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

TitleBurden of rare exome sequence variants in PROC gene is associated with venous thromboembolism: a population-based study.
Publication TypeJournal Article
Year of Publication2020
AuthorsTang W, Stimson MRachel, Basu S, Heckbert SR, Cushman M, Pankow JS, Folsom AR
Secondary AuthorsPankratz N
JournalJ Thromb Haemost
Volume18
Issue2
Pagination445-453
Date Published2020 02
ISSN1538-7836
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.

DOI10.1111/jth.14676
Alternate JournalJ Thromb Haemost
PubMed ID31680443
Grant ListHHSN268200800007C / 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