The PCSK6-CORIN Polygenic Risk Score and Ischemic Stroke: The Dose-Response Association and Partial Mediation by...

This study aimed to assess the association of single nucleotide polymorphisms (SNPs) in the PCSK6‑CORIN pathway with IS, the predictive ability of weighted genetic risk score (wGRS), and the mediating role of hypertension.

A total of 2,207 patients with IS and 2,590 community controls were included in this case-control study. The wGRS was developed using data from six TagSNPs in PCSK6 and CORIN. The associations, dose-response relationships, and mediation effects were assessed using logistic regression, restricted cubic spline, and mediation analyses.

Two SNPs (rs1135911 and rs4695253) were significantly associated with IS under the additive model: rs1135911 (OR=1.310, P_Bonferroni=1.28×10^-4) and rs4695253 (OR = 1.459, P_Bonferroni=3.17 × 10^-7). Negative multiplicative interactions were observed between rs3749585 and rs4695253/rs11934749 (OR = 0.625 and 0.548, respectively; both P＜0.001). The wGRS showed a linear dose-response relationship with IS (overall P＜0.001, nonlinear P = 0.907). Among the wGRS quartiles, the highest quartile had an OR of 1.653 and a P-value of 3.84×10^-7). The plasma CORIN levels were significantly lower in patients with IS than in the controls (973.60±589.37 pg/mL vs. 1197.85±848.46 pg/mL, P = 0.043) in 88 IS and 88 controls. A history of hypertension appeared to partially mediate the effect of wGRS on IS, with a mediation proportion of 9.4% (95% CI: 5.0%-15.7%).

Genetic variants in the PCSK6‑CORIN pathway are associated with IS risk, and the genetic risk may be partially mediated by hypertension.