Candidate Gene Polymorphisms And Susceptibility To High Altitude Pulmonary Edema: A Molecular Epidemiological Studies

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.