Hereditary variation in platelet integrin alpha(2)beta(1) density is associated with two silent polymorphisms in the alpha(2) gene coding sequence

The integrin alpha(2) beta(1) is a receptor for collagen that plays a fundamental role in the adhesion of blood platelets to the extracellular matrix. We previously reported that platelet alpha(2) beta(1) levels among randomly selected individuals can vary up to '10-fold and that this correlates with differences in adhesiveness to type-I or type-III collagens. We have now found two linked, allelic polymorphisms within the coding sequence of the alpha(2) gene that correlate with receptor density, TTT/TTC at codon phe(224) and ACA/ACG at codon Thr(246). By Southern blot hybridization of specific antisense DNA probes to segments of genomic DNA that encompass each coding region, we have determined the gene frequencies of each allele in a random donor population (n=65) to be 0.585 (TTC...ACG) and 0.415 (TTT...ACA). There is a statistically significant correlation between the alleles TTT...ACA (codons 224...246) and high receptor density (n=30; P <.002), whereas the complimentary alleles TTC...ACG are associated with low receptor density. Heterozygous individuals express intermediate levels of this receptor, and familial studies confirm that these allelic polymorphisms are inherited characteristics. These findings prove that the level of platelet alpha(2) beta(1) is an inherited trait. The molecular basis for receptor density remains to be determined, but our findings establish that these silent alleles within the coding sequence of the alpha(2) gene are linked to the genetic basis for variation in receptor density. (C) 1997 by The American Society of Hematology.