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

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.

Keywords: genomics; protein C; rare mutations; venous thrombosis; whole exome sequencing.

Fig.1.

Quantile–quantile (Q-Q) plot for the meta-analysis of gene-based burden test in ARIC EAs and CHS EAs (genomic inflation factor (lambda) = 0.99).

Fig. 2.

PROC mutations in VTE cases and non-cases of European American individuals in ARIC. Red=cases only, blue=non-cases only, green=both cases and non-cases. The protein domains are as defined by PFAM (http://pfam.xfam.org/), which include a Gla site (vitamin K-dependent carboxylation/gamma-carboxyglutamic domain), an EGF site (epidermal growth factor-like domain), a FXa.. site (coagulation factor Xa inhibitory site), and a Trypsin (a serine protease) site.

Fig. 3.

Mutation plots of rare mutations in PROC in ARIC EAs (A) and AAs (B). The protein domains are as defined by PFAM (http://pfam.xfam.org/), which include a Gla site (vitamin K-dependent carboxylation/gamma-carboxyglutamic domain), an EGF site (epidermal growth factor-like domain), a FXa.. site (coagulation factor Xa inhibitory site), and a Trypsin (a serine protease) site.