Burden of rare exome sequence variants in PROC gene is associated with venous thromboembolism: a population‐based study. (6th December 2019)

• Record Type: Journal Article
• Authors: Tang, Weihong; Stimson, Mary Rachel; Basu, Saonli; Heckbert, Susan R.; Cushman, Mary; Pankow, James S.; Folsom, Aaron R.; Pankratz, Nathan
• Is Part Of: Journal of thrombosis and haemostasis. Volume 18:Number 2(2020)
• Page Start: 445
• Page End: 453
• Publication Date: 2019-12-06
• Subjects: genomics -- protein C -- rare mutations -- venous thrombosis -- whole exome sequencing; Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.14676
• Languages: English
• ISSNs: 1538-7933

Abstract

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.