Loss of function in protein Z (PROZ) is associated with increased risk of ischemic stroke in the UK Biobank

The vitamin K-dependent coagulation factor protein Z (PZ), encoded by the PROZ gene, is canonically considered to have anticoagulant effects through negative regulation of factor Xa. Paradoxically, higher circulating PZ concentrations have repeatedly been associated with an elevated risk of acute ischemic stroke.

We performed a large-scale genetic association study to examine the relationship between germline genetic variants in PROZ and the risk of ischemic stroke.

Using whole-exome sequencing and clinical data for 416 711 participants in the UK Biobank (UKB), we identified individuals with rare (minor allele frequency ≤0.1%) putatively function-altering variants in PROZ. Using Firth's logistic regression and controlling for known stroke risk factors, we evaluated the association between variant carrier status and noncardioembolic ischemic stroke (NCEIS). Additionally, we evaluated differences in the plasma levels of 1472 proteins between PROZ variant carriers and noncarriers in a subset of 48 893 UKB participants.

After accounting for missing data, qualifying variants in PROZ were identified in 414 UKB participants (99.0% heterozygous). Variant carriers had a significantly increased risk of NCEIS (odds ratio, 2.34; 95% CI, 1.15-4.13; P = .02) but not of venous thromboembolism, myocardial infarction, or peripheral artery disease. Plasma proteomics analysis revealed that PROZ variant carriers had significantly elevated levels of 2 proteins related to the response to cerebral ischemia, peroxiredoxins 1 and 6 (PRDX1: fold change, 1.83; P = 1.3 × 10^-5; PRDX6: fold change, 1.78; P = 9.6 × 10^-10).

Lifelong exposure to decreased PZ levels confers a significantly increased risk of NCEIS, consistent with the role of PZ as an anticoagulant factor.