Nature Genetics 38, 68 - 74 (2006)
Published online: 10 November 2005; | doi:10.1038/ng1692
A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarctionAnna Helgadottir1, Andrei Manolescu1, Agnar Helgason1, Gudmar Thorleifsson1, Unnur Thorsteinsdottir1, Daniel F Gudbjartsson1, Solveig Gretarsdottir1, Kristinn P Magnusson1, Gudmundur Gudmundsson1, Andrew Hicks1, Thorlakur Jonsson1, Struan F A Grant1, Jesus Sainz1, Stephen J O'Brien2, Sigurlaug Sveinbjornsdottir3, Einar M Valdimarsson3, Stefan E Matthiasson3, Allan I Levey4, Jerome L Abramson4, Murdach P Reilly5, Viola Vaccarino4, Megan L Wolfe5, Vilmundur Gudnason6, Arshed A Quyyumi4, Eric J Topol7, Daniel J Rader5, Gudmundur Thorgeirsson3, Jeffrey R Gulcher1, Hakon Hakonarson1, Augustine Kong1
& Kari Stefansson11
deCODE Genetics, Inc., Sturlugata 8, IS-101 Reykjavik, Iceland. 2
Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland 21702, USA. 3
National University Hospital, Reykjavik, Iceland. 4
Emory University School of Medicine, Atlanta, Georgia, USA. 5
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. 6
Icelandic Heart Association, Holtasmári 1, 201 Kópavogur, Reykjavik, Iceland. 7
Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
Correspondence should be addressed to Kari Stefansson kstefans@decode.is Variants of the gene ALOX5AP (also known as FLAP) encoding arachidonate 5-lipoxygenase activating protein are known to be associated with risk of myocardial infarction1. Here we show that a haplotype (HapK) spanning the LTA4H gene encoding leukotriene A4 hydrolase, a protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggest that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also show that HapK confers a modest relative risk (1.16) in European Americans, but it confers a threefold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Our analyses indicate that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group.
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