NUCLEOTIDE POLYMORPHISMS IN THE ALPHA(2) GENE DEFINE MULTIPLE ALLELESTHAT ARE ASSOCIATED WITH DIFFERENCES IN PLATELET ALPHA(2)BETA(1) DENSITY

Three allelic differences in the alpha(2) gene are associated with exp ression levels of the alpha(2)beta(1) integrin on the platelet surface , We have previously defined two linked silent polymorphisms in the al pha(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 codi ng region at nucleotide 837 (T or C) and four additional linked polymo rphisms within the introns that flank these coding sequences. Moreover , we have determined that the alloantigenic Br polymorphism, which res ides in a distal coding region at nucleotide 1648, is also linked to t he 837 polymorphism. Thus, three cup gene alleles, defined by eight nu cleotide polymorphisms, have now been discovered. Allele 1 (807T/837T/ 873A/Br-b) is associated with increased levels of alpha(2)beta(1); all ele 2 (807C/837T/873G/Br-b) and allele 3 (807C/837C/873G/Br-a) are eac h associated with lower levels of alpha(2)beta(1). Finally, we also sh ow here that the rate of platelet attachment to type I collagen in who le blood under conditions of high shear rate (1,500/s) is proportional to the density of alpha(2)beta(1) receptors on the platelet surface. Thus, the density of platelet alpha(2)beta(1) could have an important impact on platelet adhesion to collagen in whole blood and therefore o n platelet function in vivo, contributing to an increased risk of thro mbosis or to bleeding in relevant disease states. (C) 1998 by The Amer ican Society of Hematology.