHFR, methylenetetrahydrofolate reductase gene; tHcy, total homocysteine

Relevant Article

MTHFR 677 TT genotype and hyperhomocysteinaemia: an underestimated risk TANDEM for patients with stroke

V Caso and M Paciaroni
J. Neurol. Neurosurg. Psychiatry 2006 77: 1103. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				V Caso and M Paciaroni MTHFR 677 TT genotype and hyperhomocysteinaemia: an underestimated risk TANDEM for patients with stroke J. Neurol. Neurosurg. Psychiatry, October 1, 2006; 77(10): 1103 - 1103. [Full Text] [PDF]