| High altitude polycythemia (HAPC) is a clinical syndrome characterized withexcessive erythropoiesis caused by hypoxic environment in plateau. Due to different naturalenvironment and altitude in plateau, race, age and occupation of subjects, the incidence ofHAPC is reported differently from each other, also owing to application of differentdiagnostic criteria of HAPC. With social progress and economic development, a largenumber of native plain people migrate to plateau, the composition of immigrants and theirlabor intensity have changed. So, according to new international diagnostic criteria ofHAPC (2004, Qinghai. females≥19g/dl, males≥21g/dl), we perform a epidemiologicalstudy of high altitude polycythemia in Han Chinese migrated to several districts withdifferent altitude in plateau, which will lay the foundation for the pathogenesis study ofHAPC.There are significant susceptibility tendency in HAPC within different nationality orindividual, suggesting a relationship between HAPC and heredity. Hypoxia is the mainfactor affecting normal physiological function of immigrants. Acclimatization to highaltitude is around the axis of oxygen intaking-transporting-utilizing. Mitochondrion is thecenter of cellular energy metabolism, and is a key organelle where utilization of oxygentake place. Up to90percent of ATP come from mitochondrial oxidative phosphorylation.Mitochondrion, regarded as power manufactory, act a crucial role in hypoxic cellular injuryand acclimatization to high altitude. We aim to observe distribution of mitochondrialgenomic single nucleotide polymorphisms in patients with HAPC, and study themitochondrial hereditary susceptibility mechanism of HAPC. Secondly, a number ofhypoxia related nuclear genes have been reported to correlate with HAPC. By means ofwhole genomic mRNA expression microarray technology, we detect differently expressedgenes in patients with HAPC and analyze their signaling pathway, which will profit us to study the association of hypoxia related genes polymorphisms with HAPC.The purpose of this study include as follows:①to have a epidemiological survey ofHAPC in Han Chinese migrated to plateau, analyze regularity and character of HAPC.②tostudy the association of mitochondrial genomic polymorphisms with HAPC in Han Chinesemigrated to plateau.③to observe the differently expressed genes in patients with HAPC bymeans of microarray.Results:1. Compared with control group, the concentration of hemoglobin (Hb), age, systolicpressure, diastolic pressure, heart rate and body mass index (BMI) significantly increased inHAPC group (P<0.01), and the saturation of blood oxygen (SaO2) decreased obviously inHAPC group (P<0.01).2. For Han Chinese migrated to plateau, when Hb was below21g/dL, there was nocorrelation between SaO2and Hb (P=0.158); when Hb was up to21g/dL, there wasnegative correlation between SaO2and Hb (P<0.001).3. There were positive correlations between altitude (3700m～5380m), age (18years～58years), during of exposure to plateau (3months～30years), BMI (16.51～31.02)and incidence of HAPC (P<0.01).4. There was positive correlations between plasma content of EPO and Hb (P<0.01).Compared with control group, the plasma content of EPO increased significantly in HAPCgroup (P<0.01).5. There was positive correlations between plasma content of ROS and Hb (P<0.01).Compared with control group, the plasma content of ROS increased significantly in HAPCgroup (P<0.01).6. The frequency of mtDNA8414T was significantly higher in HAPC group (vscontrol group, P＝0.04，OR＝1.615，95％CI:1.02-2.555).7. After stratification analysis, we found that:①Compared withwild type genotype,mtDNA8414T significantly increased the risk of HAPC among the individuals with nosmoking (OR=2.367,95%CI:1.001-5.644); Compared with wild type genotype, mtDNA10609C and mtDNA12406A significantly decreased the risk of HAPC among theindividuals with no smoking (respectively, OR=0.355,95%CI:0.151-0.833and OR=0.292, 95%CI:0.122-0.703);②Compared with wild type genotype,mtDNA10609Csignificantly decreased the risk of HAPC among the individuals with no alcohol drinking(OR=0.479,95%CI:0.254-0.906);③Compared with wild type genotype, mtDNA3010Asignificantly increased the risk of HAPC among the individuals with age up to25years old(OR=2.189,95%CI:1.038-4.620); Compared with wild type genotype, mtDNA12406Asignificantly decreased the risk of HAPC among the individuals with age up to25years old(OR=0.44,95%CI:0.196-0.987);④Compared with wild type genotype, mtDNA9053Aand mtDNA10609C significantly decreased the risk of HAPC among the individuals havemigrated to plateau more than one year (respectively, OR=0.382,95%CI:0.152-0.961andOR=0.385,95%CI:0.169-0.880).8. Multivariate Logistic regression analysis showed that mtDNA10609C significantlydecreased the risk of HAPC in Han Chinese migrated to plateau (P=0.01, OR=0.391,95%CI:0.191-0.800).9. Nine differentially expressed genes were identified in HAPC patients usingmicroarrays: five were up-regulated and four were down-regulated. Functional analysis ofthe array data showed that cell division cycle42(CDC42) and HLA-mediated immuneresponse may be key features underlying the mechanism and development of HAPC.Conclusion:1. It was reasonable that we considered Hb≥21g/dl as diagnostic criteria of HAPC.2. Altitude, age, during of exposure to plateau and obesity were risk factors of HAPCin Han Chinese migrated to plateau.3. There were positive correlation between plasma level of ROS and Hb, suggestingthat ROS was closely related with HAPC.4. mtDNA3010A genotype increased the risk of HAPC among the individuals withage up to25years, and was a risk factor to HAPC for this sub-group.5. The mtDNA8414C/T polymorphism was associated with the susceptibility ofHAPC in Han migrated to plateau, and was the risk factor to HAPC. ATPase6may beHAPC susceptibility gene.6. mtDNA9053A genotype decreased the risk of HAPC among the individuals withduring of exposure to plateau up to one year, and was a protection factor to HAPC for this sub-group.7. Multivariate Logistic regression analysis showed that mtDNA10609C wasprotection factor to HAPC in Han migrated to plateau, ND4L may be HAPC susceptibilitygene. mtDNA12406A genotype decreased the risk of HAPC among with the individualswith no smoking or age up to25years old, and was a protection factor to HAPC for the twosub-groups. Mitochondrial respiratory chain complex Ⅰmay be involved in thepathogenesis of HAPC.8. CDC42and FNTB may be involved in regulation of bone marrow excessivelyerythropoiesis, which induced HAPC.9. HLA-DQB1, HLA-DQA1, HLA-DRB4and ERAP2mediated HLA-immuneresponse may be a cause of HAPC or a pathological process in development of HAPC. |
PDF Full Text Request