Population-scale analysis reveals inherited C1-inhibitor deficiency 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 the loss of C1INH in the general population, we studied genetically-defined C1INH deficiency across 635 823 participants. Functionally deleterious germ line coding variation in the SERPING1 gene was rare (∼1:10 000), indicating strong genetic constraint. SERPING1 variant carriers had significantly lower plasma C1INH levels than noncarriers, as determined by Olink proteomics (P = .005) and confirmed by enzyme-linked immunosorbent assay in an independent cohort (P < .001). After adjustment for sex and ancestry, SERPING1 haploinsufficiency was associated with a significantly increased risk of venous thromboembolism (hazard ratio [HR], 4.64; 95% confidence interval [CI], 2.08-10.34; P = .0002), noncardioembolic ischemic stroke (HR, 3.29; 95% CI, 1.06-10.19; P = .039), and peripheral artery disease (HR, 3.10; 95% CI, 1.29-7.45; P = .011), with a trend toward association with myocardial infarction (HR, 2.77; 95% CI, 0.89-8.61; P = .077). Effect size estimates for all 4 thrombosis phenotypes increased when analysis was restricted to only the most functionally deleterious variants. These findings highlight the potential of population-scale data sets to address fundamental questions related to thrombosis risk.