遗传 ›› 2017, Vol. 39 ›› Issue (2): 135-142.doi: 10.16288/j.yczz.16-288

• 研究报告 • 上一篇    下一篇

应用全外显子组测序筛查一高原肺水肿家系易感基因

杨应忠1,4,5(),王亚平2,胥瑾3,格日力1,4,5()   

  1. 1. 青海大学医学院高原医学研究中心,西宁 810001
    2. 青海省人民医院,西宁 810007
    3. 青海大学医学院,西宁 810001
    4. 青海省高原医学应用基础重点实验室,西宁 810001
    5. 青海-犹他高原医学联合重点实验室,西宁 810001
  • 收稿日期:2016-11-04 修回日期:2017-01-04 出版日期:2017-01-12 发布日期:2017-01-12
  • 作者简介:杨应忠,博士,教授,研究方向：高原低氧适应与损伤。Tel：0971-8175660; E-mail: yyz77921@hotmail.com|格日力,博士,教授,研究方向：高原医学。Tel：0971-6142063; E-mail: geriligao@hotmail.com.
  • 基金资助:
    国家自然科学基金项目(31160232);青海省科技厅应用基础基金项目(2016-ZJ-706)

The susceptibility gene screening in a Chinese high-altitude pulmonary edema family by whole-exome sequencing

Yingzhong Yang1,4,5(),Yaping Wang2,Jin Xu3,Rili Ge1,4,5(),   

  1. 1. Research Center for High Altitude Medical Science, Qinghai University School of Medicine, Xining 810001, China
    2. Department of Internal Medicine, Qinghai Provincial People's Hospital, Xining 810007, China
    3. Qinghai University School of Medicine, Xining 810001, China
    4. Basic and Applied Key Laboratory for High Altitude Medical Science and Technology of Qinghai, Xining 810001, China
    5. Qinghai-Utah United Key Laboratory for High Altitude Medical Science, Xining 810001, China
  • Received:2016-11-04 Revised:2017-01-04 Online:2017-01-12 Published:2017-01-12
  • Supported by:
    the National Natural Science Foundation of China(31160232);Basic Applied Study Foundation of Qinghai(2016-ZJ-706)

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摘要：

高原肺水肿(high-altitude pulmonary edema, HAPE)是一种高原特发性疾病,其发病与遗传因素有一定关联。本研究对一个HAPE相关的家系展开遗传学调查,然后利用外显子组测序筛查了包括先证者在内的6名HAPE病史成员以及先证者的母亲共7个成员的遗传变异,结果发现18个HAPE相关的潜在遗传变异(9个SNVs和9个Indels)。利用SIFT,PolyPhen-2和PROVEAN等3种软件对这些遗传变异进行蛋白功能危害性分析,结果发现定位于CFHR4基因的SNV(p.L85F)以及定位于OXER1基因的SNV(p.R176C)具有高危害性,且OXER1的功能与HAPE低氧诱导通路存在高度关联,它们可作为该家系中HAPE相关的候选病理性变异。此外,还有部分SNVs(NMB p.S150P、APOB p.I4194T和EIF4ENIF1 p.Q763P)以及Indels(KCNJ12 p.EE333-334E、ANKRD31 p.LMN251-253LN和OR2A14 p.HFFC175-178HFC),其遗传变异同样具有一定危害,可作为潜在的HAPE相关遗传变异。本研究首次通过外显子组测序直接筛选与一中国HAPE家系相关的遗传变异,为后续揭示HAPE发病机制提供了新线索。

关键词: 高原肺水肿, 家系, 全外显子组测序, CFHR4, OXER1

Abstract:

High-altitude pulmonary edema (HAPE) is one of idiopathic mountain sicknesses that occur in healthy lowlanders when they quickly ascend to altitudes exceeding 2500 m above sea levels within 1-7 days. Growing evidence suggests that genetics plays an important role in the risk of HAPE. In this study, we recruited a Chinese HAPE family and screened genetic variations in the 7 family members (including 6 family members with a medical history of HAPE and the propositus's mother) by whole-exome sequencing. The results showed 18 genetic variations (9 SNVs and 9 Indels) were related to HAPE. Two SNV sites (CFHR4 (p.L85F) and OXER1 (p.R176C)) were predicted to be damaging and alter protein functions by SIFT, PolyPhen-2 and PROVEAN software. The biological function of OXER1 was highly related to the hypoxia-inducible factor pathway. Therefore, those two sites were identified as candidate pathological variations. Moreover, other SNVs (NMB p.S150P, APOB p.I4194T, EIF4ENIF1 p.Q763P) and Indels (KCNJ12 p.EE333-334E, ANKRD31 p.LMN251-253LN, OR2A14 p.HFFC175-178HFC) were also predicted to be damaging as well, which also might be considered as potential candidate pathological variations related to HAPE. Collectively we firstly screened the susceptibility genes in a Chinese HAPE family by whole-exome sequencing, which will provide new clues for further mechanistic studies of HAPE.

Key words: HAPE, family, whole-exome sequencing, CFHR4, OXER1