Published Online
on February 3, 2005

A more recent version of this article appeared on March 1, 2005

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Submitted on August 30, 2004
Revised on October 20, 2004
Accepted on November 26, 2004

Cumulative Effect of Predisposing Genotypes and Their Interaction With Modifiable Factors on the Risk of Ischemic Stroke in Young Adults

Alessandro Pezzini MD^*; Mario Grassi PhD; Elisabetta Del Zotto MD; Silvana Archetti PhD; Raffaella Spezi MD; Veronica Vergani MD; Deodato Assanelli MD; Luigi Caimi MD; and Alessandro Padovani MD, PhD

From Clinica Neurologica (A.P., E.D.Z., R.S., V.V., A.P.), Università degli Studi di Brescia, Brescia, Italia; the Dipartimento di Scienze Sanitarie Applicate (M.G.), Sezione di Statistica Medica ed Epidemiologia, Università degli Studi di Pavia, Pavia, Italia; III Laboratorio di Analisi (S.A.), Biotecnologie, Università degli Studi di Brescia, Brescia, Italia; the Dipartimento di Scienze Mediche e Chirurgiche (D.A.), Università degli Studi di Brescia, Brescia, Italia; and the Dipartimento di Biochimica (L.C.), Università degli Studi di Brescia, Brescia, Italia.

^* To whom correspondence should be addressed. E-mail: ale_pezzini{at}hotmail.com.

Background and Purpose--Combinations of multiple predisposing polymorphisms and their interactions with modifiable factors may result in synergistic effects on the risk of ischemic stroke. These mechanisms are more likely to play a relevant role in younger individuals.

Methods--The cumulative effect of the 20210A variant of prothrombin gene, the 1691A variant of factor V gene, the TT677 genotype of the methylenetetrahydrofolate reductase (MTHFR) gene, and the 4-carriership of the apolipoprotein (APOE) gene, as well as their interactions with modifiable predisposing factors, were determined in a series of 163 stroke patients aged younger than 45 years and 158 controls.

Results--Odds ratios (ORs) for stroke were 1.73 (95% confidence interval [CI], 1.20 to 2.51) in subjects with 1 polymorphism and 3.00 (95% CI, 1.43 to 6.30) in those with 2. Compared with nonsmokers with none of the studied polymorphisms, ORs for stroke were 1.88 (95% CI, 1.18 to 3.00) and 3.55 (95% CI, 1.40 to 8.98) for nonsmokers with 1 and 2 polymorphisms, respectively, and 3.99 (95% CI, 2.00 to 7.96) and 15.99 (95% CI, 4.01 to 63.3) for smokers. Compared with nonhypertensive subjects bearing no polymorphisms, ORs were 1.91 (95% CI, 1.28 to 2.87) and 3.68 (95% CI, 1.64 to 8.26) for nonhypertensive subjects with 1 and 2 polymorphisms, 3.28 (95% CI, 1.01 to 10.7) and 10.79 (95% CI, 1.01 to 115.4) for hypertensive.

Conclusions--These data suggest a gene-dose effect of the examined prothrombotic and proatherogenic gene variants and a synergistic effect of these polymorphisms and modifiable risk factors in the pathogenesis of cerebral ischemia in young adults.

Key words: genetics • risk factors • stroke, ischemic

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