| Title: | Population-scale analysis reveals inherited C1-inhibitor deficiency is a polyphenotypic thrombotic disorder |
| Journal: | Blood Advances |
| Published: | 10 Feb 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41026970/ |
| DOI: | https://doi.org/10.1182/bloodadvances.2025017220 |
| URL: | https://ashpublications.org/bloodadvances/article-pdf/doi/10.1182/bloodadvances.2025017220/2414933/bloodadvances.2025017220.pdf |
Publication 18326
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Abstract
ABSTRACT: 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.</p>
10 Keywords
- Adult
- Aged
- Complement C1 Inhibitor Protein
- Female
- Genetic Predisposition to Disease
- Humans
- Male
- Middle Aged
- Phenotype
- Thrombosis
16 Authors
- Alfonso Rodriguez Espada
- Amelia K. Haj
- Sean J. Jurgens
- Harish Eswaran
- Linda Sundler Björkman
- Justine Ryu
- Sharjeel Chaudhry
- Satoshi Koyama
- Xin Wang
- Seung Hoan Choi
- Simone Sanna-Cherchi
- Aleena Banerji
- Joel T. Rämö
- Patrick T. Ellinor
- Steven P. Grover
- Pavan K. Bendapudi
1 Application
| Application ID | Title |
|---|---|
| 17488 | Understanding the Genetic Basis of Cardiac Arrhythmias |
Enabling scientific discoveries that improve human health