Important Haplotype Information for P2RY12
Submitted by: Katrin Sangkuhl (PharmGKB)
Reviewed by: under review
Submitted date: Feb 28, 2008
There is One Important Haplotype for P2RY12.
- P2RY12:H2 haplotype:
| Gene HGNC Name: | P2RY12 |
|---|---|
| Haplotype Significance: | A large population study showed that ADP-induced platelet response is considerably variable [10195947]. To explain this variability of platelet aggregation responses to ADP, sequence variations in the P2RY12 gene were investigated among 98 healthy volunteers. For this study the P2RY12 gene sequence, which consists of two exons separated by a 1700 bp intron located upstream of the ATG codon was analyzed. Exon 2 encodes the entire protein. Five common polymorphisms were identified in the P2RY12 gene, four of them being in complete linkage disequilibrium (i-C139T, i-T744C, i-ins801A, G52T) (rs10935838, rs2046934, rs5853517, rs6809699 ) [12912815]. Three variants were found in the intron and one SNP in exon 2. These four polymorphisms determine two haplotypes, H1 and H2, which had respective allelic frequencies of 0.86 and 0.14. The presence of the minor haplotype H2 was associated with enhanced ADP induced platelet aggregation in healthy volunteers [12912815]. The molecular mechanism by which the H2 haplotype increases ADP-induced platelet aggregation remains unclear. Based on the investigated sequence, an amino acid substitution affecting the protein structure or splice variants could be ruled out. Thus, an increase in the number of receptors on the platelet surface is most likely the explanation [12912815]. This study further concluded that carriers of the H2 haplotype might have an increased risk of atherothrombosis and/or a lesser clinical response to drugs inhibiting platelet function [12912815]. The H2 haplotype has also been shown to be associated with peripheral arterial disease (PAD). This study found that the H2 haplotype was more frequent in patients with PAD than controls [14662702]. Conversely, other results showed an association of rs6785930 (which is not part of the haplotype) but not rs6809699 (which is part of the haplotype) with increased risk of ischemic cerebrovascular events in patients with PAD [15933261]. Another study investigated the association of the H2 haplotype with coronary artery disease (CAD), genotyping 1378 patients for the SNP i-T744C. The results showed that the gene sequence variants of the P2RY12 receptor gene are associated with the presence of significant CAD [17803810]. No evidence was found for the association of the H2 haplotype with incident myocardial infarction or ischemic stroke but an association was found between the presence of the H2 haplotype and a lower risk of incident venous tromboembolism [17707382]. Separately from the two haplotypes described above, a group recently identified seven haplotypes (H1-H7) in patients treated with percutaneous coronary interventions. Five SNPs were selected, which represent the common genetic variation of the P2RY12 locus. Only the i-T744C variant was included in those five SNPs. Haplotype H5 and H7 were associated with a higher risk of target vessel revascularization [18175333]. |
| Does this haplotype span more than one gene? | no |
| Definitive Publication or Website: | 12912815 |
| Drugs: | clopidogrel |
| Phenotypes/Diseases: | Cardiovascular Diseases |
| Phenotype Data Sets: | N/A |
| Key PubMed IDs: | 12912815 14662702 17803810 |
| How many SNPs, indels, repeats define this haplotype? | 4, including P2RY12:744T>C |