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Burden of rare exome sequence variants in PROC gene is associated with venous thromboembolism: a population-based study.
Monday,2020-03-23 16:18 America/Los_Angeles — ecterry
| 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, Pankratz, N |
| Journal | J Thromb Haemost |
| Volume | 18 |
| Issue | 2 |
| Pagination | 445-453 |
| Date Published | 2020 Feb |
| ISSN | 1538-7836 |
| Abstract | <p><b>BACKGROUND: </b>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.</p><p><b>OBJECTIVES: </b>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.</p><p><b>PATIENTS/METHODS: </b>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 ) separately in each study and ancestry group, and meta-analyzed the results for the EAs in ARIC and CHS.</p><p><b>RESULTS: </b>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 < .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.</p><p><b>CONCLUSIONS: </b>Rare coding variants in PROC contribute to increased VTE risk in EAs in this general population sample.</p> |
| 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 |
ePub date:
20/01