Abstract
IntroductionAfrican 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.MethodsWe 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).ResultsIn 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).ConclusionsWe 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.
Highlights
Introduction AfricanAmericans have a higher incidence of venous thromboembolism (VTE) than European descent individuals
PROS1 V510M was enriched in our VTE case cohort compared to African Americans in the Exome Sequencing Project (ESP) cohort (Fisher’s Exact Test, P = 0.010, OR = 2.28, 95% CI: 1.26–4.10)
Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc
Summary
Introduction AfricanAmericans have a higher incidence of venous thromboembolism (VTE) than European descent individuals. Tested genetic variants in European descent individuals include F5 R506Q (5% prevalence) (MIM#: 612309), which confers a three to fivefold increased risk of VTE in carriers and F2 G20210A (0.7 to 4% prevalence) (MIM#: 176930), which confers a two to threefold increased risk of VTE in carriers (Middeldorp and van Hylckama Vlieg 2008; Rosendaal and Reitsma 2009). Both of these variants are rare in individuals of African descent (Dowling et al 2003; Roberts et al 2009). A review of the literature shows a dearth of identified genetic risk factors for VTE in African Americans, even though African Americans have a similar rate of positive family history as European descent individuals (28–29%) (Dowling et al 2003)
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