Association Of Genes Polymorphisms Between Appetite Loss And Elevating Pulmonary Artery Pressure After Acute High Altitude Exposure

Backgroud:Nowadays,the amount of people living and working in high altitude is increasin g year by year.However,due to the harsh environment such as hypobaric and hypoxia at high altitude,rapidly ascending to high altitude without acclimatization will lead to headache,dizziness,fatigue,appetite loss and elevating of pulmonary artery pressure for some subjects,and even lead to acute mountain sickness（AMS）,high altitude pulmonary edema（HAPE）and high altitude cerebral edema（HACE）,which seriously affect people’s health and working efficiency.According to our previous study,loss of appetite is a common symptom of AMS,and the incidence of high altitude appetite loss is generally high.It often occurs within 2-3 days after ascending to high altitude.It is also found that although most of the symptoms of altitude sickness gradually disappear after acclimatization,the loss of appetite may still exists for a long time,which seriously affecting people’s life and working at high altitude.However,there are few studies about the high altitude appetite loss,and its pathophysiological mechanism is still unclear.After acute exposure to high altitude,it often induces to hypoxic pulmonary vasoconstriction,which results in the elevating of pulmonary artery pressure.For the hypoxia susceptible subjects,it will lead to elevating of pulmonary artery pressure at high altitude greatly.These subjects also are prone to suffer from severe and persistent pulmonary hypertension and right heart failure after long-term high altitude exposure.Therefore,it is necessary to improve vigilance and understanding of the elevating pulmonary artery pressure at high altitude and take preventive measures in advance.However,the mechanism of elevating pulmonary artery pressure at high altitude is still unclear.Previous studies have shown that hypoxia is an important initiating factor that leading to appetite loss and elevating pulmonary artery pressure at high altitude.Also genome-wide scans of Tibetans showed that there might exist genetic susceptibility to acute mountain sickness and elevating pulmonary artery pressure at high altitude,especially the gene polymorphism related to hypoxia pathway.Previous studies have shown that polymorphisms of PPARA,EPAS1,FIH-1,EGLN3 genes are associated with acute mountain sickness and high altitude adaptation.Therefore,we hypothesis that these genes polymorphisms may be associated with appetite loss and elevating pulmonary artery pressure at high altitude.Objectives:1.To understand the occurrence of appetite loss and elevating pulmonary artery pressure after acute high altitude exposure,which may contribute to improving our understanding the harm of acute high altitude exposure.2.Exploring the relationship between single nucleotide polymorphisms（SNPs）of the genes and appetite loss and elevating pulmonary artery pressure at high altitude is helpful to further understand the genetic characteristics of appetite loss and elevating pulmonary artery pressure after acute high altitude exposure.It also points out the direction for us to make further study on the mechanism of appetite loss and elevating pulmonary artery pressure at high altitude,which may provide new strategies and targets for its prevention and treatment in the future.Methods:1.This study was a retrospective study.From June 2012 to July 2012,416 subjects were collected from the high altitude population research database,including PPARA,EPAS1 SNPs,appetite scale,physiological factors and demographic data.All subjects flew to Lhasa from Chengdu.About 5 ml of venous blood was used to detect SNPs one week before ascending to high altitude.After ascending to high altitude for 48 to 72 hours,oxygen saturation（SaO₂）was measured,appetite score was assessed,and demographic data were filled in.Dominant gene model and logistic regression are performed to analysis the relationship between single nucleotide polymorphisms of PPARA and EPAS1 and loss of appetite at high altitude.2.This study was a retrospective study.From June 2012 to July 2012,313 subjects were collected from the high altitude population research database.The information of FIH-1,EGLN3 SNPs,physiological factors,mean pulmonary artery pressure（estimated by Echocardiography）and demographic data were collected.All subjects flew to Lhasa from Chengdu.About 5 ml of venous blood was used to detect SNPs one week before ascending to high altitude.After 72 hours ascending high altitude,blood pressure and SaO₂ were measured,demographic data were filled in,and mean pulmonary artery pressure was estimated by Echocardiography.Dominant gene model and logistic regression are performed to analysis the relationship between SNPs of FIH-1 and EGLN3 and the elevating pulmonary artery pressure at high altitude and its severity.Results:1.PPARA-rs4253747 in dominant model showed that（AG+AA）carriers had a higher risk of high altitude appetite loss than GG carriers（OR=1.79,95%CI=1.15-2.80,P=0.010）,after adjusting for age and SaO₂,the difference was still statistically significant.EPAS1-rs6756667 in dominant model showed showed that(（AG+AA）carriers had a lower risk of high altitude appetite loss than GG carriers（OR=0.54,95%CI=0.30-0.96,P=0.030）,after adjusting for age and SaO₂,the difference was still statistically significant.2.Compared with subjects with EPAS1-rs6756667 A allele variant but without PPARA-rs4253747 A allele variant,the subjects with PPARA-rs4253747 A allele variant but without PPARA-rs4253747 A allele variant had a significantly higher risk of high altitude appetite loss（OR=2.80,95%CI=1.34-5.85,P=0.003）,after adjusting for age and SaO₂,the difference was still statistically significant.3.FIH-1-rs11190602 in dominant model showed that（CT+CC）carriers had a lower risk of elevating pulmonary artery pressure at high altitude than TT carriers（OR=0.49,95%CI=0.29-0.83,P=0.008）,after adjusting for factors such as age,ethnicity and SaO₂,the difference was still statistically significant.EGLN3-rs1680710 in dominant model showed showed that(（AG+AA）carriers had a higher risk of elevating pulmonary artery pressure at high altitude than GG carriers（OR=5.09,95%CI=1.49-17.40,P=0.002）,after adjusting for factors such as age,ethnicity and SaO₂,the difference was still statistically significant.4.In dominant genetic model,the allele variation of FIH-1-rs11190602 was significantly correlated with mild elevating pulmonary artery pressure at high altitude but not moderate and severe elevating pulmonary artery pressure at high altitude,（CT+CC）carriers had a lower risk of mild elevating pulmonary artery pressure at high altitude than TT carriers（OR=0.39,95%CI=0.18-0.88 P=0.017）,after adjusting for age,ethnicity,SaO₂and other factors,the difference was still significant.The allele variation at EGLN3-rs1680710 was significantly correlated with mild,moderate and severe elevating pulmonary artery pressure at high altitude,（CT+CC）carriers had a significantly higher risk than TT carriers（mild:OR=5.42,95%CI=1.34-21.88,P=0.011;moderate:OR=6.76,95%CI=1.58-28.92,P=0.005;severe:OR=5.99,95%CI=1.22-29,P=0.026）,after adjusting for age,ethnicity,SaO₂ and other factors,the difference was still significant.5.The subjects who neither carried FIH-1-rs11190602 C allele variant nor EGLN3-rs1680710 A allele variant and those who carried EGLN3-rs1680710 A allele variant but not carried FIH-1-rs11190602 C allele variant had higher risk of elevating pulmonary artery pressure at high altitude than those who carried FIH-1-rs11190602 C allele variant but did not carry EGLN3-rs1680710 A allele variant（OR=2.22,95%CI=1.28-3.85,P=0.005;OR=7.18,95%CI=1.92-26.80,P=0.003）,after adjusting for age,ethnicity,SaO₂ and other factors,the difference was still significant.Conclusions:1.The allele “A”variation of PPARA-rs4253747 significantly increased the risk of high altitude appetite loss.2.The allele “A”variation of EPAS1-rs6756667 significantly reduced the risk of high altitude appetite loss.3.The allele “C”variation of FIH-1-rs11190602 significantly reduced the risk of elevating pulmonary arterial pressure at high altitude.4.The allele “A”variation of EGLN3-rs1680710 significantly increased the risk of elevating pulmonary arterial pressure at high altitude.5.The allele “C”variation FIH-1-rs11190602 only significantly reduced the risk of mild elevating pulmonary arterial pressure at high altitude,while the“A”allele variation of EGLN3-rs1680710 significantly increased the risk of mild,moderate and severe elevating pulmonary arterial pressure at high altitude.