Association between insulin receptor substrate-1 polymorphisms and high platelet reactivity with clopidogrel therapy in coronary artery disease patients with type 2 diabetes mellitus

Abstract

BackgroundThe mechanisms leading to the high on-treatment platelet reactivity in diabetes patients are not fully elucidated. The genetic factors may be associated with the diminished antiplatelet efficacy of dual antiplatelet therapy. We investigated the possible association between insulin receptor substrate-1 (IRS-1) polymorphisms and high platelet reactivity in coronary artery disease (CAD) patients with type 2 diabetes mellitus (T2DM).MethodsA total of 674 CAD patients with T2DM were enrolled in this study. Platelet aggregation and platelet activation were assessed with light transmission aggregometry and flow cytometry analysis, respectively. Participants were divided into high platelet reactivity (HPR) group and non-HPR group according to their maximal platelet aggregation. Genotypes were identified by polymerase chain reaction and direct sequencing of genomic DNA. The association between IRS-1 genetic variants and platelet function was assessed.ResultsThere were 233 participants in the HPR group and 441 participants in the non-HPR group. G allele frequencies of rs13431554 were 27.7 % for the HPR group and 18.6 % for the non-HPR group (p < 0.001). Adenosine diphosphate and arachidonic acid induced platelet aggregation were significantly higher in G allele carriers compared with non-carriers (56.8 ± 16.2 vs 52.0 ± 17.9 %, p < 0.01, 28.9 ± 18.6 vs 25.2 ± 17.8 %, p < 0.01, respectively). We observed that P-selectin expression and PAC-1 binding were higher in G allele carriers compared with non-carriers (40.8 ± 12.4 vs 36.2 ± 13.8, p = 0.01; 43.7 ± 15.9 vs 38.7 ± 19.9, p = 0.03, respectively).ConclusionThe G allele of rs13431554 in the IRS-1 gene was associated with a hyperreactive platelet phenotype in the CAD patients with T2DM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0362-0) contains supplementary material, which is available to authorized users.

Effect of polymorphisms in interleukin-18 gene on the susceptibility to coronary artery disease in a Chinese population

“…CAD develops as a result of vascular tract stenosis or occlusion caused by coronary atherosclerotic lesions and several environmental and lifestyle factors (Campbell et al, 1998;Erbel and Görge, 2014;Bullock-Palmer, 2015). Previous experimental studies at the molecular level have indicated that many genetic factors, including the genes encoding angiotensinogen and angiotensin-converting enzyme, hepatic lipase, insulin receptor substrate-1, kinesin family member 6, cholesteryl ester transfer protein, ATP-binding cassette subfamily A member 1, and apoptotic extrinsic death receptor, have an important role in the risk of CAD development (Bonfim-Silva et al, 2016;Cyrus et al, 2016;Kishore Kumar et al, 2016;Mohammadzadeh et al, 2016;Vatte et al, 2016;Zhang et al, 2016).…”

PRotective Effect on the coronary microcirculation of patients with DIabetes by Clopidogrel or Ticagrelor (PREDICT): study rationale and design. A randomized multicenter clinical trial using intracoronary multimodal physiology

“…The mechanisms leading to the high on-treatment platelet reactivity in T2DM patients are not fully elucidated and could potentially involved genetic factors [26]. …”

Association of Perilipin and Insulin Receptor Substrate-1 Genes Polymorphism with Lipid Profiles, Central Obesity, and Type 2 Diabetes in a Sample of an Iranian Population

“…However, the effects of the IRS-1 genotype on prediabetic mediated features were not known. Recently the researchers showed that this gene is not only associated with Type 2 diabetes in different populations but also it may have a significant correlation with diabetic complications, particularly with coronary artery disease (CAD) and obesity (9)(10)(11). Another gene that was investigated in this study was perilipin (PLIN) (rs4578621).…”