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.
Authors
- Steven P. Grover (ORCID: https://orcid.org/0000-0001-8709-8394)
- Satoshi Koyama (ORCID: https://orcid.org/0000-0002-9286-0360)
- Simone Sanna‐Cherchi (ORCID: https://orcid.org/0000-0002-6185-948X)
- Aleena Banerji (ORCID: https://orcid.org/0000-0001-9569-9915)
- Seung Hoan Choi (ORCID: https://orcid.org/0000-0002-2797-3190)
- Harish Eswaran (ORCID: https://orcid.org/0000-0001-9604-1138)
- Joel Rämö (ORCID: https://orcid.org/0000-0002-6429-5149)
- Amelia K. Haj (ORCID: https://orcid.org/0000-0002-1453-341X)
- Justine Ryu
- Pavan K. Bendapudi (ORCID: https://orcid.org/0000-0002-0754-7688)
- Patrick T. Ellinor (ORCID: https://orcid.org/0000-0002-2067-0533)
- Sharjeel Chaudhry (ORCID: https://orcid.org/0000-0002-7070-1326)
- Sean J. Jurgens (ORCID: https://orcid.org/0000-0002-1605-9782)
- Linda Sundler Björkman (ORCID: https://orcid.org/0000-0003-4146-9983)
- Xin Wang (ORCID: https://orcid.org/0009-0004-2370-0779)
- Alfonso Rodriguez Espada (ORCID: https://orcid.org/0009-0007-6743-5390)
Institutions
- Broad Institute (US)
- University of North Carolina at Chapel Hill (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Lund University (SE)
- Columbia University Irving Medical Center (US)
- Yale University (US)
- Massachusetts General Hospital (US)
- Amsterdam Neuroscience (NL)
- Institute for Molecular Medicine Finland (FI)
- University of Amsterdam (NL)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- Blood Advances
- Published
- 2025-09-30
- DOI
- https://doi.org/10.1182/bloodadvances.2025017220
- Citations
- 1
- Primary Topic
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Type
- article
- Field-Weighted Citation Impact
- 1.63
Funders
- American Heart Association
- CSL Behring
- European Commission
- Sigrid Juséliuksen Säätiö
- Svenska Läkaresällskapet
- National Institutes of Health