Genetic regulation of platelet receptor expression and function: application in clinical practice and drug development

Abstract

Understanding genetic contributions to platelet function could have profound clinical ramifications for personalizing platelet-directed pharmacotherapy, by providing insight into the risks and possible benefits associated with specific genotypes. This article represents an integrated summary of presentations related to genetic regulation of platelet receptor expression and function given at the Fifth Annual Platelet Colloquium in January 2010. It is supplemented with additional highlights from the literature covering (1) approaches to determining and evidence for the associations of genetic variants with platelet hypo- and hyperresponsive phenotypes, (2) the ramifications of these polymorphisms with regard to clinical responses to antiplatelet therapies, and (3) the role of platelet function/genetic testing in guiding antiplatelet therapy.

Figure 1. Relationship between α2β1 polymorphisms and collagen receptor density

Top, surrounding structure of the α2 gene at sites of the 807 and 873 polymorphisms, including 3 alleles defined by 8 nucleotide (nt) polymorphisms. Frequency of each allele (f) determined from a random pool of 85 individuals. “+” indicates ability of the allele to be cleaved by Bgl II or Nde I, and specific bp differences are shown affecting susceptibility to cleavage. Middle, α2 allele genotyping using Bgl II/Nde I digestion and agarose gel electrophoresis. C1 indicates control sequence 807C/837C/873G; C2, control sequence 807T/837T/873A; C3 molecular weight λHind III/φX174Hae III. Bottom, Real-time epifluorescence video microscopy showing the time courses of platelet adhesion in whole blood under high shear to surface-bound solubilized human Type I collagen at 1,500/s for individuals homozygous for allele 1 (upper) and allele 2 (lower). Adapted from Kritzik et al with permission.