Association Between CYP2C19 Genotypes With Clinical Phenotypes and Adipokine Levels Among Ischemic Stroke Patients: A Prospective Observational Study.

Abstract

Background Cytochrome P450 system is implicated in vascular pathologies, including stroke. Besides its role as a drug metabolizer, it also plays an important role in the metabolism of several endogenous substances like fatty acids, arachidonic acid, etc., which have pro-inflammatory effects. On the other hand, leptin and adiponectin are two of the most common adipose tissue-derived cytokines (adipokines), which are pro-inflammatory andanti-inflammatory in nature,respectively. Both of them are implicated in the pathogenesis of stroke. Methods We prospectively recruited ischemic stroke patients (within three months of occurrence of an attack of stroke). The occurrence of composite outcome (recurrence of transient ischemic attack/ischemic stroke or death)was evaluated for association with genetic variants of CYP2C19 (allele *2, *17, *3, and *4, i.e., single nucleotide polymorphism (SNP) 1/2/3/4, identified using TaqMan assays and DNA sequencing). Adiponectin and leptin levels weredetermined usingan enzyme-linked immunosorbent assay. Comparisons were made betweenstroke vs. control patients and between CYP2C19 intermediate metabolizer (IM)/poor metabolizer (PM) vs. extensive metabolizer (EM)/ultra metabolizer (UM) (PM: *2/*2; IM: *1/*2vs. EM: *1/*1; UM: *1/*17). P < 0.05 was taken as the threshold for statistical significance. Results A total of 204 patients and 101 controls were recruited. With regardto the occurrence of stroke, SNP2 showed a significant positive association. Haplotypes (SNP1/SNP2) AC (OR = 1.75 (1.08-2.83), p= 0.024) and GT (OR = 3.33 (1.53-7.22), p = 0.0026) were strongly associated with the occurrence of ischemic stroke even after adjustment for age and sex (global haplotype association p-value: 0.0062). Haplotype phenotype gender interaction was evident. Among stroke patients, with regardto composite outcome, only SNP1 showed a positive association. The AC haplotype was significantly associated with the occurrence of composite outcome (OR = 2.27 (1.17-4.41), p = 0.016). Among stroke patients, a significant positive association was seen between death and SNP1 (OR = 2.35 (1.13-4.90), p = 0.021) and AC haplotype (OR = 2.73 (1.20-6.22), p = 0.018). However, none of the SNPs or haplotypes showed any association with recurrence. Significant higher leptin and lower adiponectin levels were observed among stroke patients compared to controls.Leptin levels were higher in IM/PM group. IM/PM phenotypes showed a higher incidence of occurrence of composite outcome (hazard ratio = 2.07 (0.96-4.47), p = 0.056). Conclusion CYP2C19 polymorphisms may play a significant role in the pathogenesis of stroke. Leptin could serve as a prominent biomarker of atherosclerosis and inflammation in the early post-stroke period; however, further study is warranted with a larger sample size.