Interaction among COX-2, P2Y1 and GPIIIa gene variants is associated with aspirin resistance and early neurological deterioration in Chinese stroke patients

Abstract

BackgroundThe effect of genetic variants on aspirin resistance (AR) remains controversial. We sought to assess the association of genetic variants with AR and early clinical outcomes in patients with acute ischemic stroke (IS).MethodsA total of 850 acute IS patients were consecutively enrolled. Platelet aggregation was measured before and after a 7–10 day aspirin treatment. The sequences of 14 variants of COX-1, COX-2, GPIb, GPIIIa, P2Y1 and P2Y12 were determined using matrix-assisted laser desorption/ionization time of flight mass spectrometry. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR). The primary outcome was early neurological deterioration (END) within 10 days of admission. The secondary outcome was a composite of early recurrent ischemic stroke (ERIS), myocardial infarction (MI) and death within 10 days of admission.Results175 (20.6%) patients were AR, 45 (5.3%) were aspirin semi-resistant, 121 (14.2%) developed END, 17 (0.2%) had ERIS, 2 (0.2%) died, and 6 (0.7%) had MI. Single locus analysis indicated that only rs1371097 was associated with AR. However, GMDR analysis indicated that the following three sets of gene-gene interactions were significantly associated with AR: rs20417CC/rs1371097TT/rs2317676GG; rs20417CC/rs1371097TT/rs2317676GG; rs20417CC/rs1371097CT/rs2317676AG. END occurred significantly more frequently in patients with AR or high-risk interactive genotypes. Moreover, AR and high-risk interactive genotypes were independently associated with END.ConclusionSensitivity of IS patients to aspirin and END may be multifactorial and is not significantly associated with a single gene polymorphism. Combinational analysis may useful for further insight into the genetic risks for AR.

Response to clopidogrel is associated with early neurological deterioration after acute ischemic stroke

“…A number of studies have shown that END is fairly common in acute ischemic stroke [ 3 , 5 , 7 – 9 , 21 , 23 , 24 ], and related to case fatality and reduced functional outcome [ 3 ]. The underlying mechanisms for END are not completely understood, although various factors associated with END have been reported [ 8 , 9 ].…”

“…An additional NIHSS assessment was performed whenever examination deteriorated. The primary endpoint of this study was END, which was defined as an increase in NIHSS score by ≥ 2 points within 10 days after admission, while excluding a new infarct in another vascular territory or HT of infarct according to our previous studies [ 3 , 5 , 21 ]. The secondary endpoint was a composite of RIS, MI, and death during the first 10 days after admission.…”

“…Most studies on antiplatelet drug responsiveness have focused on evaluating stroke recurrence following IS, very limited studies have examined the relationship between antiplatelet drug resistance and END after acute IS. Our previous studies have shown that aspirin resistance is not only associated with RIS [ 19 , 20 ], but also associated with END after acute IS [ 5 , 21 ]. The association between CR and END following IS has not been specifically addressed, although our previous studies have shown CR is associated with RIS [ 17 , 18 ].…”

Genetic Aspects of Inflammation and Immune Response in Stroke

“…So far it was pointed that genetic factors could be associated with long-term stroke outcomes, thus further genetic analyses might bring new insights for better understanding of molecular mechanisms regarding the stroke outcome [ 1 ]. Considering the acute and subacute stroke outcomes, the early neurological deterioration is found potentially to be multifactorial, with different single nucleotide polymorphisms (SNPs) that are independently associated with such condition [ 1 , 34 , 35 ].…”

Clinical Variables and Genetic Risk Factors Associated with the Acute Outcome of Ischemic Stroke: A Systematic Review

“…There are several reports searching for the relationship of potential candidate genes with stroke outcome, most of them performed on animal models. However, regarding acute or subacute outcome, we found very few articles that attempted to find genetic factors associated with outcome [88-90]. The genes of interest in those studies were: cytochrome P450 (CYP), cyclooxygenase-2 (COX-2), prostaglandin I2 synthase (PTGIS), thromboxane A synthase 1 (TBXAS1), purinergic receptor P2Y1 (P2RY1), and integrin subunit beta 3 (ITGB3, or GPIIa).…”