Whole-exome sequencing identifies rare variants in STAB2 associated with venous thromboembolic disease.

Autor:	Desch KC; Department of Pediatrics and., Ozel AB; Department of Human Genetics, University of Michigan, Ann Arbor, MI., Halvorsen M; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC., Jacobi PM; Department of Pediatrics and., Golden K; Department of Pediatrics and., Underwood M; Department of Pediatrics and., Germain M; INSERM UMR_S 1219, Bordeaux Population Health Research Center, University of Bordeaux, Bordeaux, France., Tregouet DA; INSERM UMR_S 1219, Bordeaux Population Health Research Center, University of Bordeaux, Bordeaux, France., Reitsma PH; Einthoven Laboratory for Experimental Vascular and Regenerative Medicine, Leiden, The Netherlands., Kearon C; Department of Medicine, McMaster University, Hamilton, ON, Canada., Mokry L; Department of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal, QC, Canada., Richards JB; Department of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal, QC, Canada., Williams F; Department of Twin Research and Genetic Epidemiology, Kings College London, London, United Kingdom., Li JZ; Department of Human Genetics, University of Michigan, Ann Arbor, MI., Goldstein D; Columbia University, Institute for Genomic Medicine, New York, NY; and., Ginsburg D; Department of Pediatrics and.; Department of Human Genetics, University of Michigan, Ann Arbor, MI.; Department of Internal Medicine, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2020 Jul 30; Vol. 136 (5), pp. 533-541.
DOI:	10.1182/blood.2019004161
Abstrakt:	Deep vein thrombosis and pulmonary embolism, collectively defined as venous thromboembolism (VTE), are the third leading cause of cardiovascular death in the United States. Common genetic variants conferring increased varying degrees of VTE risk have been identified by genome-wide association studies (GWAS). Rare mutations in the anticoagulant genes PROC, PROS1 and SERPINC1 result in perinatal lethal thrombosis in homozygotes and markedly increased VTE risk in heterozygotes. However, currently described VTE variants account for an insufficient portion of risk to be routinely used for clinical decision making. To identify new rare VTE risk variants, we performed a whole-exome study of 393 individuals with unprovoked VTE and 6114 controls. This study identified 4 genes harboring an excess number of rare damaging variants in patients with VTE: PROS1, STAB2, PROC, and SERPINC1. At STAB2, 7.8% of VTE cases and 2.4% of controls had a qualifying rare variant. In cell culture, VTE-associated variants of STAB2 had a reduced surface expression compared with reference STAB2. Common variants in STAB2 have been previously associated with plasma von Willebrand factor and coagulation factor VIII levels in GWAS, suggesting that haploinsufficiency of stabilin-2 may increase VTE risk through elevated levels of these procoagulants. In an independent cohort, we found higher von Willebrand factor levels and equivalent propeptide levels in individuals with rare STAB2 variants compared with controls. Taken together, this study demonstrates the utility of gene-based collapsing analyses to identify loci harboring an excess of rare variants with functional connections to a complex thrombotic disease. (© 2020 by The American Society of Hematology.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu