Abstract: Background: Patients with T2DM have reduced responsiveness to the platelet P2Y12 receptor antagonist clopidogrel compared to non-diabetics. However, variability in clopidogrel-induced antiplatelet effects has been observed among T2DM and those with elevated platelet reactivity have a higher risk of atherothrombotic events. Since variation in insulin sensitivity modulates platelet P2Y12 signaling, the aim of this study was to evaluate if SNPs of the insulin receptor substrate-1 (IRS-1) are associated with variation in the response to clopidogrel in T2DM patients. Methods: A total of 7 tagSNPs (rs1801278, rs11683087, rs1801123, rs1896832, rs956115, rs2251692, rs6725330) were determined in 180 T2DM patients with coronary artery disease in a steady state phase of clopidogrel therapy. Patients were classified into carriers and non-carriers of the variant allele for each SNP according to a dominant model. In addition, haplotype distribution of IRS-1 genes within our population was assessed. Platelet function was determined by LTA following 20 μM adenosine diphosphate stimuli (ADP). Platelet aggregation according to genotype and haplotype was determined. Results: The 7 tagSNPs were accountable for 93% of the haplotype distribution of the IRS-1 gene. Platelet aggregation was 55±15% in the overall population. Preliminary results showed an association between carriers of the variant C allele of the rs956115 SNP (n=34) and the highest degree of platelet reactivity (60±14%; p<0.05). Conclusions: rs956115 polymorphism of IRS-1 gene is associated with lower clopidogrel-induced antiplatelet effects in T2DM patients with coronary artery disease.
Genetic polymorphisms of the insulin receptor substrate-1 (IRS1) gene and profiles of clopidogrel-induced antiplatelet effects in type 2 diabetes mellitus patients with coronary artery disease
ZANONI, Martina;PRANDINI, PAOLA;TRABETTI, Elisabetta;PIGNATTI, Pierfranco
2008-01-01
Abstract
Abstract: Background: Patients with T2DM have reduced responsiveness to the platelet P2Y12 receptor antagonist clopidogrel compared to non-diabetics. However, variability in clopidogrel-induced antiplatelet effects has been observed among T2DM and those with elevated platelet reactivity have a higher risk of atherothrombotic events. Since variation in insulin sensitivity modulates platelet P2Y12 signaling, the aim of this study was to evaluate if SNPs of the insulin receptor substrate-1 (IRS-1) are associated with variation in the response to clopidogrel in T2DM patients. Methods: A total of 7 tagSNPs (rs1801278, rs11683087, rs1801123, rs1896832, rs956115, rs2251692, rs6725330) were determined in 180 T2DM patients with coronary artery disease in a steady state phase of clopidogrel therapy. Patients were classified into carriers and non-carriers of the variant allele for each SNP according to a dominant model. In addition, haplotype distribution of IRS-1 genes within our population was assessed. Platelet function was determined by LTA following 20 μM adenosine diphosphate stimuli (ADP). Platelet aggregation according to genotype and haplotype was determined. Results: The 7 tagSNPs were accountable for 93% of the haplotype distribution of the IRS-1 gene. Platelet aggregation was 55±15% in the overall population. Preliminary results showed an association between carriers of the variant C allele of the rs956115 SNP (n=34) and the highest degree of platelet reactivity (60±14%; p<0.05). Conclusions: rs956115 polymorphism of IRS-1 gene is associated with lower clopidogrel-induced antiplatelet effects in T2DM patients with coronary artery disease.
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