The Impact of the Glycoprotein Ia Collagen Receptor Subunit A₁₆₄₈G Gene Polymorphism on Coronary Artery Disease and Acute Myocardial Infarction

Summary

Platelet glycoprotein (GP) Ia is the major receptor for collagen and plays an important role in platelet adhesion and aggregation. Different gene polymorphisms have been identified that induce either various expression levels (C₈₀₇T) or alterations of the tertiary structure (A₁₆₄₈G) of GPIa. Previously, we could demonstrate an association of the GPIa C₈₀₇T dimorphism with nonfatal myocardial infarction. We have now analysed the influence of the GPIa A₁₆₄₈G (Br, HPA-5) dimorphism on the risk of coronary artery disease (CAD) and acute myocardial infarction (AMI). DNA samples from 2163 male Caucasian patients who underwent coronary angiography were genotyped by polymerase chain reaction and restriction fragment length analysis. The relation of the GPIa A₁₆₄₈G dimorphism to the extent of CAD was determined by multiple regression analysis with adjustment for coronary risk factors. Odds ratios (OR) as an estimate of relative risk of CAD and AMI and two-tailed p-values were calculated by multiple logistic regression. In the total study sample, no association was detected between the A₁₆₄₈G dimorphism and CAD or AMI. However, upon analysis of low-risk patient subgroups we found an association of the GPIa A₁₆₄₈G polymorphism with the risk and the extent of CAD (patients with high apoAI/apoB ratio: OR 0.59, p = 0.0090; nonand ex-smokers: OR 0.66, p = 0.0131; both inclusion criteria: OR 0.44, p = 0.0003). The relative frequency of the A₁₆₄₈ allele was higher in controls whereas the GG₁₆₄₈ genotype was overrepresented in patients with CAD. This association was also detectable when individuals with low expression levels of GPIa (C₈₀₇ homozygotes) were analysed (patients with high apoAI/apoB ratio: OR 0.44, p = 0.0045; nonand ex-smokers: OR 0.61, p = 0.0370). Our findings indicate that the A₁₆₄₈G polymorphism of the platelet collagen receptor plays a role in CAD in well defined patient groups.

Keywords

Glycoprotein Ia/IIa - α₂β₁integrin - risk factor - myocardial infarction - human platelet alloantigen Br^a/Br^b (HPA-5b/a)

• References

• 1 Murata M, Kawano K, Matsubara K, Ishikawa K, Watanabe K, Ikeda Y. Genetic polymorphisms and risk of coronary artery disease. Sem Thromb Hemost 1998; 24: 245-50.
• 2 Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326: 242-50.
• 3 Santoso S, Kiefel V. Human platelet-specific alloantigens: update. Vox Sang 1998; 74 (Suppl. 02) 249-53.
• 4 Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS, Becker LC, Weiss JL, Gerstenblith G, Goldschmidt-Clermont PJ. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med 1996; 334: 1090-4.
• 5 Ridker PM, Hennekens CH, Schmitz C, Stampfer MJ, Lindpaintner K. PlA1/A2 polymorphism of platelet glycoprotein IIIa and risks of myocardial infarction, stroke, and venous thrombosis. Lancet 1997; 349: 385-8.
• 6 Sixma JJ, van Zanten GH, Huizinga EG, van der Plas RM, Verkley M, Wu YP, Gros P, de Groot PG. Platelet adhesion to collagen: an update. Thromb Haemost 1997; 78: 434-8.
• 7 Nieuwenhuis HK, Akkerman JWN, Houdijk WPM, Sixma JJ. Human blood platelets showing no response to collagen fail to express surface glycoprotein Ia. Nature 1985; 318: 470-2.
• 8 Kritzik M, Savage B, Nugent D, Santoso S, Ruggeri ZM, Kunicki TJ. Nucleotide polymorphisms in the a ₂ gene define multiple alleles that are associated with differences in platelet α₂β₁ density. Blood 1998; 92: 2382-8.
• 9 Kunicki TJ, Kritzik M, Annis DS, Nugent DJ. Hereditary variation in platelet integrin α₂β₁ density is associated with two silent polymorphisms in the α₂ gene coding sequence. Blood 1997; 89: 1939-43.
• 10 Santoso S, Kunicki TJ, Kroll H, Haberbosch W, Gardemann A. Association of the platelet glycoprotein Ia C₈₀₇T gene polymorphism with myocardial infarction in younger patients. Blood 1999; 93: 2449-53.
• 11 Moshfegh K, Wuillemin WA, Redondo M, Lämmle B, Beer J, LiechtiGallati S, Meyer BJ. Association of two silent polymorphisms of platelet glycoprotein Ia/IIa receptor with risk of myocardial infarction: a casecontrol study. Lancet 1999; 353: 351-4.
• 12 Santoso S, Kalb R, Kiefel V, Mueller-Eckhardt C, Newman PJ. The human platelet alloantigens Br^a and Br^b are associated with a single amino acid polymorphism on glycoprotein Ia (integrin α₂ subunit). J Clin Invest 1993; 92: 2427-32.
• 13 Kroll H, Kiefel V, Santoso S. Clinical aspects and typing of platelet alloantigens. Vox Sang 1998; 74 (Suppl. 02) 345-54.
• 14 Gardemann A, Schwartz O, Haberbosch W, Katz N, Weiss T, Tillmanns H, Hehrlein FW, Waas W, Eberbach A. Positive association of the beta fibrinogen H1/H2 gene variation to basal fibrinogen levels and to the increase in fibrinogen concentration during acute phase reaction but not to coronary artery disease and myocardial infarction. Thromb Haemost 1997; 77: 1120-6.
• 15 Kawasaki ES. Sample preparation from blood, cells, and other fluids. In: PCR protocols: a guide to methods and applications. Innis MA, Gelfand DH, Sninsky JJ, White TJ. San Diego: Academic Press Inc; 1990: 146-52.
• 16 Unkelbach K, Kalb R, Santoso S, Kroll H, Mueller-Eckhardt C, Kiefel V. Genomic RFLP typing of human platelet alloantigens Zw(Pl^A), Ko, Bak and Br (HPA-1, 2, 3, 5). Br J Haematol 1995; 89: 169-76.
• 17 Carlsson LE, Santoso S, Spitzer C, Kessler C, Greinacher A. The α₂ gene coding sequence T⁸⁰⁷/A⁸⁷³ of the platelet collagen receptor integrin α₂β₁ might be a genetic risk factor for the development of stroke in younger patients. Blood 1999; 93: 3583-6.
• 18 Bray PF. Integrin polymorphisms as risk factors for thrombosis. Thromb Haemost 1999; 82: 337-44.
• 19 Corral J, Rivera J, González-Conejero R, Vicente V. The number of platelet glycoprotein Ia molecules is associated with the genetically linked 807C/T and HPA-5 polymorphisms. Transfusion 1999; 39: 372-8.
• 20 Hato T, Minamoto Y, Fukuyama T, Fujita S. Polymorphisms of HPA-1 through 6 on platelet membrane glycoprotein receptors are not a genetic risk factor for myocardial infarction in the Japanese population. Am J Cardiol 1997; 80: 1222-4.
• 21 Sperr WR, Huber K, Roden M, Janisiw M, Lang T, Graf S, Maurer G, Mayr WR, Panzer S. Inherited platelet glycoprotein polymorphisms and a risk for coronary heart disease in young central Europeans. Thrombosis Research 1998; 90: 117-23.
• 22 Bray PF, Furman M, Coleman L, Hamlington J, Goldschmidt-Clermont PJ, Hendrix C, Mascelli MA, Barnard M, Kickler T, Christie D, Kundu S, Michelson A. Integrin β₃ (GPIIIa) Pl^A polymorphisms on platelets display different sensitivity to agonists and antagonists. Blood 1998; 92: 28a.