Title | Burden of rare exome sequence variants in PROC gene is associated with venous thromboembolism: a population-based study. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Tang W, Stimson MRachel, Basu S, Heckbert SR, Cushman M, Pankow JS, Folsom AR |
Secondary Authors | Pankratz N |
Journal | J Thromb Haemost |
Volume | 18 |
Issue | 2 |
Pagination | 445-453 |
Date Published | 2020 02 |
ISSN | 1538-7836 |
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 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 ). 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 CONCLUSIONS: Rare coding variants in PROC contribute to increased VTE risk in EAs in this general population sample. |
DOI | 10.1111/jth.14676 |
Alternate Journal | J Thromb Haemost |
PubMed ID | 31680443 |
Grant List | HHSN268200800007C / HL / NHLBI NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States HHSN268201700001I / HL / NHLBI NIH HHS / United States HHSN268201700002I / HL / NHLBI NIH HHS / United States HHSN268201700003I / HL / NHLBI NIH HHS / United States HHSN268201700004I / HL / NHLBI NIH HHS / United States HHSN268201700005I / HL / NHLBI NIH HHS / United States HHSN268201800001C / HL / NHLBI NIH HHS / United States HL087652 / HL / NHLBI NIH HHS / United States HL105756 / HL / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States N01HC85081 / HL / NHLBI NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States R01HL059367 / HL / NHLBI NIH HHS / United States U01HL080295 / HL / NHLBI NIH HHS / United States U01HL130114 / HL / NHLBI NIH HHS / United States 5RC2HL102419 / NH / NIH HHS / United States R01AG023629 / NH / NIH HHS / United States U54HG003273 / NH / NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States HHSN268201700001I / HL / NHLBI NIH HHS / United States HHSN268201700002I / HL / NHLBI NIH HHS / United States HHSN268201700003I / HL / NHLBI NIH HHS / United States HHSN268201700004I / HL / NHLBI NIH HHS / United States HHSN268201700005I / HL / NHLBI NIH HHS / United States HHSN268201800001C / HL / NHLBI NIH HHS / United States HL087652 / HL / NHLBI NIH HHS / United States HL105756 / HL / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States N01HC85081 / HL / NHLBI NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States R01HL059367 / HL / NHLBI NIH HHS / United States U01HL080295 / HL / NHLBI NIH HHS / United States U01HL130114 / HL / NHLBI NIH HHS / United States 5RC2HL102419 / NH / NIH HHS / United States R01AG023629 / NH / NIH HHS / United States U54HG003273 / NH / NIH HHS / United States |