CD14 Promoter Polymorphism (− 159C→t) is Not Associated with Myocardial Infarction or Coronary Artery Disease in Patients with Assumed High Genetic Risk

Abstract

Objective: Inflammation plays a major role in the pathogenesis of coronary artery disease (CAD) and myocardial infarction (MI). CD14 is the receptor for bacterial lipopolysaccharide in monocytes and mediates the production of proinflammatory cytokines. The promoter of the CD14 gene has a polymorphic site in position − 159 (C→T) and T-homozygotes have been shown to express higher amounts of CD14 by some investigators. We and others have found an association of the T-allele with past MI in former studies, but reports in the literature are contradictory. Methods and Results: We investigated a study group with an assumed high genetic risk by selecting 200 patients suffering from angiographically verified CAD or MI who were younger than 50 years or who had only one or no risk factor (hypertension, smoking, elevated body mass index, impaired glucose tolerance or elevated cholesterol levels). We used 252 healthy subjects as controls. Additionally, the levels of soluble (s) CD14 in plasma and amount of membranous (m) CD14 on the surface of monocytes were determined in different genotypes. We found no association of either genotype with CAD, extent of CAD, or a history of MI. No significant correlation was found after adjustment for vascular risk factors. In addition, no significant differences in the density of monocyte mCD14 or in plasma levels of sCD14 were detectable among the various genotypes. Conclusions: The assumed weak association of the TT-genotype of the CD14 promoter polymorphism with MI could not be not established in a well-defined group of young patients with a high genetic risk. The association of the polymorphism with expression of sCD14 or mCD14 was not confirmed.

myocardial infarction - heart disease - CD14 gene

References

• 1 Unkelbach K, Gardemann A, Kostrzewa M, Philipp M, Tillmanns H, Haberbosch W. A new promoter polymorphism in the gene of lipopolysaccharide receptor CD14 is associated with expired myocardial infarction in patients with low atherosclerotic risk profile.  Arterioscler Thromb Vasc Biol. 1999;  19 932-938
• 2 Hubacek J A, Pit'ha J, Skodova Z, Stanek V, Poledne R. C(− 260)-T polymorphism in the promoter of the CD14 monocyte receptor gene as a risk factor for myocardial infarction.  Circulation. 1999;  99 3218-3220
• 3 Shimada K, Watanabe Y, Mokuno H, Iwama Y, Daida H, Yamaguchi H. Common polymorphism in the promoter of the CD14 monocyte receptor gene is associated with acute myocardial infarction in Japanese men.  Am J Cardiol. 2000;  86 682-684
• 4 Hohda S, Kimura A, Sasaoka T, Hayashi T, Ueda K, Yasunami M, Okabe M, Fukuta N, Kurosawa T, Izumi T. Association study of CD14 polymorphism with myocardial infarction in a Japanese population.  Jpn Heart J. 2003;  44 613-622
• 5 Liao W. Endotoxin: possible roles in initiation and development of atherosclerosis.  J Lab Clin Med. 1996;  128 452-460
• 6 Baldini M, Lohman I C, Halonen M, Erickson R P, Holt P G, Martinez F D. A polymorphism in the 5′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E.  Am J Respir Cell Mol Biol. 1999;  20 976-983
• 7 Gensini G G. Coronary arteriography. Braunwald E Heart disease. Philadelphia, Penn.; WB Saunders 1980: 352-353
• 8 Gensini G G. A more meaningful scoring system for determining the severity of coronary heart disease.  Am J Cardiol. 1983;  51 606
• 9 Rose G A. The diagnosis of ischaemic heart pain and intermittent claudication in field surveys.  Bull Wld Hlth Org. 1962;  27 645-658
• 10 Ross R. Atherosclerosis: an inflammatory disease.  N Engl J Med. 1999;  340 115-126
• 11 Heyden S, Bartel A G, Tabesh E, Cassel J C, Tyroler H A, Cornomi J C, Hames C G. Angina pectoris and the Rose questionnaire.  Arch Int Med. 1971;  128 961-964
• 12 Zee R Y L, Lindpainter K, Struk B, Hennekens C H, Ridker P M. A prospective evaluation of the CD14 C(− 260)T gene polymorphism and the risk of myocardial infarction.  Atherosclerosis. 2001;  154 699-702
• 13 Longobardo M T, Cefalu A B, Pezzino F, Noto D, Emmanuele G, Barbagallo C M, Fiore B, Monastero R, Castello A, Molini V, Notarbartolo A, Travali S, Averna M R. The C(− 260)>T gene polymorphism in the promoter of the CD14 monocyte receptor gene is not associated with acute myocardial infarction.  Clin Exp Med. 2003;  3 161-165
• 14 Koenig W, Khuseyinova N, Hoffmann M M, März W, Fröhlich M, Hoffmeister A, Brenner H, Rothenbacher D. CD14 C(− 260)-T polymorphism, plasma levels of the soluble endotoxin receptor CD14, their association with chronic infections and risk of stable coronary artery disease.  J Am Coll Cardiol. 2002;  40 34-42
• 15 Koch W, Kastrati A, Mehilli J, von Beckerath N, Schomig A. CD14 gene − 159C/T polymorphism is not associated with coronary artery disease and myocardial infarction.  Am Heart J. 2002;  143 971-976
• 16 Agema W R, Wouter Jukema J, de Maat M P, Zwindermann A H, Kastelein J J, Rabelink T J, van der Wall E E. Pharmacogenetics of the CD14 endotoxin receptor polymorphism and progression of coronary atherosclerosis.  Thromb Haemost. 2004;  91 986-990
• 17 Nauck M, Winkelmann B R, Hoffmann M M, Böhm B O, Wieland H, März W. C(− 260)T polymorphism in the promoter of the CD14 gene is not associated with coronary artery disease and myocardial infarction in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.  Am J Cardiol. 2002;  90 1249-1252
• 18 Ito D, Murata M, Tanahashi N, Sato H, Sonoda A, Saito I, Watanabe K, Fukuuchi Y. Polymorphism in the promoter of lipopolysaccharide receptor CD14 and ischemic cerebrovascular disease.  Stroke. 2000;  31 2661-2664
• 19 Heesen M, Blömeke B, Schlüter B, Heussen N, Rossaint R, Kunz D. Lack of association between the − 260 C–T promoter polymorphism of the endotoxin receptor CD14 gene and the CD14 density of unstimulated human monocytes and soluble CD14 plasma levels.  Intensive Care Med. 2001;  27 1770-1775
• 20 Eng H L, Wang C H, Chen C H, Chou M H, Cheng C T, Lin T M. A CD14 promoter polymorphism is associated with CD14 expression and chlamydia-stimulated TNF alpha production.  Genes Immun. 2004;  5 426-430
• 21 Kabesch M, Hasemann K, Schickinger V, Tzotcheva I, Bohnert A, Carr D, Baldini M, Hackstein H, Leupold W, Weiland S K, Martinez F D, Mutius E, Bein G. A promoter polymorphism in the CD14 gene is associated with elevated levels of soluble CD14 but not with IgE or atopic diseases.  Allergy. 2004;  59 520-525
• 22 Obana N, Takahashi S, Kinouchi Y, Negoro K, Takagi S, Hiwatashi N, Shimosegawa T. Ulcerative colitis is associated with a promoter polymorphism of lipopolysaccharide receptor gene, CD14.  Scand J Gastroenterol. 2002;  37 699-704
• 23 Karhukorpi J, Yan Y, Niemela S, Valtonen J, Koistinen P, Joensuu T, Saikku P, Karttunen R. Effect of CD14 promoter polymorphism and H. pylori infection and its clinical outcomes on circulating CD14.  Clin Exp Immunol. 2002;  128 326-332
• 24 Amar J, Ruidavets J B, Bal dit Sollier C, Bongard V, Boccalon H, Chamontin B, Drouet L, Ferrieres J. CD14 C(− 260)T gene polymorphism, circulating soluble CD14 levels and arteriosclerosis.  J Hypertens. 2004;  22 1523-1528