Open AccessPopulation‐specific single‐nucleotide polymorphism confers increased risk of venous thromboembolism in African Americans
Author(s) -
Daneshjou Roxana,
Cavallari Larisa H.,
Weeke Peter E.,
Karczewski Konrad J.,
Drozda Katarzyna,
Perera Minoli A.,
Johnson Julie A.,
Klein Teri E.,
Bustamante Carlos D.,
Roden Dan M.,
Shaffer Christian,
Denny Joshua C.,
Zehnder James L.,
Altman Russ B.
Publication year - 2016
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.226
Subject(s) - medicine , cohort , population , protein s , exact test , incidence (geometry) , cohort study , allele frequency , exome sequencing , exome , allele , genetics , protein c , biology , mutation , gene , environmental health , optics , physics
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 ( PROS 1 ) V510M (rs138925964). We assessed the population impact of PROS 1 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 PROS 1 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, PROS 1 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, PROS 1 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, PROS 1 V510M is a population‐specific genetic risk factor for VTE in African Americans.