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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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
Volume18
Issue number2
DOIs
StatePublished - Feb 1 2020

Bibliographical note

Funding Information:
The National Heart, Lung, and Blood Institute (NHLBI) provided support for LITE via R01 HL059367. This work was carried out in part using computing resources at the University of Minnesota Supercomputing Institute. Funding support for ?Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium? was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). Data for ?Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium? was provided by Eric Boerwinkle on behalf of the Atherosclerosis Risk in Communities (ARIC) Study and Bruce Psaty, principal investigator for the Cardiovascular Health Study (CHS). Sequencing was carried out at the Baylor Genome Center (U54 HG003273). The Atherosclerosis Risk in Communities study has been funded in whole or in part with federal funds from the NHLBI, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I). The authors thank the staff and participants of the ARIC study for their important contributions. The Cardiovascular Health Study (CHS) research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295, HL087652, HL105756, and U01HL130114 from the NHLBI, with additional contribution from National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institutes on Aging (NIA). A full list of CHS principal investigators and institutions can be found at CHS-NHLBI.org. The authors wish to acknowledge the support of the NHLBI and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research. The content of the manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
The National Heart, Lung, and Blood Institute (NHLBI) provided support for LITE via R01 HL059367. This work was carried out in part using computing resources at the University of Minnesota Supercomputing Institute. Funding support for “Building on GWAS for NHLBI‐diseases: the U.S. CHARGE consortium” was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). Data for “Building on GWAS for NHLBI‐diseases: the U.S. CHARGE consortium” was provided by Eric Boerwinkle on behalf of the Atherosclerosis Risk in Communities (ARIC) Study and Bruce Psaty, principal investigator for the Cardiovascular Health Study (CHS). Sequencing was carried out at the Baylor Genome Center (U54 HG003273). The Atherosclerosis Risk in Communities study has been funded in whole or in part with federal funds from the NHLBI, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I). The authors thank the staff and participants of the ARIC study for their important contributions. The Cardiovascular Health Study (CHS) research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295, HL087652, HL105756, and U01HL130114 from the NHLBI, with additional contribution from National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institutes on Aging (NIA). A full list of CHS principal investigators and institutions can be found at CHS‐NHLBI.org. The authors wish to acknowledge the support of the NHLBI and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research. The content of the manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Keywords

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

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, American Recovery and Reinvestment Act

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