Association between MEF2A variants and ischemic stroke risk: a case-control study and two prospective cohort studies in a Chinese population

Transcriptional regulators encoded by the myocyte enhancer factor 2 (MEF2) gene family play a crucial role in cardiac development, homeostasis, and pathology. The relationship between MEF2A and ischemic stroke (IS) remains unclear. We performed MEF2A polymorphism genotyping in a case-control study (2497 patients with IS vs. 3135 controls) and a cohort study involving 4080 non-stroke participants, which included up to 11.54 years of follow-up. Additionally, the mortality outcomes of 2298 patients with IS were followed up for 6.49 years. Furthermore, 301 IS and 313 controls were selected from the case-control study for MEF2A mRNA expression quantification using RT-qPCR. The modified Rankin Scale (mRS) scores of IS at the time of discharge and, one, three, six month post-discharge was collected. Multiple Cox regression analyses were used to estimate the hazard ratio (HR) with 95% confidence interval (CI). Restricted cubic spline (RCS) regression analyses were used to evaluate the dose-response relationship between mRNA expression levels and IS. Linear mixed-effects models were applied to examine the associations of the two SNPs and mRNA expression with the mRS scores. Carriers of the 2292288-rs3743248 G-T haplotype had a higher IS risk compared with carriers of the G-C haplotype; OR (95% CI]) were as follows: 1.417(1.120, 1.792), 1.581 (1.172, 2.133), 1.314 (0.991, 1.741) for patients with IS, large-artery atherosclerosis subtype, small-artery occlusion, respectively. Sex-stratified analysis identified rs2292288-AA as a female-specific risk factor for IS prevalence (HR = 1.755, 95% CI: 1.179–2.613), while in patients > 65 years, A-allele carriers showed worse functional recovery (higher mRS, P = 0.012). There was a non-linear correlation between MEF2A mRNA expression level and IS risk (Pnonlinear= 0.001), after adjustment for covariates. Our findings indicate that the MEF2A G-T haplotype is associated with IS susceptibility. While the rs2292288 variant demonstrates sex-specific effects on disease incidence and age-specific effects on recovery. Lower MEF2A mRNA expression was associated with an increased IS risk.