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。

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.