Hereditary variation in platelet integrin α2β1 density is associated with two silent polymorphisms in the α2 gene coding sequence

Abstract

The integrin α2β1 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 α2β1 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 α2 gene that correlate with receptor density, TTT/TTC at codon Phe224 and ACA/ACG at codon Thr246. 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 α2β1 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 α2 gene are linked to the genetic basis for variation in receptor density.