候选基因多态性与高原肺水肿易感性的分子流行病学研究
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摘要
高原肺水肿（high altitude pulmonary edema，HAPE）是急性高原病(acute mountainsickness，AMS)的重型。已有研究结果显示，HAPE发病具有明显的种族特异性和个体易感倾向，提示HAPE的发生与遗传因素有关。近年来国内外已有研究对多个基因的多态性与HAPE易感性的关系进行了探讨，但是由于各研究在种族、地域及研究方法上存在差异，因而研究结果并不完全一致。本研究在对HAPE易感性的关联研究予以定性分析的基础上，采用分子流行病学、Meta分析及生物信息学等方法对相关易感基因与HAPE发病的关联进行了探讨与分析，旨在从基因水平和蛋白水平探讨候选基因多态性与HAPE的关联，相关结果对深入开展HAPE发病机制及防治研究有重要意义。研究发现：
1.高原肺水肿遗传易感性的系统评价：从1998年至2011年，在HAPE易感性关联研究中，共涉及23种候选基因。其中，被研究报道次数位居前两位的HAPE易感基因依次为ACE基因和NOS3基因。迄今为止，共有15个候选基因的32个多态性位点被报道与HAPE的发病可能存在关联。这些结果为我们后续人群研究提供了理论基础。
2.候选基因多态性与高原肺水肿易感性的关联研究：ACE基因两个tagSNP位点即rs8066114位点和rs4461142位点，以及NOS3基因rs1799983位点均与HAPE发病存在关联，可增加HAPE患病风险。ACE基因rs4340位点、rs4291位点、rs434位点和rs4363位点，TH基因rs6356位点，ENaC基因rs3759324位点、rs10849447位点及rs2228576位点均未发现与与HAPE发病相关。为进一步扩大样本量验证实验结果，我们将NOS3基因多态性与HAPE易感性的相关研究综合后予以了Meta分析，分析结果进一步验证了NOS3基因rs1799983位点确与HAPE的发病存在关联。
3.高原肺水肿易感基因eNaC、NOS3及TH突变的生物学效应预测：（1）eNaC基因rs2228576位点：预测结果显示，该位点突变导致该蛋白质的第663位氨基酸由一个侧链带有羟基的极性氨基酸即苏氨酸（Thr)变成一个侧链为甲基的非极性氨基酸即丙氨酸（Ala）。突变后，β-转角增加，而无规则卷曲减少；该通道蛋白质结构域2、3、4所覆盖的氨基酸范围较突变前有明显改变。根据相关理论推测，这些变化有可能影响该蛋白质跨膜区的特性及通道的转运功能。（2）NOS3基因rs1799983位点：预测结果显示，该位点突变导致NOS3酶的第298位氨基酸发生了改变，由突变前的天冬氨酸（Asp）变成突变后的谷氨酸（Glu）；突变后ɑ-螺旋和无规则卷曲均有所减少，而延伸链和β-转角均有所增加；rs1799983SNP位点所对应的氨基酸空间结构肽链长度有所延伸。根据相关理论推测，这些改变有可能会影响到NOS3酶与Ca2+或钙调蛋白的结合能力。（3）TH基因rs6356SNP位点：预测结果显示，该位点突变导致该蛋白质的第81位氨基酸发生了改变，由突变前的缬氨酸（Val）变成突变后的甲硫氨酸（Met）；突变后，ɑ-螺旋减少，而延伸链和β-转角均有所增加。rs6356SNP位点所对应的氨基酸空间结构肽链长度有所延伸。根据相关理论推测，这些变化有可能导致TH酶C-端催化结构域部分蛋白质折叠方式发生改变，从而降低TH酶的活性。
HAPE (high altitude pulmonary edema, HAPE) is the life-threatening form of acutemountain sickness (acute mountain sickness, AMS). Existing research results indicated thatHAPE showed obvious racial specificity and individual susceptible tendency, suggestingthe occurrence of HAPE was associated with genetic factors. In recent years, therelationship between some gene polymorphisms and susceptibility to HAPE were studied athome and abroad, but the results were inconsistent across studies for the race of participantsand research methods were different. In this study, association studies of susceptibility toHAPE were carried out by qualitative analysis. Besides, molecular epidemiology,meta-analysis and bioinformatics methods were adopted to discover the relationshipbetween susceptibility genes and the onset of HAPE. The purpose of this study is to explorethe association of candidate gene polymorphisms with HAPE on the level of gene andprotein. This study is of great importance to in-depth research of pathogenesis andprevention of HAPE.
Main foundings:
1. A systematic review of the genetic susceptibility to HAPE: from1998to2011, atotal of23candidate genes were involved in all studies about the susceptibility to HAPEassociation,. Among them, the susceptibility genes which were most frequently studiedwere ACE gene and NOS3gene. So far a total of32polymorphic loci of the15candidategenes have been reported that they may be associated with the occurrence of HAPE. Theseresults provide a theoretical basis for our population-based study.
2. Association studies of candidate gene polymorphisms and susceptibility to HAPE:rs8066114and rs4461142which are the tagSNP of ACE gene, as well as the rs1799983ofNOS3gene are associated of increased risk of HAPE. rs4340, rs4291, rs434and rs4363of ACE gene, rs6356of the TH gene, rs3759324, rs10849447and rs2228576of eNaC genewere not found to be associated with the HAPE risk. To verify the experimental results, wedid meta-analysis to ascertain the association between NOS3gene polymorphisms andsusceptibility to HAPE. The results validate the association between NOS3gene rs1799983and HAPE risk.
3. Biological effects prediction of HAPE susceptible gene eNaC, NOS3and THmutations:(1) rs2228576of eNaC gene: predictive results showed that mutation of thislocus leads to the663rd amino acids of the protein mutate from threonine (Thr) to alanine(Ala). After mutation, the beta-turn increased and random coil reduced; a obvious changewas observed in the amino acids coverage of eNaC2,3,4protein domain. According tospeculation of relevant theoretical, these changes may affect the characteristics of thetransmembrane region of the protein and transport function of the channel.(2) rs1799983ofNOS3gene: predictive results showed that the298th amino acids of NOS3enzymes hadchanged due to mutation, changing from spartic acid (Asp) to glutamic acid (Glu); aftermutation ɑ-helix and random coil reduced, and extended strand and beta-turn increased;peptide chain length of corresponding amino acid of rs1799983SNP has been extended.According to the relevant theoretical speculation, these changes may affect binding capacitybetween Ca2+or calmodulin and NOS3enzyme.(3) rs6356of TH gene SNP: predictiveresults showed that the mutation cause the change of81st amino acids of the protein. Valine(Val) had changed to methionine (Met); mutation resulted to decrease of ɑ-helix, andincrease in extension chain and the beta-turn. The corresponding amino acid peptide chainlength of rs6356SNP has been extended. According to the relevant theoretical speculation,these changes may lead to changes in protein folding way of the the TH enzyme C-terminalcatalytic domain portion, therefore reducing the activity of TH enzyme.
1.高原肺水肿遗传易感性的系统评价：从1998年至2011年，在HAPE易感性关联研究中，共涉及23种候选基因。其中，被研究报道次数位居前两位的HAPE易感基因依次为ACE基因和NOS3基因。迄今为止，共有15个候选基因的32个多态性位点被报道与HAPE的发病可能存在关联。这些结果为我们后续人群研究提供了理论基础。
2.候选基因多态性与高原肺水肿易感性的关联研究：ACE基因两个tagSNP位点即rs8066114位点和rs4461142位点，以及NOS3基因rs1799983位点均与HAPE发病存在关联，可增加HAPE患病风险。ACE基因rs4340位点、rs4291位点、rs434位点和rs4363位点，TH基因rs6356位点，ENaC基因rs3759324位点、rs10849447位点及rs2228576位点均未发现与与HAPE发病相关。为进一步扩大样本量验证实验结果，我们将NOS3基因多态性与HAPE易感性的相关研究综合后予以了Meta分析，分析结果进一步验证了NOS3基因rs1799983位点确与HAPE的发病存在关联。
3.高原肺水肿易感基因eNaC、NOS3及TH突变的生物学效应预测：（1）eNaC基因rs2228576位点：预测结果显示，该位点突变导致该蛋白质的第663位氨基酸由一个侧链带有羟基的极性氨基酸即苏氨酸（Thr)变成一个侧链为甲基的非极性氨基酸即丙氨酸（Ala）。突变后，β-转角增加，而无规则卷曲减少；该通道蛋白质结构域2、3、4所覆盖的氨基酸范围较突变前有明显改变。根据相关理论推测，这些变化有可能影响该蛋白质跨膜区的特性及通道的转运功能。（2）NOS3基因rs1799983位点：预测结果显示，该位点突变导致NOS3酶的第298位氨基酸发生了改变，由突变前的天冬氨酸（Asp）变成突变后的谷氨酸（Glu）；突变后ɑ-螺旋和无规则卷曲均有所减少，而延伸链和β-转角均有所增加；rs1799983SNP位点所对应的氨基酸空间结构肽链长度有所延伸。根据相关理论推测，这些改变有可能会影响到NOS3酶与Ca2+或钙调蛋白的结合能力。（3）TH基因rs6356SNP位点：预测结果显示，该位点突变导致该蛋白质的第81位氨基酸发生了改变，由突变前的缬氨酸（Val）变成突变后的甲硫氨酸（Met）；突变后，ɑ-螺旋减少，而延伸链和β-转角均有所增加。rs6356SNP位点所对应的氨基酸空间结构肽链长度有所延伸。根据相关理论推测，这些变化有可能导致TH酶C-端催化结构域部分蛋白质折叠方式发生改变，从而降低TH酶的活性。
HAPE (high altitude pulmonary edema, HAPE) is the life-threatening form of acutemountain sickness (acute mountain sickness, AMS). Existing research results indicated thatHAPE showed obvious racial specificity and individual susceptible tendency, suggestingthe occurrence of HAPE was associated with genetic factors. In recent years, therelationship between some gene polymorphisms and susceptibility to HAPE were studied athome and abroad, but the results were inconsistent across studies for the race of participantsand research methods were different. In this study, association studies of susceptibility toHAPE were carried out by qualitative analysis. Besides, molecular epidemiology,meta-analysis and bioinformatics methods were adopted to discover the relationshipbetween susceptibility genes and the onset of HAPE. The purpose of this study is to explorethe association of candidate gene polymorphisms with HAPE on the level of gene andprotein. This study is of great importance to in-depth research of pathogenesis andprevention of HAPE.
Main foundings:
1. A systematic review of the genetic susceptibility to HAPE: from1998to2011, atotal of23candidate genes were involved in all studies about the susceptibility to HAPEassociation,. Among them, the susceptibility genes which were most frequently studiedwere ACE gene and NOS3gene. So far a total of32polymorphic loci of the15candidategenes have been reported that they may be associated with the occurrence of HAPE. Theseresults provide a theoretical basis for our population-based study.
2. Association studies of candidate gene polymorphisms and susceptibility to HAPE:rs8066114and rs4461142which are the tagSNP of ACE gene, as well as the rs1799983ofNOS3gene are associated of increased risk of HAPE. rs4340, rs4291, rs434and rs4363of ACE gene, rs6356of the TH gene, rs3759324, rs10849447and rs2228576of eNaC genewere not found to be associated with the HAPE risk. To verify the experimental results, wedid meta-analysis to ascertain the association between NOS3gene polymorphisms andsusceptibility to HAPE. The results validate the association between NOS3gene rs1799983and HAPE risk.
3. Biological effects prediction of HAPE susceptible gene eNaC, NOS3and THmutations:(1) rs2228576of eNaC gene: predictive results showed that mutation of thislocus leads to the663rd amino acids of the protein mutate from threonine (Thr) to alanine(Ala). After mutation, the beta-turn increased and random coil reduced; a obvious changewas observed in the amino acids coverage of eNaC2,3,4protein domain. According tospeculation of relevant theoretical, these changes may affect the characteristics of thetransmembrane region of the protein and transport function of the channel.(2) rs1799983ofNOS3gene: predictive results showed that the298th amino acids of NOS3enzymes hadchanged due to mutation, changing from spartic acid (Asp) to glutamic acid (Glu); aftermutation ɑ-helix and random coil reduced, and extended strand and beta-turn increased;peptide chain length of corresponding amino acid of rs1799983SNP has been extended.According to the relevant theoretical speculation, these changes may affect binding capacitybetween Ca2+or calmodulin and NOS3enzyme.(3) rs6356of TH gene SNP: predictiveresults showed that the mutation cause the change of81st amino acids of the protein. Valine(Val) had changed to methionine (Met); mutation resulted to decrease of ɑ-helix, andincrease in extension chain and the beta-turn. The corresponding amino acid peptide chainlength of rs6356SNP has been extended. According to the relevant theoretical speculation,these changes may lead to changes in protein folding way of the the TH enzyme C-terminalcatalytic domain portion, therefore reducing the activity of TH enzyme.
引文
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