Nucleotide Polymorphisms in the α2 Gene Define Multiple Alleles That Are Associated With Differences in Platelet α2β1 Density

Author:

Kritzik Marcie1,Savage Brian1,Nugent Diane J.1,Santoso Sentot1,Ruggeri Zaverio M.1,Kunicki Thomas J.1

Affiliation:

1. 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.

Abstract

AbstractThree allelic differences in the α2 gene are associated with expression levels of the α2β1 integrin on the platelet surface. We have previously defined two linked silent polymorphisms in the α2 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 α2 gene alleles, defined by eight nucleotide polymorphisms, have now been discovered. Allele 1 (807T/837T/873A/Brb) is associated with increased levels of α2β1; allele 2 (807C/837T/873G/Brb) and allele 3 (807C/837C/873G/Bra) are each associated with lower levels of α2β1. 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 α2β1 receptors on the platelet surface. Thus, the density of platelet α2β1 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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