Association of TNF-α serum levels and TNFA promoter polymorphisms with risk of myocardial infarction


      Elevated levels of tumor necrosis factor-alpha (TNF-α), and presence of polymorphisms of the TNFA gene have been implicated in cardiovascular disease pathogenesis. We explored the relationship between polymorphisms in the TNFA gene (−1031C/T, −863C/A −857T/C, −308G/A, −238G/A), protein levels of TNF-α and their association to myocardial infarction (MI) using a sample of 1213 post-MI patients and 1561 healthy controls.
      MI risk was higher among men with elevated TNF-α levels, with the highest compared to the lowest TNF-α quartile giving a 70% risk increase (OR [95% CI]: 1.7 [1.1; 2.6]). Obese subjects who also had elevated TNF-α levels were at even higher risk for MI (OR [95% CI]: 3.4 [2.1; 5.6]). Higher TNF-α levels were seen among smokers (but not among non-smokers) carrying the −857T allele. Furthermore, a rare haplotype occurred more frequently among the cases than the controls.
      Elevated TNF-α levels are associated with increased MI risk. Obese subjects with elevated TNF-a levels, and carriers of polymorphisms in or near TNFA are particularly susceptible to the hazards of smoking, results which may have implications for cardiovascular preventive measures.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Hansson G.K.
        Immune mechanisms in atherosclerosis.
        Arterioscler Thromb Vasc Biol. 2001; 21: 1876-1890
        • Cesari M.
        • Penninx B.W.
        • Newman A.B.
        • et al.
        Inflammatory markers and onset of cardiovascular events: results from the Health ABC Study.
        Circulation. 2003; 108: 2317-2322
        • Ridker P.M.
        • Rifai N.
        • Pfeffer M.
        • et al.
        Elevation of tumour necrosis factor-α and increased risk of recurrent coronary events after myocardial infarction.
        Circulation. 2000; 101: 2149-2153
        • Skoog T.
        • Dichtl W.
        • Boquist S.
        • et al.
        Plasma tumour necrosis factor-α and early carotid atherosclerosis in healthy middle-aged men.
        Eur Heart J. 2002; 23: 376-383
        • Jovinge S.
        • Hamsten A.
        • Tornvall P.
        • et al.
        Evidence for a role of tumor necrosis factor α in disturbances of triglyceride and glucose metabolism predisposing to coronary heart disease.
        Metabolism. 1998; 47: 113-118
        • Reuterwall C.
        • Hallqvist J.
        • Ahlbom A.
        • et al.
        Higher relative but lower absolute risk of myocardial infarction in women than in men for some major risk factors in the SHEEP study.
        J Int Med. 1999; 246: 161-174
        • Haddy N.
        • Sass C.
        • Droesch S.
        • et al.
        IL-6, TNF-α and atherosclerosis risk indicators in a healthy family population: the Stanislas cohort.
        Atherosclerosis. 2003; 170: 277
        • Sethi J.K.
        • Hotamisligil G.S.
        The role of TNF-α in adipocyte metabolism.
        Semin Cell Dev Biol. 1999; 10: 19-29
        • Dandona P.
        • Weinstock R.
        • Thusu K.
        • et al.
        Tumour necrosis factor-α in sera of obese patients: fall with weight loss.
        J Clin Endocrinol Metab. 1998; 83: 2907-2910
        • Zinman B.
        • Hanley A.J.G.
        • Harris S.B.
        • Kwan J.
        • Fantus G.I.
        Circulating tumour necrosis factor-α concentrations in a Native Canadian population with high rates of type 2 diabetes mellitus.
        J Clin Endocrinol Metab. 1999; 84: 272-278
        • Skoog T.
        • van’t Hooft F.M.
        • Kallin B.
        • et al.
        A common functional polymorphism (C → A substitution at position −863) in the promoter region of the tumour necrosis factor-alpha (TNF-alpha) gene associated with reduced circulating levels of TNF-alpha.
        Hum Mol Genet. 1999; 8: 1443-1449
        • Koch W.
        • Kastrati A.
        • Böttiger C.
        • et al.
        Interleukin-10 and tumor necrosis factor gene polymorphisms and risk of coronary artery disease and myocardial infarction.
        Atherosclerosis. 2001; 159: 137-144
        • Keso T.
        • Perola M.
        • Laippala P.
        • et al.
        Polymorphisms within the tumor necrosis factor locus and prevalence of coronary artery disease in middle-aged men.
        Atherosclerosis. 2001; 154: 691-697
        • Herrmann S.M.
        • Ricard S.
        • Nicaud V.
        • et al.
        Polymorphisms of the tumour necrosis factor-α gene, coronary heart disease and obesity.
        Eur J Clin Invest. 1998; 28: 59-66
        • Prince J.A.
        • Feuk L.
        • Howell M.W.
        • et al.
        Robust and accurate single nucleotide polymorphism genotyping by dynamic allele-specific hybridization (DASH): design criteria and assay validation.
        Genet Res. 2001; 11: 152-162
        • Rothman K.J.
        Interaction between causes.
        Modern epidemiology. 1st ed. Little, Brown & Co., Boston1986 (pp. 311–326)
        • Lundberg M.
        • Fredlund P.
        • Hallqvist J.
        • Diderichsen F.
        A SAS program calculating three measures of interaction with confidence intervals.
        Epidemiology. 1996; 7: 655-656
        • Stephens M.
        • Donnelly P.
        A comparison of Bayesian methods for haplotype reconstruction from population genotype data.
        Am J Hum Genet. 2003; 73: 1162-1169
        • Stephens M.
        • Smith N.J.
        • Donnelly P.
        A new statistical method for haplotype reconstruction from population data.
        Am J Hum Genet. 2001; 68: 978-989
        • Branen L.
        • Hovgaard L.
        • Nitulescu M.
        • et al.
        Inhibition of tumor necrosis factor-alpha reduces atherosclerosis in apolipoprotein E knockout mice.
        Arterioscler Thromb Vasc Biol. 2004; 24: 2137-2142
        • Galis Z.S.
        • Muszynski M.
        • Sukhova G.K.
        • et al.
        Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion.
        Circ Res. 1994; 75: 181-189
        • Balbay Y.
        • Tikiz H.
        • Baptiste R.J.
        • et al.
        Circulating interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and soluble ICAM-1 in patients with chronic stable angina and myocardial infarction.
        Angiology. 2001; 52: 109-114
        • Tsiara S.
        • Elisaf M.
        • Mikhailidis D.
        Influence of smoking on predictors of vascular disease.
        Angiology. 2003; 54: 507-530
        • Grunfeld C.
        • Feingold K.R.
        The metabolic effects of tumor necrosis factor and other cytokines.
        Biotherapy. 1991; 3: 143-158
        • Tsigos C.
        • Kyrou I.
        • Chala E.
        • et al.
        Circulating tumor necrosis factor alpha concentrations are higher in abdominal versus peripheral obesity.
        Metabolism. 1999; 48: 1332-1335
        • Anto R.J.
        • Mukhopadhyay A.
        • Shishodia S.
        • Gairola G.C.
        • Aggarwal B.B.
        Cigarette smoke condensate activates nuclear transcription factor-κB through phosphorylation and degradation of IκBa: correlation with induction of cyclooxygenase-2.
        Carcinogenesis. 2002; 23: 1511-1518
        • van Heel D.A.
        • Udalova I.A.
        • de Silva A.P.
        • et al.
        Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF-κB transcription factors.
        Hum Mol Genet. 2002; 11: 1281-1289
        • Noguchi E.
        • Yokouchi Y.
        • Shibasaki M.
        • et al.
        Association between TNFA polymorphism and the development of asthma in the Japanese population.
        Am J Respir Crit Care Med. 2002; 166: 43-46
        • Ozaki K.
        • Ohnishi Y.
        • Iida A.
        • et al.
        Functional SNPs in the lymphotoxin-a gene that are associated with susceptibility to myocardial infarction.
        Nat Genet. 2002; 32: 650-654
        • Knight J.C.
        • Keating B.J.
        • Rockett K.A.
        • Kwiatowski D.P.
        In vivo characterization of regulatory polymorphisms be allele-specific quantification of RNA polymerase loading.
        Nat Genet. 2003; 33: 469-475
        • Hamsten A.
        • Wiman B.
        • de Faire U.
        • Blombäck M.
        Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction.
        N Engl J Med. 1985; 313: 1557-1563
        • Anon.
        Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin survival study (4S).
        Lancet. 1994; 344: 1383-1389