Population-scale Analysis Reveals Germline Loss of SERPING1 (C1-Inhibitor) is a Polyphenotypic Thrombotic Disorder.

Deficiency in C1 inhibitor (C1INH, SERPING1) is canonically associated with hereditary angioedema (HAE-C1INH) but not thrombosis. To determine the thrombosis risk conferred by loss of C1INH in the general population, we studied genetically-defined C1INH deficiency across 635,823 participants. Functionally deleterious germline coding variation in SERPING1 was rare (~1:10,000), indicating strong genetic constraint. SERPING1 variant carriers had significantly lower plasma C1INH levels than non-carriers as determined by Olink® proteomics (P=0.005) and confirmed by ELISA in an independent cohort (P<0.001). After adjustment for age, sex, and ancestry, SERPING1 haploinsufficiency was associated with a significantly increased risk of venous thromboembolism (HR=4.64, 95% CI: 2.08-10.34, P=0.0002), non-cardioembolic ischemic stroke (HR=3.29, 95% CI: 1.06-10.19, P=0.039), and peripheral artery disease (HR=3.10, 95% CI: 1.29-7.45, P=0.011), with a trend towards association with myocardial infarction (HR=2.77, 95% CI: 0.89-8.61, P=0.077). Effect size estimates for all four thrombosis phenotypes increased when analysis was restricted to only the most functionally deleterious variants. Furthermore, the lifetime attributable risks of thrombosis and HAE-C1INH were similar among SERPING1 variant carriers. Taken together, our data suggest that SERPING1 haploinsufficiency represents a polyphenotypic thrombotic disorder and that thrombosis is as likely as HAE-C1INH to be a manifestation of C1INH deficiency. These findings highlight the potential of population-scale datasets to address fundamental questions related to thrombosis risk.