Burden of rare exome sequence variants in PROC gene is associated with venous thromboembolism: a population-based study

Weihong Tang, Mary Rachel Stimson, Saonli Basu, Susan R. Heckbert, Mary Cushman, James S. Pankow, Aaron R. Folsom, Nathan Pankratz

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1 Scopus citations


Background: Rare coding mutations underlying deficiencies of antithrombin and proteins C and S contribute to familial venous thromboembolism (VTE). It is uncertain whether rare variants play a role in the etiology of VTE in the general population. Objectives: We conducted a deep whole-exome sequencing (WES) study to investigate the associations between rare coding variants and the risk of VTE in two population-based prospective cohorts. Patients/Methods: Whole-exome sequencing was performed in the Longitudinal Investigation of Thromboembolism Etiology (LITE), which combines the Atherosclerosis Risk in Communities (ARIC) study (316 incident VTE events among 3159 African Americans [AAs] and 458 incident VTEs among 7772 European Americans [EAs]) and the Cardiovascular Healthy Study (CHS; 60 incident VTEs among 1751 EAs). We performed gene-based tests of rare variants (allele frequency < 1%, exome-wide significance P < 1.47 × 10−6) separately in each study and ancestry group, and meta-analyzed the results for the EAs in ARIC and CHS. Results: In the meta-analysis of EAs, we identified one gene, PROC, in which the burden of rare, coding variants was significantly associated with increased risk of VTE (HR = 5.42 [3.11, 9.42] for carriers versus non-carriers, P = 2.27 × 10−9). In ARIC EAs, carriers of the PROC rare variants had on average 0.75 standard deviation (SD) lower concentrations of plasma protein C and 0.28 SD higher D-dimer (P <.05) than non-carriers. Adjustment for low protein C status did not eliminate the association of PROC burden with VTE. In AAs, rare coding PROC variants were not associated with VTE. Conclusions: Rare coding variants in PROC contribute to increased VTE risk in EAs in this general population sample.

Original languageEnglish (US)
Pages (from-to)445-453
Number of pages9
JournalJournal of Thrombosis and Haemostasis
Issue number2
StatePublished - Feb 1 2020



  • genomics
  • protein C
  • rare mutations
  • venous thrombosis
  • whole exome sequencing

PubMed: MeSH publication types

  • Journal Article

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