Published Online
on March 6, 2008

A more recent version of this article appeared on April 1, 2008

This Article Full Text (PDF) All Versions of this Article: 39/4/1109    most recent STROKEAHA.107.491969v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bevan, S. Articles by Markus, H. S. Search for Related Content PubMed PubMed Citation Articles by Bevan, S. Articles by Markus, H. S. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Medline Plus Health Information Stroke Related Collections Embolic stroke Genetics of Stroke Genetics of cardiovascular disease Related Article

Submitted on April 23, 2007
Revised on July 30, 2007
Accepted on August 16, 2007

Genetic Variation in Members of the Leukotriene Biosynthesis Pathway Confer an Increased Risk of Ischemic Stroke. A Replication Study in Two Independent Populations

Steve Bevan BSc, PhD^*; Martin Dichgans MD; H. Erich Wiechmann PhD; Andreas Gschwendtner MD; Thomas Meitinger PhD; and Hugh S. Markus DM, FRCP

From Centre for Clinical Neuroscience (S.B., H.S.M.), St. Georges, University of London, UK; Neurologische Klinik (M.D., A.G.), Ludwig-Maximilians-University, Munich, Germany; Institute of Human Genetics (H.E.W., T.M.), GSF—National Research Institute for Environment and Health, Neuherberg, Germany.

^* To whom correspondence should be addressed. E-mail: sbevan{at}sgul.ac.uk.

Background and Purpose—The recent finding that genetic variants in 5-lipoxygenase activating protein and leukotriene A4 hydrolase may confer an increased risk of ischemic stroke has implicated the leukotriene family as potential mediators of cardiovascular disease. Using a case control replication methodology, all members of the leukotriene synthesis pathway and their receptors were examined for genetic variants, which may act as risk factors for all ischemic stroke and stroke subtypes.

Methods—A case control methodology using a UK stroke cohort (872 cases, 933 controls) was adopted, with additional 5-lipoxygenase activating protein genotyping and replication of positive findings undertaken in an independent stroke population from Germany (601 cases, 736 controls).

Results—Association was identified with variants in 5-lipoxygenase activating protein, leukotriene C4 synthase (leukotriene A4 hydrolase),and the leukotriene B4 receptor complex. Differing risks were identified for ischemic stroke subtypes. A variant in leukotriene C4 synthase was found to confer a 1.5-fold increase in risk of small vessel disease (RR, 1.515; 1.041 to 2.262; P=0.043) with replication in an independent cohort showing a similar risk (RR, 1.687; 1.065 to 2.675; P=0.026). A haplotype in the leukotriene B4 receptor complex was found to confer a 2.3-fold increase in risk of cardioembolic stroke (RR, 2.118; 1.194 to 3.760; P=0.01) and replication in a German cohort revealed a similar risk with a second distinct haplotype (RR, 2.060; 1.162 to 3.665; P=0.013).

Conclusions—Genetic variation in leukotriene pathway members and their receptors confer an increased risk of ischemic stroke in 2 independent populations. These risks show different magnitudes depending on ischemic stroke subtype.

Key words: genetics • inflammation • stroke

Related Article:

Where Do We Go for Atherothrombotic Disease Genetics?

Stefan-Martin Brand-Herrmann
Stroke 2008 39: 1070-1075. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				L. Folkersen, D. Diez, C. E. Wheelock, J. Z. Haeggstrom, S. Goto, P. Eriksson, and A. Gabrielsen GeneRegionScan: a Bioconductor package for probe-level analysis of specific, small regions of the genome Bioinformatics, August 1, 2009; 25(15): 1978 - 1979. [Abstract] [Full Text] [PDF]

				M. Dichgans and R. A. Hegele Update on the Genetics of Stroke and Cerebrovascular Disease 2008 Stroke, May 1, 2009; 40(5): e289 - e291. [Full Text] [PDF]

				S. Debette and S. Seshadri Genetics of Atherothrombotic and Lacunar Stroke Circ Cardiovasc Genet, April 1, 2009; 2(2): 191 - 198. [Full Text] [PDF]

				E. Zintzaras, P. Rodopoulou, and N. Sakellaridis Variants of the Arachidonate 5-Lipoxygenase-Activating Protein (ALOX5AP) Gene and Risk of Stroke: A HuGE Gene-Disease Association Review and Meta-Analysis Am. J. Epidemiol., March 1, 2009; 169(5): 523 - 532. [Abstract] [Full Text] [PDF]

				S. Bevan, M. W Lorenz, M. Sitzer, and H. S. Markus Genetic Variation in the Leukotriene Pathway and Carotid Intima-Media Thickness: A 2-Stage Replication Study Stroke, March 1, 2009; 40(3): 696 - 701. [Abstract] [Full Text] [PDF]

				G. Riccioni, V. Capra, N. D'Orazio, T. Bucciarelli, and L. A. Bazzano Leukotriene modifiers in the treatment of cardiovascular diseases J. Leukoc. Biol., December 1, 2008; 84(6): 1374 - 1378. [Abstract] [Full Text] [PDF]

				S.-M. Brand-Herrmann Where Do We Go for Atherothrombotic Disease Genetics? Stroke, April 1, 2008; 39(4): 1070 - 1075. [Full Text] [PDF]