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/829003215nas a2200481 4500008004100000022001400041245015300055210006900208260001600277520174000293100002102033700001402054700002302068700002002091700001902111700002502130700002602155700001802181700002102199700001802220700002202238700002102260700002102281700002202302700002402324700001902348700002102367700002302388700001902411700002202430700002302452700001702475700002002492700001802512700002802530700002302558700001902581700003002600700002002630700002402650700002302674856003602697 2022 eng d a1460-208300aWhole exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors.0 aWhole exome sequencing of 14 389 individuals from the ESP and CH c2022 May 123 a

Plasma levels of fibrinogen, coagulation factors VII and VIII, and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium and the National Heart, Lung, and Blood Institute's Exome Sequencing Project (ESP). Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5%) in FGG (with fibrinogen, p = 9.1x10-13), F7 (with factor VII, p = 1.3x10-72; seven novel variants), and VWF (with factor VIII and vWF; p = 3.2x10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; p = 4.2x10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to African Americans (rs3211938) in CD36. This variant has previously been linked to dyslipidemia but not with levels of a hemostatic factor. These efforts represent the largest integration of whole exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.

1 aPankratz, Nathan1 aWei, Peng1 aBrody, Jennifer, A1 aChen, Ming-Huei1 aVries, Paul, S1 aHuffman, Jennifer, E1 aStimson, Mary, Rachel1 aAuer, Paul, L1 aBoerwinkle, Eric1 aCushman, Mary1 aMaat, Moniek, P M1 aFolsom, Aaron, R1 aFranco, Oscar, H1 aGibbs, Richard, A1 aHaagenson, Kelly, K1 aHofman, Albert1 aJohnsen, Jill, M1 aKovar, Christie, L1 aKraaij, Robert1 aMcKnight, Barbara1 aMetcalf, Ginger, A1 aMuzny, Donna1 aPsaty, Bruce, M1 aTang, Weihong1 aUitterlinden, André, G1 aRooij, Jeroen, G J1 aDehghan, Abbas1 aO'Donnell, Christopher, J1 aReiner, Alex, P1 aMorrison, Alanna, C1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/9107