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Burden of rare exome sequence variants in PROC gene is associated with venous thromboembolism: a population‐based study
Author(s) -
Tang Weihong,
Stimson Mary Rachel,
Basu Saonli,
Heckbert Susan R.,
Cushman Mary,
Pankow James S.,
Folsom Aaron R.,
Pankratz Nathan
Publication year - 2020
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.14676
Subject(s) - medicine , exome sequencing , exome , etiology , allele , population , bioinformatics , genetics , gene , mutation , biology , environmental health
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.