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Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

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In This Section
Volume 49, Issue 9 (Sep 2011)


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

Johan Hultdin
  • Clinical Chemistry, Department of Medical Biosciences, Umeå University, Umeå, Sweden
/ Bethany Van Guelpen
  • Pathology, Department of Medical Biosciences, Umeå University, Umeå, Sweden
/ Anna Winkvist
  • Department of Clinical Nutrition, Göteborg University, Gothenburg, Sweden
/ Göran Hallmans
  • Nutrition Research, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
/ Lars Weinehall
  • Epidemiology, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
/ Birgitta Stegmayr
  • Medicine, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
/ Torbjörn K. Nilsson
  • Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden
  • Email:
Published Online: 2011-06-15 | DOI: https://doi.org/10.1515/CCLM.2011.234


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 [OR for the highest vs. lowest tHcy quartile 8.13 (95% CI 1.83–36.1), ptrend=0.002; OR for MTHFR 677TT vs. 677CC genotype 3.62 (95% CI 0.77–17.0), ptrend=0.040]. Haplotype analyses confirmed that the MTHFR 677T–1298A haplotype was positively associated with hemorrhagic stroke [OR 1.81 (95% CI 1.09–3.00), p=0.022], 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.

Keywords: cerebral hemorrhage; homocysteine; MTHFR; risk factors; stroke

About the article

Corresponding author: Torbjörn K. Nilsson, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden Phone: +46-19-602-1733, Fax: +46-19-602-3785

Received: 2010-12-20

Accepted: 2011-04-19

Published Online: 2011-06-15

Published in Print: 2011-09-01

Citation Information: Clinical Chemistry and Laboratory Medicine, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/CCLM.2011.234. Export Citation

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