Platelet genomics

Abstract

Human platelets are anucleate cells that contain no genomic DNA although they contain both mRNAs and microRNAs derived from precursor megakaryocytes. Nonetheless, genetic variability encompassed within both intronic and exonic sequences are clearly implicated in a wide range of functional parameters known to regulate gene expression and protein function, with concomitant effects on platelet reactivity, volume, peripheral counts, and cellular responsiveness (Hematol Oncol Clin North Am 27:443-463, 2013; Semin Thromb Hemost 39:291-305, 2013; Curr Opin Hematol 19:371-379, 2012). In this chapter, we will review the current status of genetic variations that have been implicated in functional platelet responsiveness, many of which have recently been identified using genome-wide association studies (GWAS) (Genes 5:51-64, 2014; Nat Rev Genet 11:241-246, 2010; Curr Opin Genet Dev 23:339-344, 2013). For synergistic information relevant to platelet genetics, the reader should refer to accompanying chapters on platelet mRNAs (Rowley et al. 2017), platelet noncoding RNAs (Edelstein and Bray 2017), and transcriptomic changes associated with thrombotic risk (Gnatenko et al. 2017). Many genetic variants have subtle effects and it is likely that complex platelet-related phenotypes associated with cerebro- or cardiovascular risk result from additive effects from multiple loci, contributing to a final common pathway for defective platelet functional and clinical outcome (J Thromb Haemost 5:188-195, 2007; Curr Vasc Pharmacol 9:479-489, 2011; J Thromb Thrombolysis 32:201-208, 2011). Thus, a single subtle effect may be difficult to delineate or consistently reproduce across cohorts. In addition, other confounding variables (e.g., age, sex, body mass index, alcohol consumption, concomitant drugs, nutritional status, and environmental pollutants) may also affect platelet function (Thromb Haemost 105:S60-S66, 2011). Thus, well-defined phenotypes provide the most informative outcomes. Additionally,GWAS with large cohort sizes provide the most robust information relevant for reliable identification of new genetic variations with subtle effect (s) on platelet functional parameters (Fig. 1).