Genetic Susceptibility to Adult Cerebral Venous Thrombosis: An Updated Meta-Analysis of Candidate Gene Studies.

Abstract

Genetic predisposition is increasingly recognized as an important contributor to cerebral venous thrombosis (CVT), yet findings from individual studies remain inconsistent. We conducted an updated meta-analysis to quantify associations between specific genetic variants and adult CVT. We systematically searched PubMed, EMBASE, and Web of Science up to January 2025 for case-control studies comparing the prevalence of genetic variants in adults with CVT versus healthy controls. Pooled odds ratios (ORs) with 95% CIs were calculated using random-effects models in this meta-analysis. Sixty-one studies comprising 4106 patients with CVT and 12 323 controls were analyzed. Significant associations were identified for germline variants, including <i>factor V Leiden</i> (238/2753 [8.6%] versus 387/8747 [4.4%]; OR, 2.59 [95% CI, 2.06-3.26]; <i>P</i><0.00001), <i>prothrombin G20210A</i> (290/2483 [11.7%] versus 235/8197 [2.9%]; OR, 6.05 [95% CI, 4.59-7.98]; <i>P</i><0.00001), and inherited deficiencies of <i>protein C</i> (24/624 [3.8%] versus 7/2027 [0.3%]; OR, 10.30 [95% CI, 4.19-25.30]; <i>P</i><0.00001), <i>protein S</i> (9/567 [1.6%] versus 1/1125 [0.1%]; OR, 6.86 [95% CI, 2.12-22.24]; <i>P</i>=0.001), and <i>antithrombin</i> (11/440 [2.5%] versus 3/989 [0.3%]; OR, 5.73 [95% CI, 1.98-16.55]; <i>P</i>=0.001). The somatic <i>JAK-2 (Janus kinase-2) V617F</i> mutation was likewise associated with increased risk (27/569 [4.7%] versus 13/1777 [0.7%]; OR, 9.17 [95% CI, 3.61-23.27]; <i>P</i><0.00001). By contrast, <i>MTHFR (methylenetetrahydrofolate reductase) C677T</i> and <i>PAI-1 (plasminogen activator inhibitor-1) 4G/5G</i> polymorphisms showed no significant associations. Overall effect sizes were comparable to those reported in pediatric CVT but exceeded those in adult arterial ischemic stroke. These findings support a genetic basis for adult CVT. Risk associations are broadly similar to pediatric CVT yet stronger than those reported for adult arterial ischemic stroke, highlighting distinct patterns of genetic susceptibility in venous stroke and the potential value of selective genetic testing for risk stratification and management.