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Population-scale analysis reveals inherited C1-inhibitor deficiency is a polyphenotypic thrombotic disorder

Alfonso Rodriguez Espada1,2, Amelia Haj1,3,4, Sean Joseph Jurgens1,5,6

  • 1Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA.

Blood Advances
|September 30, 2025
PubMed

Insights

Loss of C1 inhibitor (C1INH) significantly increases thrombosis risk, including venous thromboembolism and ischemic stroke. This genetic deficiency is as likely to cause thrombosis as hereditary angioedema, revealing a new thrombotic disorder.

Area of Science:

  • Genetics and Genomics
  • Cardiovascular and Hematologic Diseases
  • Immunology

Background:

  • C1 inhibitor (C1INH, SERPING1) deficiency is primarily linked to hereditary angioedema (HAE-C1INH).
  • The association between C1INH deficiency and thrombosis risk in the general population remains underexplored.
  • Understanding genetic contributions to thrombosis is crucial for risk stratification and prevention.

Purpose of the Study:

  • To investigate the association between genetically defined C1INH deficiency and the risk of various thrombotic events.
  • To determine if SERPING1 variants confer increased susceptibility to venous thromboembolism, ischemic stroke, peripheral artery disease, and myocardial infarction.
  • To compare the lifetime attributable risks of thrombosis versus HAE-C1INH in SERPING1 variant carriers.

Main Methods:

  • Analysis of germline coding variation in SERPING1 across a large population cohort (635,823 participants).
  • Quantification of plasma C1INH levels using Olink® proteomics and ELISA.
  • Cox proportional hazards modeling to assess the risk of thrombotic events, adjusted for covariates.

Main Results:

  • Functionally deleterious SERPING1 variants were rare, indicating strong genetic constraint.
  • SERPING1 variant carriers exhibited significantly lower plasma C1INH levels.
  • SERPING1 haploinsufficiency was associated with significantly increased risks of venous thromboembolism (HR=4.64), ischemic stroke (HR=3.29), and peripheral artery disease (HR=3.10), with a trend for myocardial infarction (HR=2.77).

Conclusions:

  • SERPING1 haploinsufficiency represents a polyphenotypic thrombotic disorder, increasing the risk for multiple cardiovascular and thromboembolic events.
  • Thrombosis is as likely a manifestation of C1INH deficiency as HAE-C1INH.
  • Population-scale genetic data can elucidate fundamental questions regarding thrombosis risk and genetic determinants.

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