Antibodies to N-homocysteinylated albumin as a marker for earlyonset coronary artery disease in men

Summary

N-homocysteinylated (Nε-Hcy) proteins and corresponding antibodies have recently been discovered in humans and animals. Increased autoimmune response to Nε -Hcy-proteins has been reported in stroke patients. The aim of the present study was to investigate whether antibodies against N-homocysteinylated albumin are associated with coronary artery disease (CAD).We studied 88 male patients aged 50 years or under with angiographically documented CAD and 100 age-matched apparently healthy men as controls. Serum levels of IgG antibodies against Nε-Hcy-albumin were determined using an enzymelinked immunosorbent assay. Seropositivity to anti-Nε -Hcy-albumin antibodies was 5-fold more frequent in CAD patients than in controls (52.3 % vs 10.0 %; p<0.0001). Plasma Hcy levels in CAD patients were also significantly higher in the former than in the latter group (medians, 13.0 μ M vs 12.1 μ M; p=0.026). Importantly, 41.2% of subjects with plasma total Hcy >14.5 mM were seropositive compared with 25.5 % of normohomocysteinemic individuals (p=0.048).There was a weak correlation between anti-Nε-Hcy-albumin antibodies and Hcy levels (r=0.16; p=0.03). By multivariate logistic regression analysis, seropositivity to anti-Nε-Hcy-albumin antibodies was an independent predictor of early CAD (OR, 14.82; 95% CI, 4.47 to 49.19; p=0.00002). Interestingly, anti-Nε-Hcy-albumin antibodies were associated with C-reactive protein levels (r=0.24; p=0.002). Seropositivity to anti-Nε-Hcy-albumin antibodies showed no association with the MTHFR C677T polymorphism. Our results suggest that seropositivity to antibodies against Nε-homocysteinylated albumin is associated with early-onset CAD. An autoimmune response to Nε-Hcy-albumin may represent a novel mechanism involved in the early development of CAD.

Keywords

Antibodies - homocysteine - coronary artery disease

• References

• 1 Genest JJ, McNamara JR, Salem DN. et al Plasma homocysteine levels in men with premature coronary artery disease.. J Am Coll Cardiol 1990; 16: 1114-9.
• 2 Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis.. J Am Coll Cardiol 1996; 27: 517-27.
• 3 Boers GH. Hyperhomocysteinemia as a risk factor for arterial and venous disease. A review of evidence and relevance.. Thromb Haemost 1997; 78: 520-2.
• 4 Cattaneo M. Hyperhomocysteinemia, atherosclerosis and thrombosis.. Thromb Haemost 1999; 81: 165-76.
• 5 Klerk M, Verhoef P, Clarke R. et al MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis.. JAMA 2002; 288: 2023-31.
• 6 Homocysteine Studies Collaboration Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis JAMA. 2002; 288: 2015-22.
• 7 Jakubowski H.. Molecular basis of homocysteine toxicity in humans Cell Mol Life Sci. 2004; 61: 470-87.
• 8 Hankey GJ, Eikelboom JW. Homocysteine and vascular disease.. Lancet 1999; 354: 407-13.
• 9 Poddar R, Sivasubramanian N, DiBello PM. et al Homocysteine induces expression and secretion of monocyte chemoattractant ptotein-1 and interleukin-8 in human aortic endothelial cells.. Circulation 2002; 103: 2717-23.
• 10 Welch GN, Loscalzo J. Homocysteine and atherothrombosis.. N Engl J Med 1998; 338: 1042-50.
• 11 Domagala TB, Undas A, Libura M. et al Pathogenesis of vascular disease in hyperhomocysteinaemia.. J Cardiovasc Risk 1998; 5: 239-47.
• 12 Robinson K, Arheart K, Refsum H. et al Low circulating folate and vitamin B concentrations. Risk factors for stroke, peripheral vascular disease, and coronary artery disease.. Circulation 1998; 97: 437-43.
• 13 Chambers JC, Kooner JS. Homocysteine – an innocent bystander in vascular disease?. Eur Heart J 2001; 22: 717-9.
• 14 Morris MS. Homocysteine and Alzheimer’s disease.. Lancet Neurol 2003; 2: 425-8.
• 15 Jakubowski H. The determination of homocysteine- thiolactone in biological samples.. Analyt Biochem 2002; 308: 112-9.
• 16 Jakubowski H, Zhang L, Bardeguez A. et al Homocysteine thiolactone and protein homocysteinylation in human endothelial cells: implications for atherosclerosis.. Circ Res 2000; 87: 45-51.
• 17 Jakubowski H. Protein homocysteinylation: Possible mechanism underlying pathological consequences of elevated homocysteine levels.. FASEB J 1999; 13: 2277-83.
• 18 Glowacki R, Jakubowski H. Cross-talk between Cys-34 and lysine residues in human serum albumin revealed by N-homocysteinylation.. J Biol Chem 2004; 279: 10864-71.
• 19 Jakubowski H. Homocysteine thiolactone: Metabolic origin and protein homocysteinylation in the human.. J Nutr 2000; 130 (Suppl) 377-81.
• 20 Jakubowski H. Homocysteine is a protein amino acid in humans: Implications for homocysteine-linked disease.. J Biol Chem 2002; 277: 30425-8.
• 21 Uji Y, Motomiya Y, Hanyu N. et al Protein-bound homocystamide measured in human plasma by HPLC.. Clin Chem 2002; 48: 941-4.
• 22 Ferguson E, Parthasarathy S, Joseph J. et al Generation and initial characterization of a novel polyclonal antibody directed against homocysteine thiolactonemodified low density lipoprotein.. J Lipid Res 1998; 39: 925-33.
• 23 Undas A, Perla J, Lacinski M. et al Autoantibodies against N -homocysteinylated proteins in humans: implications for atherosclerosis.. Stroke 2004; 35: 1295-304.
• 24 Mansoor MA, Svardal AM, Ueland PM. Determination of the in vivo redox status of cysteine, cysteinylglycine, homocysteine and glutathione in human plasma.. Analyt Biochem 1991; 200: 218-29.
• 25 Szczeklik A, Sanak M, Jankowski M. et al Mutation A1298C of methylenetetrahydrofolate reductase: risk for early coronary disease not associated with hyperhomocysteinemia.. Am J Med Genet 2001; 101: 36-9.
• 26 Frosst P, Blom HJ, Milos R. et al A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111-3.
• 27 Hansson GK. Immune mechanisms in atherosclerosis.. Arterioscler Thromb Vasc Biol 2001; 21: 1876-90.
• 28 Binder CJ, Chang MK, Shaw PX. et al Innate and acquired immunity in atherosclerosis.. Nat Med 2002; 8: 1218-26.
• 29 Jakubowski H, Ambrosius W, Pratt JH. Genetic determinants of homocysteine thiolactonase activity in humans: implications for atherosclerosis.. FEBS Lett 2001; 491: 35-9.
• 30 Widner B, Leblhuber F, Frick B. et al D. Moderate hyperhomocysteinemia and immune activation in Parkinson’s disease.. J Neurol Transm 2002; 109: 1445-52.
• 31 Schroecksnadel K, Frick B, Winkler C. et al Hyperhomocysteinemia and immune activation.. Clin Chem Lab Med 2003; 41: 1438-43.
• 32 Ansar Ahmed S, Talal N. Effect of sex hormones on immune reponses and autoimmune diseases: an update. In: A decade of autoimmunity.. Elsevier 1998; 325-9.