Platelet glycoprotein Ibα and integrin α2β1 polymorphisms: gene frequencies and linkage disequilibrium in a population diversity panel

Paola, Jorge Di; Jugessur, Astanand; Goldman, T.; Reiland, Jane; Tallman, D.; Sayago, C.; Murray, Jeff

doi:10.1111/j.1538-7836.2005.01273.x

Cited by 32 publications

(27 citation statements)

References 41 publications

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“…Consequently, although the reported associations for ITGA2 C807T (rs1126643), 22 GP1BA T-5C, 27,31 and the GP6 haplotype b 23 have been replicated, others have not been as reproducible. 32,33 Genes for the following proteins and their representative SNPs have been included in various gene association studies to assess variation in platelet function among normal persons ( 36,37 C-52T, 38 and G1648A) 39 ; 8. Integrin subunit ␣IIb (platelet GPIIb) (ITGA2B I843S) 40 ; 9.…”

Section: Candidate Gene Association Studiesmentioning

confidence: 99%

The genetics of normal platelet reactivity

Kunicki

Nugent

2010

Blood

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Genetic and environmental factors contribute to a substantial variation in platelet function seen among normal persons. Candidate gene association studies represent a valiant effort to define the genetic component in an era where genetic tools were limited, but the single nucleotide polymorphisms identified in those studies need to be validated by more objective, comprehensive approaches, such as genome-wide association studies (GWASs) of quantitative functional traits in much larger cohorts of more carefully selected normal subjects. During the past year, platelet count and mean platelet volume, which indirectly affect platelet function, were the subjects of GWAS. IntroductionInterindividual platelet responsiveness to a variety of agonists is highly variable, as documented in several studies of large cohorts of normal persons. [1][2][3][4][5][6][7][8][9][10][11][12] At the same time, these and other studies of siblings, twins, and families with a history of coronary artery disease (CAD) have documented that intraindividual responsiveness is highly reproducible over time, regardless of the agonist tested or the chosen method of assessment. These findings strongly suggest that there is a high level of heritability of platelet function, and this has prompted numerous attempts to define the genetic basis for platelet function variability. A summary of platelet functionTo fully appreciate the gene association studies, it is necessary to briefly summarize key aspects of platelet function and establish a molecular and physiologic basis for the selection of genes to study.When a blood vessel is damaged, circulating platelets interact with components of the extracellular matrix, particularly collagen, and a complex series of receptor-ligand interactions ensues that ultimately leads to the formation of a stable platelet plug or thrombus. This process is a continuum of at least 3 phases that we can describe as initiation, extension, and consolidation, each of which entails the cooperation of a different group of receptors.In the initiation phase, plasma von Willebrand factor (VWF) binds to collagen via its A3 domain and becomes structurally altered such that its A1 domain then binds to the platelet membrane receptor glycoprotein Ib-IX-V complex (GPIb complex). It is the GPIb␣ or larger subunit of GPIb that makes direct contact with VWF. This association is a requisite step in the adhesion of platelets to exposed thrombogenic surfaces at sites of vessel wall injury or in regions of atherosclerotic plaque rupture. Concurrently, a more stable platelet monolayer is formed on the collagen surface mediated predominantly by the platelet-specific receptor glycoprotein VI (GPVI) and platelet integrin ␣ 2 ␤ 1 .The engagement of these receptors enhances platelet activation leading to the extension phase, mediated largely by the conversion of prothrombin to thrombin at the activated platelet surface and the secretion of active compounds from platelet granules (␣-granules and ␦-granules), which can further stimulate platelets. One of...

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Section: Candidate Gene Association Studiesmentioning

confidence: 99%

The genetics of normal platelet reactivity

Kunicki

Nugent

2010

Blood

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“…These seemingly disparate findings in two separate studies are actually complementary manifestations of a similar genetic influence. Based on our own genotype data and the report of DiPaola et al [23], there is strong LD between -52T and 807C, defined by two haplotypes with a combined frequency in the Italian (Milan) population of 0.35. Both of these SNPs have been associated with attenuated expression of platelet integrin a2b1 and thereby could increase the risk for bleeding.…”

Section: Discussionmentioning

confidence: 60%

“…Existing ITGA2 haplotype frequency data and more recent information from the International HapMap project can be combined to define linkage disequilibrium (LD) between previously characterized single nucleotide polymorphisms (SNPs), such as -52 T/C and 807 T/C [23]. Thus, the -52 T/C polymorphism is apparently one of the oldest associated with ITGA2 and distinguishes two ancient ITGA2 haplotypes.…”

Section: Discussionmentioning

confidence: 99%

An association of candidate gene haplotypes and bleeding severity in von Willebrand disease type 2A, 2B, and 2M pedigrees

Kunicki

Baronciani

Canciani

et al. 2006

Journal of Thrombosis and Haemostasis

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Summary. We analyzed the association of bleeding severity with candidate gene haplotypes within pedigrees of 11 index cases of von Willebrand disease (VWD) type 2 (two type 2A, three type 2B and six type 2M), using the QTL Association model (MENDEL 5.5). In addition to the 11 index cases, these pedigrees included 47 affected and 49 unaffected relatives, as defined by VWF mutations and/or phenotype. A bleeding severity score was derived from a detailed history and adjusted for age. Donors were genotyped using a primer extension method, and eight candidate genes were selected for analysis. VWF antigen (or ristocetin cofactor activity) levels had the strongest influence on bleeding severity score. After Bonferroni correction for multiple testing, only ITGA2 promoter haplotype -52T was associated with an increased bleeding severity score (P < 0.01). This association remained statistically significant when the three type 2B pedigrees were excluded (P ¼ 0.012) or when genderspecific bleeding categories were excluded (P < 0.01). The major haplotypes of seven other candidate genes, GP1BA, ITGA2B, ITGB3, GP6, VWF, FGB, and IL6, were not associated with bleeding severity. These results establish that genetic differences in the expression of the integrin subunit a 2 can influence the bleeding phenotype of VWD type 2 and complement our previous findings in VWD type 1. Genetically controlled attenuation of platelet collagen receptor expression can influence risk for morbidity in clinical settings where hemostasis is compromised.

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“…The SNPs analyzed in this study and the minor allele frequency (MAF) of each were: for integrin α2β1, ITGA2 rs1126643 (0.38), 7 ITGA2 rs28095 (0.36), 8,9 and ITGA2 rs1801106 (0.08); 1 for integrin αIIbβ3, ITGA2B rs5911 (0.41) 10 and ITGB3 rs5918 (0.17); 11 for GP Ibα, GP1BA rs6065 (0.1); 12 for GPVI, GP6 rs1613662 (0.16); 13 and for the purinergic receptor P2Y1, P2RY1 rs1065776 (0.05).…”

Section: Design and Methodsmentioning

confidence: 99%