Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction

  • An Erratum to this article was published on 01 January 2003

Abstract

By means of a large-scale, case-control association study using 92,788 gene-based single-nucleotide polymorphism (SNP) markers, we identified a candidate locus on chromosome 6p21 associated with susceptibility to myocardial infarction. Subsequent linkage-disequilibrium (LD) mapping and analyses of haplotype structure showed significant associations between myocardial infarction and a single 50 kb halpotype comprised of five SNPs in LTA (encoding lymphotoxin-α), NFKBIL1 (encoding nuclear factor of κ light polypeptide gene enhancer in B cells, inhibitor-like 1) and BAT1 (encoding HLA-B associated transcript 1). Homozygosity with respect to each of the two SNPs in LTA was significantly associated with increased risk for myocardial infarction (odds ratio = 1.78, χ2 = 21.6, P = 0.00000033; 1,133 affected individuals versus 1,006 controls). In vitro functional analyses indicated that one SNP in the coding region of LTA, which changed an amino-acid residue from threonine to asparagine (Thr26Asn), effected a twofold increase in induction of several cell-adhesion molecules, including VCAM1, in vascular smooth-muscle cells of human coronary artery. Moreover, the SNP, in intron 1 of LTA, enhanced the transcriptional level of LTA. These results indicate that variants in the LTA are risk factors for myocardial infraction and implicate LTA in the pathogenesis of the disorder.

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Figure 1: Linkage disequilibrium and haplotype block in the genomic region including the LTA locus.
Figure 2: Transcriptional regulatory activity affected by SNPs.
Figure 3: Differing abilities of 26Asn-LTA and 26Thr-LTA to induce mRNA expression of adhesion molecules.

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References

  1. 1

    Ohnishi, Y. et al. A high-throughput SNP typing system for genome-wide association studies. J. Hum. Genet. 46, 471–477 (2001).

    CAS  Article  Google Scholar 

  2. 2

    Haga, H., Yamada, R., Ohnishi, Y., Nakamura, Y. & Tanaka, T. Gene-based SNP discovery as part of the Japanese Millennium Genome project: identification of 190,562 genetic variations in the human genome. J. Hum. Genet. 47, 605–610 (2002).

    CAS  Article  Google Scholar 

  3. 3

    Lander, E.S. The new genomics: global views of biology. Science 274, 536–539 (1996).

    CAS  Article  Google Scholar 

  4. 4

    Ross, R. Atherosclerosis—an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).

    CAS  Article  Google Scholar 

  5. 5

    Ware, C.F., VanArsdale, T.L., Crowe, P.D. & Browning, J.L. The ligands and receptors of the lymphotoxin system. Curr. Top. Microbiol. Immunol. 198, 175–218 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Vanhaesebroeck, B. et al. Two discrete types of tumor necrosis factor-resistant cells derived from the same cell line. Cancer Res. 51, 2469–2477 (1991).

    CAS  PubMed  Google Scholar 

  7. 7

    Libby, P. Molecular bases of the acute coronary syndrome. Circulation 21, 2844–2850 (1995).

    Article  Google Scholar 

  8. 8

    Davies, M.J. & Thomas, A.C. Plaque fissuring—the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br. Heart J. 53, 363–373 (1985).

    CAS  Article  Google Scholar 

  9. 9

    Ross, R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362, 801–809 (1993).

    CAS  Article  Google Scholar 

  10. 10

    van der Wal, A.C., Becker, A.E., van der Loos, C.M. & Das, P.K. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 89, 36–44 (1994).

    CAS  Article  Google Scholar 

  11. 11

    Jonasson, L., Holm, J., Skalli, O., Bondjers, G. & Hansson, G.K. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 6, 131–138 (1986).

    CAS  Article  Google Scholar 

  12. 12

    Kaartinen, M., Penttila, A. & Kovanen, P.T. Accumulation of activated mast cells in the shoulder region of human coronary atheroma, the predilection site of atheromatous rupture. Circulation 90, 1669–1678 (1994).

    CAS  Article  Google Scholar 

  13. 13

    Galis, Z.S. et al. Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion. Circ. Res. 75, 181–189 (1994).

    CAS  Article  Google Scholar 

  14. 14

    Kaartinen, M., Penttila, A. & Kovanen, P.T. Mast cells in rupture-prone areas of human coronary atheromas produce and store TNF-α. Circulation 94, 2787–2792 (1996).

    CAS  Article  Google Scholar 

  15. 15

    O'Brien, K.D., McDonald, T.O., Chait, A., Allen, M.D. & Alpers, C.E. Neovascular expression of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Circulation 93, 672–682 (1996).

    CAS  Article  Google Scholar 

  16. 16

    Hwang, S.J. et al. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study. Circulation 96, 4219–4225 (1997).

    CAS  Article  Google Scholar 

  17. 17

    Morisaki, N. et al. New indices of ischemic heart disease and aging: studies on the serum levels of soluble intercellular adhesion molecule-1 (ICAM-1) and soluble vascular cell adhesion molecule-1 (VCAM-1) in patients with hypercholesterolemia and ischemic heart disease. Atherosclerosis 131, 43–48 (1997).

    CAS  Article  Google Scholar 

  18. 18

    Squadrito, F. et al. Thrombolytic therapy with urokinase reduces increased circulating endothelial adhesion molecules in acute myocardial infarction. Inflamm. Res. 45, 14–19 (1996).

    CAS  Article  Google Scholar 

  19. 19

    Belch, J.J. et al. The white blood cell adhesion molecule E-selectin predicts restenosis in patients with intermittent claudication undergoing percutaneous transluminal angioplasty. Circulation 95, 2027–2031 (1997).

    CAS  Article  Google Scholar 

  20. 20

    Schreyer, S.A, Vick, C.M. & LeBoeuf, R.C. Loss of lymphotoxin-α but not tumor necrosis factor-α reduces atherosclerosis in mice. J. Biol. Chem. 277, 12364–12368 (2002).

    CAS  Article  Google Scholar 

  21. 21

    Breslow, J.L. Cardiovascular disease burden increases, NIH funding decreases. Nature Med. 3, 600–601 (1997).

    CAS  Article  Google Scholar 

  22. 22

    Braunwald, E. Shattuck lecture—cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities. N. Engl. J. Med. 337, 1360–1369 (1997).

    CAS  Article  Google Scholar 

  23. 23

    Iida, A. et al. Catalog of 258 single-nucleotide polymorphisms (SNPs) in genes encoding three organic anion transporters, three organic anion-transporting polypeptides, and three NADH:ubiquinone oxidoreductase flavoproteins. J. Hum. Genet. 46, 668–683 (2001).

    CAS  Article  Google Scholar 

  24. 24

    Excoffier, L. & Slatkin, M. Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol. Biol. Evol. 12, 921–927 (1995).

    CAS  Google Scholar 

  25. 25

    Daly, M.J., Rioux, J.D., Schaffner, S.F., Hudson, T.J. & Lander, E.S. High-resolution haplotype structure in the human genome. Nature Genet. 29, 229–232 (2001).

    CAS  Article  Google Scholar 

  26. 26

    Yamada, R. et al. Association between a single-nucleotide polymorphism in the promoter of the human interleukin-3 gene and rheumatoid arthritis in Japanese patients, and maximum-likelihood estimation of combinatorial effect that two genetic loci have on susceptibility to the disease. Am. J. Hum. Genet. 68, 674–685 (2001).

    CAS  Article  Google Scholar 

  27. 27

    Andrews, N.C. & Faller, D.V. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res. 11, 2499 (1991).

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Acknowledgements

We thank Y. Ariji, M. Yoshii, M. Omotezako, S. Abiko and K. Tabei for their assistance; H. Kawakami, A. Takahashi and M. Yamaguchi for their expertise in computer programming; M. Takahashi for her excellent technical expertise; and all the other members of SNP Research Center, The Institute of Physical and Chemical Research and Osaka Acute Coronary Insufficiency Study for their contribution to the completion of our study. This work was supported by a grant from the Japanese Millennium Project.

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Correspondence to Toshihiro Tanaka.

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Ozaki, K., Ohnishi, Y., Iida, A. et al. Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction. Nat Genet 32, 650–654 (2002). https://doi.org/10.1038/ng1047

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