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A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction

Nature Genetics volume 38, pages 68–74 (2006)Cite this article

Abstract

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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Figure 1: Structure of the LTA4H gene.

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Acknowledgements

We thank the participants who made this study possible; the nurses at the Icelandic Heart Association; personnel at the deCODE core facilities; A. Rosen, T. Kamineni, J. Pareira and the CRIN staff for recruiting subjects; J. Pritchard for discussion on the admixture analyses; and members of the International HapMap Consortium for providing data which were crucial for our analysis. This work was supported by grants from the US National Institutes of Health (NIH) and by the Emory Alzheimer's Disease Center. Research in Atlanta was supported by NIH grant U54 ES012068 and by Emory General Clinic Research Center grant MO1-RR00039. Research in Cleveland was supported by NIH grant P50 HL077107-01.

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Authors and Affiliations

  1. deCODE Genetics, Inc., Sturlugata 8, Reykjavik, IS-101, Iceland

    Anna Helgadottir, Andrei Manolescu, Agnar Helgason, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Daniel F Gudbjartsson, Solveig Gretarsdottir, Kristinn P Magnusson, Gudmundur Gudmundsson, Andrew Hicks, Thorlakur Jonsson, Struan F A Grant, Jesus Sainz, Jeffrey R Gulcher, Hakon Hakonarson, Augustine Kong & Kari Stefansson

  2. Laboratory of Genomic Diversity, National Cancer Institute, Frederick, 21702, Maryland, USA

    Stephen J O'Brien

  3. National University Hospital, Reykjavik, Iceland

    Sigurlaug Sveinbjornsdottir, Einar M Valdimarsson, Stefan E Matthiasson & Gudmundur Thorgeirsson

  4. Emory University School of Medicine, Atlanta, Georgia, USA

    Allan I Levey, Jerome L Abramson, Viola Vaccarino & Arshed A Quyyumi

  5. University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Murdach P Reilly, Megan L Wolfe & Daniel J Rader

  6. Icelandic Heart Association, Holtasmári 1, 201 Kópavogur, Reykjavik, Iceland

    Vilmundur Gudnason

  7. Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, 44195, Ohio, USA

    Eric J Topol

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Correspondence to Kari Stefansson.

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Competing interests

The following authors are employed by deCODE Genetics and own stock or stock options in the company: A. Helgadottir, A.M., A. Helgason, G.T., U.T., D.F.G., S.G., K.P.M., G.G., A.H., T.J., S.F.A.G., J.S., J.R.G., H.H., A.K. and K.S.

Supplementary information

Supplementary Fig. 1

Genealogical relationship between haplotypes in the LTA4H region. (PDF 812 kb)

Supplementary Fig. 2

Linkage disequilibrium between SNPs in the LTA4H gene region. (PDF 367 kb)

Supplementary Fig. 3

Haplotype risk comparison. (PDF 12 kb)

Supplementary Table 1

SNP allelic assocation to MI. (PDF 77 kb)

Supplementary Table 2

Frequency of haplotypes derived from HapK SNPs. (PDF 91 kb)

Supplementary Table 3

LTB4 levels after ionomycin stimulation of granulocytes. (PDF 57 kb)

Supplementary Table 4

Microsatellite markers used for the evaluation of the European and African ancestry. (PDF 63 kb)

Supplementary Table 5

Markers used to evaluate the local ancestry around LTA4H. (PDF 76 kb)

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Helgadottir, A., Manolescu, A., Helgason, A. et al. A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction. Nat Genet 38, 68–74 (2006). https://doi.org/10.1038/ng1692

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