The Study Of Individual Susceptibility To Acute Mountain Sickness And High Altitude Headache In Subjects Rapidly Entering High Altitude

Background:Ascending to high altitude?HA?for the purposes of work,travelling,sports competition and military training has become increasingly popular.However,acute HA exposure over2500 m above sea level may trigger the incidence of acute mountain sickness?AMS?,and high altitude headache?HAH?is the most common symtom.Investigation of the risk factors to identify susceptible individuals is important,but no consensus has been reached.Although previous studies have suggested that single nucleotide polymorphism?SNP?sites,exercise testing and sex difference are involved in the individual susceptibility to AMS,to date,the results have been controversial and inconclusive.Therefore,we aim to investigate the possible association between SNP sites of hypoxia-inducible factor?HIF?-related genes and AMS and HAH,and to explore the physiological risk factors of AMS and their sex differences in the prediction of AMS by exercise testing.Methods:1.In this prospective cohort study,604 healthy young Chinese Han men rapidly ascended to HA above 3700 m from lowland by plane in 2 hours.Basic demographic parameters were collected,and heart rate?HR?,pulse oxygen saturation?SpO2?,systolic blood pressure?SBP?and diastolic blood pressure?DBP?were measured.Related symptoms were collected and AMS was diagnosed by using Lake Louise Scoring System?LLSS?.Venous blood was collected for the genotyping of 48 selected SNP sites,and associations between selected SNP sites and AMS were identified by logistic regression,and were adjusted by potential confounders.2.In this prospective cohort study,580 healthy young Chinese Han men rapidly ascended to HA above 3700 m from lowland by plane in 2 hours.Basic demographic parameters were collected,and HR,SpO₂,SBP and DBP were measured.HAH self-rating scale was completed and HAH was diagnosed by using International Classification of Headache.Venous blood was collected for the genotyping of 35 selected SNP sites,and linkage disequilibrium?LD?was evaluated by Haploview software.Associations between selected SNP sites and HAH were identified by logistic regression,and were adjusted by potential confounders.3.In this prospective cohort study,99 healthy Chinese Han subjects?67 men and 32women?rapidly ascended to HA above 4100 m from lowland by bus within two days.All subjects completed the exercise testing with a mechanically braked bicycle ergometer at sea level.Basic demographic parameters were collected,and HR,SpO₂,SBP and DBP were measured before and after exercise testing and after arrival at HA.Related symptoms were collected and AMS was diagnosed by using LLSS.Associations of relevant risk factors with AMS were investigated by regression analysis,and were adjusted by potential confounders.Results:1.AMS patients showed significantly lower SpO₂ compared with non-AMS group?P=0.001?.EPAS1 rs6756667,VEGFA rs3025039 and VEGFA rs3025040 were found to be associated with the incidence of AMS and its severity.In comparison with wild types,EPAS1rs6756667 AG/AA genotype was associated with decreased risk of AMS[odd ratio?OR?=0.56,P=0.003],VEGFA rs3025039 CT/TT genotype?OR=1.51,P=0.024?and VEGFA rs3025040 CT/TT genotype?OR=1.45,P=0.043?were relevant to increased risk of AMS.EPAS1 rs6756667,VEGFA rs3025039 and VEGFA rs3025040 were correlated with the incidence of mild AMS.EPAS1 and VEGFA gene have synergistic effects,and the combination of EPAS1 rs6756667 GG genotype and VEGFA rs3025039 CT/TT genotype further increased the risk of AMS?OR=2.69,P<0.001?.2.HAH patients showed significantly higher HR?P=0.016?and lower SpO₂?P=0.007?compared with non-HAH group.In comparison with wild types,the EPAS1 rs4953354AG/GG genotype?OR=0.59,P=0.016?,EPAS1 rs6756667 AG/AA genotype?OR=0.64,P=0.044?and PPARA rs6520015 CT/CC genotype?OR=0.62,P=0.018?were significantly associated with decreased risk of HAH.EPAS1 rs4953354 AG/GG genotype was correlated with decreased risk of mild HAH and moderate-severe HAH,while PPARA rs6520015CT/CC genotype was correlated with decreased risk of mild HAH but not moderate-severe HAH.The rs7292407-rs6520015 C-C haplotype in PPARA was identified as a protective factor?OR=0.41,P=0.030?.Importantly,EPAS1 and PPARA gene have synergistic effects,and the combination of EPAS1 rs4953354 AG/GG genotype and PPARA rs6520015 CT/CC genotype further decreased the risk of HAH?OR=0.36,P=0.003?.3.Compared with subjects without AMS,the proportion of men,height,weight,the calculated body mass index and proportion of smokers in patients with AMS were lower.Being women?OR=6.32,P<0.001?and the change in SpO₂ value after the exercise testing??eSpO2??OR=0.63,P=0.002?were independently associated with AMS.Compared with men,the women showed higher changes in SpO₂ value after HA exposure??hSpO₂?,SpO₂value after the exercise testing?eSpO₂?,AMS scores and incidence of AMS or AMS-related symptoms?except headache?.?eSpO₂ was associated with the incidence of AMS?OR=0.56,P=0.001?and AMS scores?r=-0.408,P<0.001?in the men but not the women.Conclusions:1.EPAS1 rs6756667,VEGFA rs3025039 and VEGFA rs3025040 are associated with the incidence of AMS and its severity.EPAS1 and VEGFA gene have synergistic effects,and the combination of EPAS1 rs6756667 GG genotype and VEGFA rs3025039 CT/TT genotype increased the risk of AMS.2.EPAS1 rs4953354 and PPARA rs6520015 are associated with the incidence of HAH and its severity.LD phenomenon exists in PPARA,and rs7292407-rs6520015 C-C haplotype is associated with HAH.EPAS1 and PPARA gene have synergistic effects,and the combination of EPAS1 rs4953354 AG/GG genotype and PPARA rs6520015 CT/CC genotype decreased the risk of HAH.3.Women are more prone to suffer from AMS and AMS-related symptoms?except headache?.Being women and exercise-induced desaturation are independent risk factors of AMS.Prediction of exercise-induced changes in physiological factors at sea level for AMS is sex dependent.