Genetic Susceptibility Of High Altitude Cerebral Edema

BackgroundsThe land with altitude of 3000 m or more is known as high altitude land.The characteristic is low atmospheric pressure and partial pressure of oxygen.Hypoxia is a state of oxygen deficiency in the body which is sufficient to cause an impairment of function.Hypoxia is caused by the reduction in partial pressure of oxygen,in adequate oxygen transport,or the inability of the tissues to use oxygen.Hypoxia may be caused by a high altitude exposure,it may cause a variety of psychological and neurological abnormalities.If lack of acclimatization,it may cause high altitude sickness.Its mechanism is high altitude hypoxemia,resulting in overperfusion of cerebral and lung microcirculation,and furthermore causes high altitude cerebral edema and lung edema. Every year amongst the millions of people who sojourn to high altitude,many suffer from AMS,and an unfortunate few present with life threatening HACE and HAPE.In recent years,with the development of economy and the reason of military,more and more people will come to west plateau in our homeland.AMS is a common affliction in those healthy persons who go rapidly to high altitude.Altitude illness,which comprises of acute mountain sickness(AMS) and its life threatening complications,high altitude cerebral edema(HACE) and high altitude pulmonary edema(HAPE) is now a well recognized disease process.AMS and HACE are generally thought to be a continuum.HACE is a complex disease,which affected by individual and environmental factors and its occurrence varies in individuals and race.The mechanism of HACE is not clear until now,which prevents its prediction,prevention and treatment.The genetic variation in human populations may contribute to susceptibility to HACE.However,there are still no report about that which variant in genes have shown association with HACE up to now.Methods In this context,we studied Han population from workers participating for the first time in the Qinghai-Tibet railway construction during the period from January 2002 to December 2005 and Tibetan from highway workers who born and live in Qinghai plateau. In the proximal promoter region of a_2A adrenergic receptor gene the SNPs was detected by polymerase chain reaction- single-strand conformation polymorphism(PCR-SSCP) and sequencing.Then the polymorphisms in the proximal promoter region of a_2A adrenergic receptor gene were detected by polymerase chain reaction- restriction fragment length polymorphism(PCR-RFLP)and PCR-SSCP in 200 health Han workers,90 Tibetan workers, 48 HACE patients.We also carried out the association analysis between the SNPs in the proximal promoter region of a_2A adrenergic receptor gene and the susceptibility to HACE in those people.ResultsWe systematically screen polymorphisms in the 2137bp promoter region of a_2A adrenergic receptor gene using PCR-SSCP and sequencing method.No new SNP was detected except for polymorphism -1296G/C,which have reported previously in han population.The distribution of the SNPs of a_2A adrenergic receptor gene promoter region was examined by PCR-RFLP and PCR-SSCP.The frequencies of genotype and allele were compared in populations with different susceptibility to HACE using association study.It was found that the GG genotype and G allele frequency of SNP- 1296G/C were distributed as follows:in population HACE patients was significantly higher than that in population Han controls(P＜0.05),Genotypes with G allele have 3.79 times risk of HACE than CC homozygote,in population HACE patients was significantly higher than that in population Tibetan controls(P＜0.05),Genotypes with G allele have 4.85 times risk of HACE than CC homozygote,no significant difference for the GG genotype and G allele frequency between Han controls and Tibetan controls.There is no significant difference for SNP-727C/G genotypic frequency between case and control.There also no significant difference for C and G allele frequency between case and control.AA genotypic frequencies and A allele frequency of SNP-262A/G are higher in case group than that in Tibetan control group;but there is no significant difference for AA genotypic frequencies and A allele frequency of SNP-262G/A between case and Han control group;and there is significant difference for AA genotypic frequencies and A allele frequency of SNP-262G/A between Tibetan control group and Han control group.So the difference of case and Tibetan control group resulted from differences in the polymorphisms frequencies that construct the specific genetic architecture of different ethic population.ConclusionFrom the case-control studies performed in Han workers,Tibetan workers and HACE patients,the data presented here suggest that the SNP at site-1296 in a_2A-AR gene promoter region could associate with the susceptibility to HACE;the GG genotype with G allele in a_2A-AR gene -1296G/C locus maybe a risk factor for HACE.The difference of case and Tibetan control group for AA genotypic frequencies and A allele frequency of SNP-262G/A resulted from differences in the polymorphisms frequencies that construct the specific genetic architecture of different ethic population.As a consequence,the relative contribution of any given variant varies from the different studied population.Based on this,reproduction of the finding in a different ethnic population is considered to be important.