EGLN1 variants influence expression and SaO2 levels to associate with high-altitude pulmonary oedema and adaptation
EGLN1 variants influence expression and SaO2 levels to associate with high-altitude pulmonary oedema and adaptation
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DOI：
10.1042/cs20120371
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发表时间：
2013-04-01
期刊：
影响因子：
6
通讯作者：
Pasha, M. A. Qadar
中科院分区：
文献类型：
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作者：
Mishra, Aastha;Mohammad, Ghulam;Pasha, M. A. Qadar
EGLN 1 [编码HIF（缺氧诱导因子）-脯氨酰羟化酶2]在HIF途径中起着关键作用，并已成为HA（高海拔）生理学方面最有趣的基因之一。EGLN 1作为一种实际的氧传感器，似乎在对低压低氧环境的功能适应中具有潜在的作用。在本研究中，我们筛选了EGLN 1的30个多态性，评估其基因表达并进行关联分析。此外，还研究了等位基因变体在改变TF（转录因子）结合位点中的作用，并因此研究了这些位点处TF的替换。该研究在250名HAPE-p [HAPE（HA肺水肿）患者]、210名HAPE-f（无HAPE对照）和430名HL（健康的拉达克高地原住民）中进行。rs 1538664、rs 479200、rs 2486729、rs 2790879、rs 480902、rs 2486736和rs 973252 7个多态性位点的基因型在HAPE-p和HAPE-f组间差异有统计学意义（P < 0.008）。rs 1538664、rs 479200、rs 2486729、rs 2790879、rs 480902、rs 2486736和rs 973252的AA、TT、M、GG、CC、AA和GG基因型在HAPE-p中流行，被鉴定为危险基因型，而在HL中流行的对应纯合子被鉴定为保护基因型。EGLN 1在HAPE-p中表达上调4.56倍（P = 0.0084）。EGLN 1表达上调与危险基因型、单倍型及互作基因型有关（P < 0.05）。同样，回归分析显示，风险等位基因和易感单倍型与三组中SaO（2）（动脉血氧饱和度）水平降低相关。SaO（2）水平与肺动脉收缩压（PASP）和EGLN 1表达呈显著负相关，这些多态性与SaO（2）水平和EGLN 1表达的相关性有助于揭示低压低氧适应和适应不良的分子机制。
EGLN1 [encoding HIF (hypoxia-inducible factor)-prolyl hydroxylase 2] plays a pivotal role in the HIF pathway and has emerged as one of the most intriguing genes with respect to physiology at HA (high altitude). EGLN1, being an actual oxygen sensor, appears to have a potential role in the functional adaptation to the hypobaric hypoxic environment. In the present study, we screened 30 polymorphisms of EGLN1, evaluated its gene expression and performed association analyses. In addition, the role of allelic variants in altering TF (transcription factor)-binding sites and consequently the replacement of TFs at these loci was also investigated. The study was performed in 250 HAPE-p [HAPE (HA pulmonary oedema)-patients], 210 HAPE-f (HAPE-free controls) and 430 HLs (healthy Ladakhi highland natives). The genotypes of seven polymorphisms, rs1538664, rs479200, rs2486729, rs2790879, rs480902, rs2486736 and rs973252, differed significantly between HAPE-p and HAPE-f (P < 0.008). The genotypes AA, TT, M, GG, CC, AA and GG of rs1538664, rs479200, rs2486729, rs2790879, rs480902, rs2486736 and rs973252, prevalent in HAPE-p, were identified as risk genotypes and their counterpart homozygotes, prevalent in HLs, were identified as protective. EGLN1 expression was up-regulated 4.56-fold in HAPE-p (P = 0.0084). The risk genotypes, their haplotypes and interacting genotypes were associated with up-regulated EGLN1 expression (P < 0.05). Similarly, regression analysis showed that the risk alleles and susceptible haplotypes were associated with decreased SaO(2) (arterial oxygen saturation) levels in the three groups. The significant inverse correlation of SaO(2) levels with PASP (pulmonary artery systolic pressure) and EGLN1 expression and the association of these polymorphisms with SaO(2) levels and EGLN1 expression contributed to uncovering the molecular mechanism underlying hypobaric hypoxic adaptation and maladaptation.