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Prospective study of first stroke in relation to plasma homocysteine and MTHFR 677C>T and 1298A>C genotypes and haplotypes - evidence for an association with hemorrhagic stroke.

Journal article
Authors Hultdin Johan
Bethany Van Guelpen
Anna Winkvist
Göran Hallmans
Lars Weinehall
Birgitta Stegmayr
Torbjörn Nilsson
Published in Clinical Chemistry and Laboratory Medicine
Volume 49
Issue 9
Pages 1555-1562
ISSN 1434-6621
Publication year 2011
Published at Institute of Medicine, Department of Clinical Nutrition
Pages 1555-1562
Language en
Keywords cerebral hemorrhage; homocysteine; MTHFR;risk factors; stroke.
Subject categories Clinical chemistry, Public health medicine research areas


Background: Abnormalities in homocysteine metabolism have been suggested as risk factors for stroke. The aim of this prospective study was to examine whether total plasma homocysteine concentration (tHcy) and its main genetic determinant, methylene tetrahydrofolate reductase (MTHFR) polymorphisms, were associated with first ischemic or hemorrhagic stroke. Methods: This was a nested case-referent study of 321 ischemic and 60 hemorrhagic stroke cases, defined by WHO MONICA criteria and each matched with two event-free referents for sex, age, cohort, recruitment date and geographical area. All subjects were from the population-based Northern Sweden Health and Disease Study cohorts. Odds ratios were determined by conditional logistic regression. Results: The mean follow-up time was 4.2 years. Both tHcy and MTHFR were independent predictors of hemorrhagic stroke in multivariate models including body mass index, hypertension and, for MTHFR, tHcy wOR for the highest vs. lowest tHcy quartile 8.13 (95% CI 1.83–36.1), ptrends0.002; OR for MTHFR 677TT vs. 677CC genotype 3.62 (95% CI 0.77–17.0), ptrends0.040x. Haplotype analyses confirmedthat the MTHFR 677T–1298A haplotype was positively associated with hemorrhagic stroke wOR 1.81 (95% CI 1.09–3.00), ps0.022x, whereas the MTHFR 677C–1298C haplotype was not significantly related to either hemorrhagic or ischemic stroke. Neither tHcy nor the MTHFR polymorphisms were significant predictors of ischemic stroke. Conclusion: Both elevated plasma homocysteine levels and the MTHFR 677T allele are indicators of increased risk of hemorrhagic stroke in the northern Swedish population.

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