@article {8290, title = {Burden of rare exome sequence variants in PROC gene is associated with venous thromboembolism: a population-based study.}, journal = {J Thromb Haemost}, volume = {18}, year = {2020}, month = {2020 Feb}, pages = {445-453}, 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~{\texttimes}~10 ) 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~{\texttimes}~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.

CONCLUSIONS: Rare coding variants in PROC contribute to increased VTE risk in EAs in this general population sample.

}, issn = {1538-7836}, doi = {10.1111/jth.14676}, author = {Tang, Weihong and Stimson, Mary Rachel and Basu, Saonli and Heckbert, Susan R and Cushman, Mary and Pankow, James S and Folsom, Aaron R and Pankratz, Nathan} }