Page 1875 - Williams Hematology ( PDFDrive )

1850 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1851

function can be used as diagnostic criteria, but they have been reported However, there were inconsistent and conflicting results in these candi-
as symptoms. 545 date studies.

PLATELET GENOMICS, THE PLATELET Genome-Wide Associations Studies
No unbiased GWAS has been performed using documented arterial
TRANSCRIPTOME, AND PLATELET thrombosis as the clinical phenotype, but many have been performed
PROTEOMICS with coronary artery disease (CAD). Multiple studies have demon-
strated that the Chr9p21.3 locus is associated with both myocardial
infarction (MI) and CAD. A meta-analysis of all CAD GWAS studies
PLATELET GENOMICS that included 63,746 patients with acute and chronic CAD and 130,681
The Homo sapiens genome is comprised of approximately 3.2 billion controls identified 46 loci meeting genome-wide significance. These
548
base pairs and has approximately 3.5 million single nucleotide poly- loci explain less than 11 percent of CAD heritability and although a
morphisms (SNPs) that occur at frequencies of 1 percent or greater, substantial proportion of the identified genes regulate lipid metabolism
but continued sequencing of more genomes indicates there are at least and inflammation, most loci are not located in previously well-known
an additional 43 million rare or “private” SNPs. dbSNP (www.ncbi.nlm or well-characterized platelet genes. Few of these loci have been tested
.nih.gov/projects/SNP) maintains information about sequence varia- for functional effects in platelets. There are numerous possible explana-
tion, allele frequencies, differences in frequencies between populations tions for the non-association with well-studied platelet candidate genes,
of different ethnicity and their functional consequences. New technol- including small platelet gene effect sizes in under-powered heteroge-
ogies, such as next-generation sequencing, and new analytic method- neous clinical phenotypes. 549
ologies have driven and continue to drive expansion of genomics at a
very rapid pace. Both epidemiologic and experimental approaches have Whole-Exome Sequencing
been and are used to assess significance and functionality of platelet Whole exome-sequencing is well-suited to identify variants in protein-
gene variants and gene expression, including genetic epidemiology, bio- coding genes and was used to identify NBEAL2 as the causative gene in
chemistry, cell biology, physiology, and animal studies. the gray platelet syndrome. 550,551

GENE VARIANTS ASSOCIATED WITH DISEASE Pharmacogenetics
The CYP2C19*2 allele (681G>A; rs4244285) causes a loss of function
Candidate Genes of the CYP2C19 enzyme and reduced platelet inhibition by clopido-
Because platelets play a central role in acute ischemic syndromes, anti- grel as a result of decreased conversion to the active metabolite. It
552
platelet therapy is a mainstay of therapy. Platelets may also contribute could account for approximately 12 percent of the variation in plate-
to the pathophysiology of the chronic process of atherosclerosis, let inhibition in response to clopidogrel. Several large meta-analyses
546
553
although the data are less consistent than with thrombosis. The earli- have shown the loss-of-function CYP2C19*2 allele is associated with
est platelet genetic association studies considered associations between both stent thrombosis and cardiovascular ischemic events or death in
atherothrombotic disease outcomes and candidate platelet gene vari- patients undergoing percutaneous coronary interventions. 554,555
ants that altered amino acids in platelet membrane adhesion receptors.
Numerous studies reported associations between myocardial infarction GENE VARIANTS ASSOCIATED WITH PLATELET
and stroke with SNPs in integrin β (ITGB3), integrin α (ITGA2), and
2
3
547
GPIbα (GP1BA) and GPVI (GP6). In these relatively small studies, TRAITS
positive associations were more likely to be observed in patients with Many cellular pathways in multiple tissues contribute to the patho-
acute thrombosis and less likely in patients with stable atherosclerosis. genic processes resulting in an atherothrombotic event (Fig. 112–7),

Complex Trait:
Atherothrombosis

20% 20% 20% 20% 20%

Platelet Blood Lipid EC Fibrin
reactivity pressure metabolism biology formation

50% 50% 50% 50% 50% 50% 50% 50% 50% 50%
Genes 1 2 3 4 5 6 7 8 9 10

Figure 112–7. Intermediate phenotypes in association studies. Atherothrombosis is a complex phenotype that is regulated by many intermediate
traits, of which platelet reactivity is only one. Because a large number of genes contribute to multiple traits, the effect of any one gene on atheroth-
rombotic events, such as myocardial infarction, is small. This highly simplified diagram assumes five traits each contribute 20 percent to the complex
trait (heavy solid arrows) and two different genes equally regulate each intermediate trait. Thus, each gene contributes 50 percent to the intermediate
trait (thin arrows), but only 10 percent to the clinical end point (faint dashed arrows). Thus, for any given sample size, there is more power to detect
genetic associations with intermediate phenotypes than with complex traits. (Reproduced with permission from Bray PF: Platelet genomics beats the
catch-22. Blood 13;114(7):1286–1287, 2009.)

Kaushansky_chapter 112_p1829-1914.indd 1850 17/09/15 3:27 pm