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Blood, Vol. 92 No. 7 (October 1), 1998: pp. 2382-2388

Nucleotide Polymorphisms in the alpha 2 Gene Define Multiple Alleles That Are Associated With Differences in Platelet alpha 2beta 1 Density

Marcie Kritzik, Brian Savage, Diane J. Nugent, Sentot Santoso, Zaverio M. Ruggeri, and Thomas J. Kunicki

From the Roon Research Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis of the Department of Molecular and Experimental Medicine and The Department of Vascular Biology, The Scripps Research Institute, La Jolla; the Children's Hospital of Orange County, Orange, CA; and the Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, Giessen, Germany.

Three allelic differences in the alpha 2 gene are associated with expression levels of the alpha 2beta 1 integrin on the platelet surface. We have previously defined two linked silent polymorphisms in the alpha 2 gene coding region at nucleotides 807 (C or T) and 873 (G or A). We have now identified one rarer nucleotide polymorphism in the coding region at nucleotide 837 (T or C) and four additional linked polymorphisms within the introns that flank these coding sequences. Moreover, we have determined that the alloantigenic Br polymorphism, which resides in a distal coding region at nucleotide 1648, is also linked to the 837 polymorphism. Thus, three alpha 2 gene alleles, defined by eight nucleotide polymorphisms, have now been discovered. Allele 1 (807T/837T/873A/Brb) is associated with increased levels of alpha 2beta 1; allele 2 (807C/837T/873G/Brb) and allele 3 (807C/837C/873G/Bra) are each associated with lower levels of alpha 2beta 1. Finally, we also show here that the rate of platelet attachment to type I collagen in whole blood under conditions of high shear rate (1,500/s) is proportional to the density of alpha 2beta 1 receptors on the platelet surface. Thus, the density of platelet alpha 2beta 1 could have an important impact on platelet adhesion to collagen in whole blood and therefore on platelet function in vivo, contributing to an increased risk of thrombosis or to bleeding in relevant disease states.


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