Interactions amongCOX-2,GPIIIaandP2Y1variants are associated with aspirin responsiveness and adverse events in patients with ischemic stroke.
BACKGROUND
The effect of gene variants and their interactions on response to aspirin and clinical adverse outcomes after an acute ischemic stroke (IS) is not fully understood. The aim of this study was to investigate the association of aspirin-relevant gene variants and their interactions with clinical adverse outcomes in IS patients taking aspirin.


METHODS
A total of 14 variants from six genes encoding COX enzymes (COX-1, COX-2), platelet membrane receptors (TXAS1, P2Y1, P2Y12) and glycoprotein receptor(GPIIIa)were examined in 850 acute IS patients. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) analysis. All patients were followed up for 1 year after admission. Primary outcome was a composite of recurrent ischemic stroke (RIS), myocardial infarction (MI) and death.


RESULTS
The primary outcome occurred in 112 (13.5%) patients (81 RIS, 16 MI and 15 deaths). There were no significant differences in the frequencies of the genotypes of the 14 variants between the patients with and without primary outcome using single-locus analytical approach. However, there was significant gene-gene interaction among rs20417, rs1371097 and rs2317676. The high-risk interactive genotypes of rs20417, rs1371097 and rs2317676 were independently associated with primary adverse outcome of RIS, MI, and death after acute IS.


CONCLUSIONS
The three-loci interactions are associated with sensitivity of IS patients to aspirin and aspirin-induced adverse clinical events. The combinatorial analysis used in this study may be helpful to elucidate complex genetic risk of aspirin resistance (AR).


BACKGROUND
The study described here is registered at http://www.chictr.org/ (unique identifier: ChiCTR-OCH-14004724).
Department of Neurology, People's Hospital of Deyang City, 173 North Taishan Road, Deyang, Sichuan 618000, China.
Xingyang
X
Yi
Department of Neurology, The 2nd affiliated hospital and Yuying children hospital of Wenzhou Medical University, No 109, Xueyuan West Road, Wenzhou, Zhejiang 325027, China.
Zhao
Z
Han
Department of Neurology, Third Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang, China.
Qiang
Q
Zhou
Department of Neurology, Third Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang, China.
Jing
J
Lin
Department of Neurology, People's Hospital of Deyang City, Deyang, Sichuan, China.
Chun
C
Wang
aspirin resistance; genetic variants; ischemic stroke; outcome; pharmacogenetics