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Interleukin-18 promoter polymorphism associates with the occurrence of sudden cardiac death among Caucasian males: The Helsinki Sudden Death Study

      Abstract

      Objective

      The increased plasma concentrations of pro-atherogenic and cardiomyocyte hypertrophic cytokine interleukin 18 (IL-18) predict mortality in patients with coronary heart disease (CHD) in addition to predicting the outcome of heart failure. The IL-18 gene has a functional −137 G/C polymorphism (rs187238) in the promoter region. The C allele carriage is associated with attenuated IL-18 production. The effect of IL-18 genotype on SCD is unknown. We studied the association of the IL-18 gene −137 G/C polymorphism with the occurrence of sudden cardiac death (SCD).

      Methods

      Using the TaqMan 5′ nuclease assay, we genotyped two independent consecutive and prospective autopsy series which were included in the Helsinki Sudden Death Study.

      Results

      Of the 663 men, 359 (54.1%) had the wild-type GG-genotype, 261 (39.4%) were heterozygotes (CG) and 43 (6.5%) were CC homozygotes. Compared to the GG homozygotes, the C allele carriers (i.e. subjects having CC or CG genotypes) had a lower adjusted risk for SCD from any cause (odds ratio [OR] 0.49; 95% confidence interval [CI], 0.31–0.77, p = 0.002), for SCD due to CHD (OR 0.51; 95% CI, 0.32–0.82, p = 0.005), and for SCD caused by non-coronary heart diseases (OR 0.34; 95% CI 0.13–0.90, p = 0.030).

      Conclusion

      IL-18 promoter −137 G/C polymorphism, which regulates the expression of IL-18, is an important predictor of SCD from any cause as well as SCD in patients with and without underlying CHD.

      Keywords

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      References

        • Rubart M.
        • Zipes D.P.
        Mechanisms of sudden cardiac death.
        J Clin Invest. 2005; 115: 2305-2315
        • Sexton P.T.
        • Walsh J.
        • Jamrozik K.
        • Parsons R.
        Risk factors for sudden unexpected cardiac death in Tasmanian men.
        Aust N Z J Med. 1997; 27: 45-50
        • Jouven X.
        • Desnos M.
        • Guerot C.
        • Ducimetiere P.
        Predicting sudden death in the population: the Paris Prospective Study I.
        Circulation. 1999; 99: 1978-1983
        • Mikkelsson J.
        • Perola M.
        • Laippala P.
        • Penttilä A.
        • Karhunen P.J.
        Glycoprotein IIIa Pl(A1/A2) polymorphism and sudden cardiac death.
        J Am Coll Cardiol. 2000; 36: 1317-1323
        • Mikkelsson J.
        • Perola M.
        • Penttilä A.
        • Karhunen P.J.
        Platelet glycoprotein Ibalpha HPA-2 Met/VNTR B haplotype as a genetic predictor of myocardial infarction and sudden cardiac death.
        Circulation. 2001; 104: 876-880
        • Snapir A.
        • Mikkelsson J.
        • Perola M.
        • Penttilä A.
        • Scheinin M.
        • Karhunen P.J.
        Variation in the alpha2B-adrenoceptor gene as a risk factor for prehospital fatal myocardial infarction and sudden cardiac death.
        J Am Coll Cardiol. 2003; 41: 190-194
        • Nakamura K.
        • Okamura H.
        • Wada M.
        • Nagata K.
        • Tamura T.
        Endotoxin-induced serum factor that stimulates gamma interferon production.
        Infect Immun. 1989; 57: 590-595
        • Espinola-Klein C.
        • Rupprecht H.J.
        • Bickel C.
        • et al.
        Inflammation, atherosclerotic burden and cardiovascular prognosis.
        Atherosclerosis. 2007; 1: 1
        • Mallat Z.
        • Henry P.
        • Fressonnet R.
        • et al.
        Increased plasma concentrations of interleukin-18 in acute coronary syndromes.
        Heart. 2002; 88: 467-469
        • Blankenberg S.
        • Tiret L.
        • Bickel C.
        • et al.
        Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina.
        Circulation. 2002; 106: 24-30
        • Rosso R.
        • Roth A.
        • Herz I.
        • Miller H.
        • Keren G.
        • George J.
        Serum levels of interleukin-18 in patients with stable and unstable angina pectoris.
        Int J Cardiol. 2005; 98: 45-48
        • Tiret L.
        • Godefroy T.
        • Lubos E.
        • et al.
        Genetic analysis of the interleukin-18 system highlights the role of the interleukin-18 gene in cardiovascular disease.
        Circulation. 2005; 112 (Epub July 25, 2005): 643-650
        • Hulthe J.
        • McPheat W.
        • Samnegard A.
        • Tornvall P.
        • Hamsten A.
        • Eriksson P.
        Plasma interleukin (IL)-18 concentrations is elevated in patients with previous myocardial infarction and related to severity of coronary atherosclerosis independently of C-reactive protein and IL-6.
        Atherosclerosis. 2006; 4: 4
        • Koenig W.
        • Khuseyinova N.
        • Baumert J.
        • et al.
        Increased concentrations of C-reactive protein and IL-6 but not IL-18 are independently associated with incident coronary events in middle-aged men and women: results from the MONICA/KORA Augsburg case-cohort study 1984–2002.
        Arterioscler Thromb Vasc Biol. 2006; 26 (Epub 2006 Sep 28): 2745-2751
        • Okamura H.
        • Tsutsui H.
        • Kashiwamura S.
        • Yoshimoto T.
        • Nakanishi K.
        Interleukin-18: a novel cytokine that augments both innate and acquired immunity.
        Adv Immunol. 1998; 70: 281-312
        • McInnes I.B.
        • Gracie J.A.
        • Leung B.P.
        • Wei X.Q.
        • Liew F.Y.
        Interleukin 18: a pleiotropic participant in chronic inflammation.
        Immunol Today. 2000; 21: 312-315
        • Dinarello C.A.
        Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process.
        Am J Clin Nutr. 2006; 83: 447S-455S
        • Mallat Z.
        • Corbaz A.
        • Scoazec A.
        • et al.
        Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability.
        Circulation. 2001; 104: 1598-1603
        • Naito Y.
        • Tsujino T.
        • Fujioka Y.
        • Ohyanagi M.
        • Okamura H.
        • Iwasaki T.
        Increased circulating interleukin-18 in patients with congestive heart failure.
        Heart. 2002; 88: 296-297
        • Seta Y.
        • Kanda T.
        • Tanaka T.
        • et al.
        Interleukin-18 in patients with congestive heart failure: induction of atrial natriuretic peptide gene expression.
        Res Commun Mol Pathol Pharmacol. 2000; 108: 87-95
        • Mallat Z.
        • Heymes C.
        • Corbaz A.
        • et al.
        Evidence for altered interleukin 18 (IL)-18 pathway in human heart failure.
        FASEB J. 2004; 18 (Epub 2004 Sep 15): 1752-1754
        • Liang X.H.
        • Cheung W.
        • Heng C.K.
        • Wang de Y.
        Reduced transcriptional activity in individuals with IL-18 gene variants detected from functional but not association study.
        Biochem Biophys Res Commun. 2005; 338 (Epub October 13, 2005): 736-741
        • Arimitsu J.
        • Hirano T.
        • Higa S.
        • et al.
        IL-18 gene polymorphisms affect IL-18 production capability by monocytes.
        Biochem Biophys Res Commun. 2006; 342 (Epub 2006 Feb 28): 1413-1416
        • Giedraitis V.
        • He B.
        • Huang W.X.
        • Hillert J.
        Cloning and mutation analysis of the human IL-18 promoter: a possible role of polymorphisms in expression regulation.
        J Neuroimmunol. 2001; 112: 146-152
        • Marenberg M.E.
        • Risch N.
        • Berkman L.F.
        • Floderus B.
        • de Faire U.
        Genetic susceptibility to death from coronary heart disease in a study of twins.
        N Engl J Med. 1994; 330: 1041-1046
        • Ilveskoski E.
        • Perola M.
        • Lehtimäki T.
        • et al.
        Age-dependent association of apolipoprotein E genotype with coronary and aortic atherosclerosis in middle-aged men: an autopsy study.
        Circulation. 1999; 100: 608-613
        • Isola J.
        • DeVries S.
        • Chu L.
        • Ghazvini S.
        • Waldman F.
        Analysis of changes in DNA sequence copy number by comparative genomic hybridization in archival paraffin-embedded tumor samples.
        Am J Pathol. 1994; 145: 1301-1308
        • Livak K.J.
        Allelic discrimination using fluorogenic probes and the 5’ nuclease assay.
        Genet Anal. 1999; 14: 143-149
        • Mikkelsson J.
        • Perola M.
        • Penttilä A.
        • Goldschmidt-Clermont P.J.
        • Karhunen P.J.
        The GPIIIa (beta3 integrin) PlA polymorphism in the early development of coronary atherosclerosis.
        Atherosclerosis. 2001; 154: 721-727
        • Blankenberg S.
        • Luc G.
        • Ducimetiere P.
        • et al.
        Interleukin-18 and the risk of coronary heart disease in European men: the Prospective Epidemiological Study of Myocardial Infarction (PRIME).
        Circulation. 2003; 108 (Epub October 27, 2003): 2453-2459
        • Okamura H.
        • Tsutsi H.
        • Komatsu T.
        • et al.
        Cloning of a new cytokine that induces IFN-gamma production by T cells.
        Nature. 1995; 378: 88-91
        • Gerdes N.
        • Sukhova G.K.
        • Libby P.
        • Reynolds R.S.
        • Young J.L.
        • Schonbeck U.
        Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis.
        J Exp Med. 2002; 195: 245-257
        • Falk E.
        Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion.
        Circulation. 1985; 71: 699-708
        • Fuster V.
        • Badimon L.
        • Badimon J.J.
        • Chesebro J.H.
        The pathogenesis of coronary artery disease and the acute coronary syndromes (1).
        N Engl J Med. 1992; 326: 242-250
        • Fuster V.
        Elucidation of the role of plaque instability and rupture in acute coronary events.
        Am J Cardiol. 1995; 76: 24C-33C
        • Chandrasekar B.
        • Mummidi S.
        • Claycomb W.C.
        • Mestril R.
        • Nemer M.
        Interleukin-18 is a pro-hypertrophic cytokine that acts through a phosphatidylinositol 3-kinase-phosphoinositide-dependent kinase-1-Akt-GATA4 signaling pathway in cardiomyocytes.
        J Biol Chem. 2005; 280 (Epub December 1, 2004): 4553-4567
        • Jeremias I.
        • Kupatt C.
        • Martin-Villalba A.
        • et al.
        Involvement of CD95/Apo1/Fas in cell death after myocardial ischemia.
        Circulation. 2000; 102: 915-920
        • Felzen B.
        • Shilkrut M.
        • Less H.
        • et al.
        Fas (CD95/Apo-1)-mediated damage to ventricular myocytes induced by cytotoxic T lymphocytes from perforin-deficient mice: a major role for inositol 1,4,5-trisphosphate.
        Circ Res. 1998; 82: 438-450