特定人群的单核苷酸多态性会增加非裔美国人发生静脉血栓栓塞的风险。
Population-specific single-nucleotide polymorphism confers increased risk of venous thromboembolism in African Americans.
作者信息
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
机构信息
Department of Genetics Stanford University School of Medicine Stanford California 94305.
Department of Pharmacotherapy and Translational Research University of Florida Gainesville Florida 32610.
出版信息
Mol Genet Genomic Med. 2016 Jun 21;4(5):513-20. doi: 10.1002/mgg3.226. eCollection 2016 Sep.
INTRODUCTION
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.
引言
非裔美国人静脉血栓栓塞症（VTE）的发病率高于欧洲裔个体。然而，欧洲裔人群中典型的遗传风险因素在非裔美国人中几乎不存在，影响较高VTE发生率的特定人群遗传因素尚未得到充分表征。
方法
我们对一个有复发性VTE的外显子测序非裔美国家庭进行了候选基因分析，并在蛋白S（PROS1）V510M（rs138925964）中鉴定出一个变体。我们使用一个多中心非裔美国人队列评估了PROS1 V510M对人群的影响，该队列包括306例VTE患者和370例对照。此外，我们将我们的病例队列与美国国立卫生研究院心肺血液研究所外显子测序项目（ESP）中的2203名非裔美国人的背景人群队列进行了比较。
结果
在有复发性VTE的非裔美国家庭中，我们发现我们病例的先前实验室检查表明游离蛋白S水平较低，为PROS1 V510M作为致病突变提供了功能支持。此外，在我们的多中心病例对照研究的VTE病例中，该变体显著富集（Fisher精确检验，P = 0.0041，OR = 4.62，95% CI：1.51 - 15.20；等位基因频率 - 病例：2.45%，对照：0.54%）。同样，与ESP队列中的非裔美国人相比，PROS1 V510M在我们的VTE病例队列中也有富集（Fisher精确检验，P = 0.010，OR = 2.28，95% CI：1.26 - 4.10）。
结论
我们在一个有VTE且蛋白S存在临床实验室异常的非裔美国家庭中发现了一个变体PROS1 V510M。此外，我们发现在一项非裔美国人的病例对照研究中，该变体增加了VTE风险。在ESP队列中，该变体在ESP欧洲裔受试者中几乎不存在（n = 3，等位基因频率：0.03%）。此外，在千人基因组计划第三阶段数据中，该变体仅出现在非洲裔人群中。因此，PROS1 V510M是非裔美国人中VTE的特定人群遗传风险因素。
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