02552nas a2200229 4500008004100000022001400041245012500055210006900180260001300249300001200262490000700274520184000281100001802121700002602139700001702165700002302182700001802205700002102223700002102244700002102265856003602286 2020 eng d a1538-783600aBurden of rare exome sequence variants in PROC gene is associated with venous thromboembolism: a population-based study.0 aBurden of rare exome sequence variants in PROC gene is associate c2020 Feb a445-4530 v183 a

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 ) 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 ). 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.

1 aTang, Weihong1 aStimson, Mary, Rachel1 aBasu, Saonli1 aHeckbert, Susan, R1 aCushman, Mary1 aPankow, James, S1 aFolsom, Aaron, R1 aPankratz, Nathan uhttps://chs-nhlbi.org/node/8290