title: Population-specific single-nucleotide polymorphism confers increased risk of venous thromboembolism in African Americans.
abstract: BACKGROUND
  African Americans have a higher incidence of venous thromboembolism (VTE) than European descent individuals. However, the typical genetic risk factors in populations of European descent are nearly absent in African Americans, and population-specific genetic factors influencing the higher VTE rate are not well characterized.
  
  
  METHODS
  We performed a candidate gene analysis on an exome-sequenced African American family with recurrent VTE and identified a variant in Protein S (PROS1) V510M (rs138925964). We assessed the population impact of PROS1 V510M using a multicenter African American cohort of 306 cases with VTE compared to 370 controls. Additionally, we compared our case cohort to a background population cohort of 2203 African Americans in the NHLBI GO Exome Sequencing Project (ESP).
  
  
  RESULTS
  In the African American family with recurrent VTE, we found prior laboratories for our cases indicating low free Protein S levels, providing functional support for PROS1 V510M as the causative mutation. Additionally, this variant was significantly enriched in the VTE cases of our multicenter case-control study (Fisher's Exact Test, P = 0.0041, OR = 4.62, 95% CI: 1.51-15.20; allele frequencies - cases: 2.45%, controls: 0.54%). Similarly, PROS1 V510M was also enriched in our VTE case cohort compared to African Americans in the ESP cohort (Fisher's Exact Test, P = 0.010, OR = 2.28, 95% CI: 1.26-4.10).
  
  
  CONCLUSIONS
  We found a variant, PROS1 V510M, in an African American family with VTE and clinical laboratory abnormalities in Protein S. Additionally, we found that this variant conferred increased risk of VTE in a case-control study of African Americans. In the ESP cohort, the variant is nearly absent in ESP European descent subjects (n = 3, allele frequency: 0.03%). Additionally, in 1000 Genomes Phase 3 data, the variant only appears in African descent populations. Thus, PROS1 V510M is a population-specific genetic risk factor for VTE in African Americans.
authors.affiliation: Department of Genetics Stanford University School of Medicine Stanford California 94305.
authors.forename: Roxana
authors.initials: R
authors.lastname: Daneshjou
authors.affiliation: Department of Pharmacotherapy and Translational Research University of Florida Gainesville Florida 32610.
authors.forename: Larisa H
authors.initials: LH
authors.lastname: Cavallari
authors.affiliation: Department of MedicineVanderbilt UniversityNashvilleTennessee37201; The Department of CardiologyCopenhagen University HospitalGentofteDenmark.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Weeke
authors.affiliation: Department of GeneticsStanford University School of MedicineStanfordCalifornia94305; Biomedical Informatics Training ProgramStanford University School of MedicineStanfordCalifornia 94305.
authors.forename: Konrad J
authors.initials: KJ
authors.lastname: Karczewski
authors.affiliation: Department of Pharmacy Practice University of Illinois at Chicago Chicago Illinois 60612.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Drozda
authors.affiliation: Department of Medicine University of Chicago Chicago Illinois 60637.
authors.forename: Minoli A
authors.initials: MA
authors.lastname: Perera
authors.affiliation: Department of Pharmacotherapy and Translational Research University of Florida Gainesville Florida 32610.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: Department of Genetics Stanford University School of Medicine Stanford California 94305.
authors.forename: Teri E
authors.initials: TE
authors.lastname: Klein
authors.affiliation: Department of Genetics Stanford University School of Medicine Stanford California 94305.
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bustamante
authors.affiliation: Department of MedicineVanderbilt UniversityNashvilleTennessee37201; Department of PharmacologyVanderbilt UniversityNashvilleTennessee37201; Department of BiomedicalInformatics Vanderbilt UniversityNashvilleTennessee37201.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.affiliation: Department of Medicine Vanderbilt University Nashville Tennessee 37201.
authors.forename: Christian
authors.initials: C
authors.lastname: Shaffer
authors.affiliation: Department of Medicine Vanderbilt University Nashville Tennessee 37201.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
authors.affiliation: Department of Medicine Stanford University School of Medicine Stanford California 94305.
authors.forename: James L
authors.initials: JL
authors.lastname: Zehnder
authors.affiliation: Department of GeneticsStanford University School of MedicineStanfordCalifornia94305; Department of BioengineeringStanford University School of MedicineStanfordCalifornia94305.
authors.forename: Russ B
authors.initials: RB
authors.lastname: Altman
keywords: African American; hypercoagulability; pulmonary embolism; venous thromboembolism