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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Variants in clopidogrel-relevant genes and early neurological deterioration in ischemic stroke patients receiving
Xingyang Yi1, Qiang Zhou2, Yongyin Zhang3
1Department of Neurology, the People's Hospital of Deyang City, Deyang, 618000, Sichuan, China.
Insights
Early neurological deterioration (END) is common in acute ischemic stroke (IS) patients treated with clopidogrel. Gene interactions, particularly among CYP2C19*2, P2Y12, and GPIIIa variants, significantly increase END risk.
Area of Science:
- Pharmacogenomics
- Neurology
- Cardiovascular Medicine
Background:
- Early neurological deterioration (END) is a frequent complication in acute ischemic stroke (IS).
- The precise mechanisms driving END remain incompletely understood.
- This study investigates genetic factors influencing END in IS patients undergoing clopidogrel therapy.
Purpose of the Study:
- To assess the association of 16 clopidogrel-related gene variants with END in acute IS patients.
- To explore potential gene-gene interactions contributing to END risk.
- To identify genetic markers that may predict END in patients receiving clopidogrel.
Main Methods:
- 375 acute IS patients were enrolled, with platelet aggregation measured at baseline and after 7-10 days of clopidogrel treatment.
- Genotyping of 16 clopidogrel-relevant gene variants was performed using mass spectrometry.
- Generalized multifactor dimensionality reduction (GMDR) was employed to analyze gene-gene interactions and their association with END.
Main Results:
- 95 out of 375 patients (25.3%) experienced END within 10 days of admission.
- The CYP2C19*2 (rs4244285) variant showed a single-locus association with END.
- GMDR analysis identified a synergistic interaction between CYP2C19*2 rs4244285, P2Y12 rs16863323, and GPIIIa rs2317676, significantly predicting END risk (HR: 2.82; P=0.003).
Conclusions:
- END is a significant concern in acute IS patients, likely driven by multifactorial mechanisms.
- Interactions among CYP2C19*2, P2Y12, and GPIIIa variants represent a critical genetic risk factor for END.
- Personalizing clopidogrel therapy based on these high-risk genotypes is crucial for managing END risk.
Background:
Early neurological deterioration (END) is common in acute ischemic stroke (IS). However, the underlying mechanisms for END are unclear. The aim of this study was to evaluate the associations of 16 variants in clopidogrel-relevant genes and interactions among these variants with END in acute IS patients receiving clopidogrel treatment.
Methods:
We consecutively enrolled 375 acute IS patients between June 2014 and January 2015. Platelet aggregation was measured on admission and after the 7-10 days of clopidogrel treatment. The 16 variants in clopidogrel-relevant genes were examined using mass spectrometry. The primary outcome was END within the 10 days of admission. Gene-gene interactions were analyzed by generalized multifactor dimensionality reduction (GMDR) methods.
Results:
Among the 375 patients, 95 (25.3%) patients developed END within the first 10 days of admission. Among the 16 variants, only CYP2C19*2 (rs4244285) AA/AG was associated with END using single-locus analytical approach. GMDR analysis revealed that there was a synergistic effect of gene-gene interactions among CYP2C19*2 rs4244285, P2Y12 rs16863323, and GPIIIa rs2317676 on the risk for END. The high-risk interactions among the three variants were associated with the higher platelet aggregation and independent predictor for END after adjusting for the covariates (hazard ratio: 2.82; 95% confidence interval: 1.36-7.76; P = 0.003).
Conclusions:
END is very common in patients with acute IS. The mechanisms leading to END are most likely multifactorial. Interactions among CYP2C19*2 rs4244285, P2Y12 rs16863323, and GPIIIa rs2317676 may confer a higher risk for END. It was very important to modify clopidogrel therapy for the patients carrying the high-risk interactive genotypes.
Clinical Trial Registration Information:
The study described here is registered at http://www.chictr.org/ (unique Identifier: ChiCTR-OCH-14004724). The date of trial registration was May 30, 2014.
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