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

Rodriguez Espada, Alfonso ; Haj, Amelia ; Jurgens, Sean Joseph ; Eswaran, Harish ; Sundler Björkman, Linda LU orcid ; Ryu, Justine ; Chaudhry, Sharjeel ; Koyama, Satoshi ; Wang, Xin and Choi, Seung Hoan , et al. (2025) In Blood Advances
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 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... (More)

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.

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Contribution to journal
publication status
epub
subject
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Blood Advances
publisher
American Society of Hematology
external identifiers
  • pmid:41026970
ISSN
2473-9529
DOI
10.1182/bloodadvances.2025017220
language
English
LU publication?
yes
additional info
Copyright © 2025 American Society of Hematology.
id
11227f56-2356-4475-a01d-9705f8a7fa58
date added to LUP
2025-10-29 14:06:30
date last changed
2025-10-29 14:06:30
@article{11227f56-2356-4475-a01d-9705f8a7fa58,
  abstract     = {{<p>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&lt;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.</p>}},
  author       = {{Rodriguez Espada, Alfonso and Haj, Amelia and Jurgens, Sean Joseph and Eswaran, Harish and Sundler Björkman, Linda and Ryu, Justine and Chaudhry, Sharjeel and Koyama, Satoshi and Wang, Xin and Choi, Seung Hoan and Sanna-Cherchi, Simone and Banerji, Aleena and Rämö, Joel T and Ellinor, Patrick T and Grover, Steven P and Bendapudi, Pavan K}},
  issn         = {{2473-9529}},
  language     = {{eng}},
  month        = {{09}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood Advances}},
  title        = {{Population-scale Analysis Reveals Germline Loss of SERPING1 (C1-Inhibitor) is a Polyphenotypic Thrombotic Disorder}},
  url          = {{http://dx.doi.org/10.1182/bloodadvances.2025017220}},
  doi          = {{10.1182/bloodadvances.2025017220}},
  year         = {{2025}},
}