缺氧相关基因单核苷酸多态性与急性高原病易感性的研究
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摘要
背景和目的：急性高原病(AMS)严重影响我国青藏高原移居人群的健康,目前尚无有效的防治对策。高原习服和适应过程中个体差异的存在提示AMS的发生可能是环境和遗传因素共同作用的结果。因此推测遗传因素可能与AMS易感性存在关联。本研究通过对AMS易感人群与不易感人群缺氧相关基因的单核苷酸多态性(SNP)进行对比研究,旨在探索SNP与AMS易感者之间的关系。
方法：以由内地空运急进海拔3658米高原(拉萨)的汉族入伍新兵为研究对象,症状评分法调查AMS发病率,测定SpO2、采集外周静脉血并提取DNA,ELISA测定40名AMS患者和40名未发病人群的血浆VEGF浓度。采用病例对照研究的方法,从AMS患者中随机选取200人作为病例组,从未发病人群中选取匹配的200人作为对照组。以引物延伸结合基质辅助激光解吸附离子化飞行时间质谱技术检测缺氧相关基因不同SNP位点的多态性,这些基因包括血管内皮生长因子(VEGF)、缺氧诱导因子1(HIF1A)、谷胱甘肽过氧化物酶M3(GSTM3),谷胱甘肽过氧化物酶P1(GSTP1)、诱导型一氧化氮合酶(NOS2)、内皮型一氧化氮合酶(NOS3)、血管紧张素转化酶(ACE)和热休克蛋白A4(HSPA4)基因。统计遗传学软件分析其与AMS的关联性。
结果：入伍新兵急进高原(拉萨)后AMS发病率为35.68%。AMS组SpO2从505米处的98.02±1.69%降至3,658 m处的85.16±5.42%(P<0.01)。对照组SpO2从505米处的98.02±1.40%降至3658米处的86.30±4.63%(P<0.01)。在海拔3658米高原,与对照组比较,AMS组氧饱和度明显下降(P<0.05)。与基线水平比较,海拔3658米高原对照组血浆VEGF浓度从41.03±37.37pg／ml降至16.98±11.61pg/ml(P<0.01),AMS组从79.276±27.48 pg／ml降至55.58±20.19 pg/ml(P<0.01).不论在平原或高原,AMS组血浆VEGF浓度均显著高于对照组(P<0.01)。除HSPA4基因的rs35853823位点外,AMS组与对照组的13个SNP位点均存在SNP,且处于Hardy-Weinberg平衡。VEGF基因rs3025039位点中等位基因T与AMS存在关联(P=0.01,比值比(OR),0.62,95%可信区间(CI)0.43-0.90)。该位点基因型CC、CT和TT频率在AMS组与对照组间存在显著性差异(P=0.0297),等位基因T为加性模式时,CT基因型与AMS存在关联(P=0.010,OR,0.56,95%CI0.36～0.87)；等位基因T为显性模式时,CT+TT基因型与AMS存在关联(P=0.008,OR,0.56,95%CI0.37～0.86)。VEGF基因rs3025030位点等位基因C与AMS存在关联(P=0.019,OR,0.64,95%CI0.44～0.93)。该位点等位基因C为显性模式时,CC+CG与AMS显著相关(P=0.0184,OR,1.66,95%CI1.10-2.45)。NOS2基因rs1137933位点等位基因T为加性模式时,TT基因型与AMS显著相关(P=0.049,OR,3.04,95%CI0.96～9.68)。该位点等位基因T为隐性模式时,TT基因型与AMS存在关联(P=0.04,OR,3.13,95%CI0.99-9.87)。ACE基因rs4309位点等位基因C为隐性模式时,CC基因型与AMS存在关联(P=0.049,OR,1.83,95%CI 1.00-3.34)。NOS2基因的rs2297518位点,HIF1A基因的rs8005745、rs2301108和rs10873142位点,GSTP1的rS1695位点,GSTM3的rs7483位点,NOS3的rs1799983. rs3918188和rs7830位点以及HSPA4基因的rs35853823位点等位基因频率和基因型在AMS组和对照组间均不存在显著性差异(P>0.05)。在单体型水平,由VEGFA基因rs3025030(G／C)和rs3025039(C／T)组成的单体型GC／CT频率在AMS组与对照组间存在显著性差异(P=0.029).AMS组与对照组间由HIF1A基因SNP位点rs8005745、rs2301108和rs10873142构成的单体型AGT／TAC／AGC频率分布没有显著性差异(P>0.05)。
结论：1、入伍新兵急进海拔3658米高原(拉萨)后AMS发病率为35.68%。2、高原低氧条件下人体SpO2和血浆VEGF蛋白浓度明显下降,平原和高原条件下AMS患者血浆VEGF浓度均明显高于未发病人群。3、中国汉族人群VEGF基因的rs3025039和rs3025030位点与AMS发病相关联,等位基因T和C是AMS发生的保护因素；4、NOS2基因的rs1137933位点纯合基因型TT和ACE基因的rs4309位点CC基因型与AMS存在关联。携带这2种基因型的个体发生AMS的风险增加。5. NOS2基因的rs2297518位点,HIF1A基因的rs8005745、rs2301108和rs10873142位点,GSTP1的rs1695位点,GSTM3的rs7483位点,NOS3的rs1799983、rs3918188和rs7830位点以及HSPA4基因的rs35853823位点均与AMS发病无关联的依据。
BACKGROUND AND OBJECTIVE:Acute mountain sickness (AMS) is a potentially serious affliction to health in immigrants to Tibetan Plateau above 2500 m. There are no effective treatment and prevention strategy of AMS now.Interindividual variation in acclimatization and adaptation to high altitude suggest that the probability of developing AMS depends on genetic and environmental factors. So we speculated that genetic factors may be associated with AMS susceptivity. The research aimed to explore the association between single nucleotide polymorphism(SNP) of hypoxic gene and AMS by comparing the difference of hypoxic gene SNP betwween AMS-susceptible and acclimatized individuals.
METHODS:The study enrolled Chinese ethnicity soldiers that join the army for the first time flew to high altitude(3658m,Lhasa) from lowland (505m). AMS was diagnosed on the basis of the AMS Questionnaire. Venous blood was collected and then analyzed by ELISA for VEGF and for extraction of genomic DNA and peripheral arterial oxygen saturation (SpO2) was recorded at low altitude and after 24h-48h at high altitude. By case-control study method, we selected 200 cases of AMS as AMS group and 200 individuals which not developed AMS as control group randomly from these soldiers respectively. The selected subjects were genotyped for the fourteen polymorphisms of the hypoxic genes by primer extension of multiplex products with detection by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectroscopy. These hypoxic genes include vascular endothelial growth factor (VEGF), hypoxia inducible factor 1 alpha subunit (HIF1A) Glutathione S-transferase mu 3 (GSTM3), Glutathione S-transferase pi 1 (GSTP1), Nitric oxide synthase 2 (NOS 2) nitric oxide synthase 3 (NOS 3), AngiotensinⅠ converting enzyme (ACE) and heat shock 70kDa protein 4(HSPA4). The association between SNP and AMS was analysed by genetic statistical software.
RESULTS:Morbidity of AMS in the soldiers that join the army for the first time flew to high altitude was 35.68%. SpO2 fell from 98.02±1.69% at 505m to 85.16±5.42% at 3,658 m in subjects with AMS (P＜0.01) and from 98.02±1.40% at 505m to 86.30±4.63% at 3,658 m in subjects without AMS (P＜0.01). SpO2 in subjects with AMS fell signifcantly compared with those wothout AMS at a height of 3658 m(P<0.05). Plasma VEGF concentration decreased at an altitude of 3658 m (16.98±11.61 pg/ml vs 41.03±37.37pg/ml,P<0.01,in group without AMS; 55.58±20.19 pg/ml vs 79.27±27.48 pg/ml, P＜0.01, in group with AMS) compared with the baseline level. The plasma VEGF concentration were significantly higher in group with AMS than in group without AMS at baseline level and at altitude of 3658 m (79.27±27.48 pg/ml vs 41.03±37.37 pg/ml,55.58±20.19 pg/ml vs 16.98±11.61 pg/ml,respectively,P<0.01). All 13 gene locuses exist polymorphisms and were in Hardy-Weinberg equilibrium in both AMS group and controls except for HSPA4 which only have a allelee T. The T allele of rs3025039 of VEGF was significantly associated with AMS(P=0.012, OR=0.62,95% CI 0.43 to 0.90). The rs3025039 of VEGF genotypic frequency distribution differed significantly between AMS and control group (P=0.0297).CT genotype of rs3025039 was significantly associated with AMS (P=0.010, OR=0.56,95% CI 0.36 to 0.87) assuming a additive effect of the T allele; CT+TT genotype of rs3025039 was significantly associated with AMS(P=0.008,OR=0.56,95% CI 0.37 to 0.86) assuming a dominant effect of the T allele. The C allele of rs3025030 of VEGF was significantly associated with AMS (P=0.019,OR=0.64,95% CI 0.44 to 0.93). CC+CG genotype of rs3025030 was significantly associated with AMS (P=0.018, OR=1.66,95% CI 1.10 to 2.45) assuming a dominant effect of the T allele. In terms of NOS2, TT genotype of rs1137933 was significantly associated with AMS (P=0.049,OR=3.045,95% CI 0.96 to 9.68) assuming a additive effect of the T allele. TT genotype of rs1137933 was significantly associated with AMS(P=0.04,OR=3.13,95% CI 0.99 to 9.87) assuming a recessive effect of the T allele. For ACE, CC genotype of rs4309 was significantly associated with AMS (P=0.049, OR=1.83,95% CI 1.00 to 3.34) assuming a recessive effect of the C allele. Genotypic and allelic frequencies of the rs2297518 of NOS2; rs8005745, rs2301108, rs10873142 of HIF1A; rs1695 of GSTP1; rs7483 of GSTM3; rs1799983, rs3918188 and rs7830 of NOS3 and rs35853823 of HSPA4 were not significantly different between AMS and control group (P>0.05). At the haplotype level, a haplotype GC/CT frequencies consisting of rs3025030 (G/C) and rs3025039 (C/T) of VEGF was significantly differences between the AMS group and control group (P=0.029).There were no statistically significant differences in the haplotype AGT/TAC/AGC frequencies consisting of rs8005745,rs2301108 and 10873142 of HIF1A between the AMS group and control group at high altitude (P>0.05).
CONCLUSIONS:1、Morbidity of AMS in the soldiers that join the army for the first time flew to high altitude was 35.68%; 2、SpO2 and VEGF is down-regulated significantly in AMS group and control at athigh altitude, but VEGF level of AMS group still higher significantly than control not only at high altitude but also at sea level; 3、Polymorphism of rs3025039 and rs3025030 in VEGF gene were significantly associated with AMS. Individuals carrying the allele T of rs3025039 and C of rs3025030 significantly decrease the risk of AMS in a Chinese population. 4、Polymorphic loci of rs1137933 in NOS2 and rs4309 in ACE were significantly associated with AMS. Individuals carrying the genotypic TT of rs1137933and genotypic CC rs4309 significantly increase the risk of AMS.5. This study did not provide evidence that SNPs of the rs2297518 of NOS2, rsl799983, rs3918188, rs7830 of NOS3, rsl695 of GSTP1, rs7483 of GSTM3, rs8005745, rs2301108, rs10873142 of HIF1A and rs35853823 of HSPA4 gene are associated with susceptibility to AMS in a Chinese population.
方法：以由内地空运急进海拔3658米高原(拉萨)的汉族入伍新兵为研究对象,症状评分法调查AMS发病率,测定SpO2、采集外周静脉血并提取DNA,ELISA测定40名AMS患者和40名未发病人群的血浆VEGF浓度。采用病例对照研究的方法,从AMS患者中随机选取200人作为病例组,从未发病人群中选取匹配的200人作为对照组。以引物延伸结合基质辅助激光解吸附离子化飞行时间质谱技术检测缺氧相关基因不同SNP位点的多态性,这些基因包括血管内皮生长因子(VEGF)、缺氧诱导因子1(HIF1A)、谷胱甘肽过氧化物酶M3(GSTM3),谷胱甘肽过氧化物酶P1(GSTP1)、诱导型一氧化氮合酶(NOS2)、内皮型一氧化氮合酶(NOS3)、血管紧张素转化酶(ACE)和热休克蛋白A4(HSPA4)基因。统计遗传学软件分析其与AMS的关联性。
结果：入伍新兵急进高原(拉萨)后AMS发病率为35.68%。AMS组SpO2从505米处的98.02±1.69%降至3,658 m处的85.16±5.42%(P<0.01)。对照组SpO2从505米处的98.02±1.40%降至3658米处的86.30±4.63%(P<0.01)。在海拔3658米高原,与对照组比较,AMS组氧饱和度明显下降(P<0.05)。与基线水平比较,海拔3658米高原对照组血浆VEGF浓度从41.03±37.37pg／ml降至16.98±11.61pg/ml(P<0.01),AMS组从79.276±27.48 pg／ml降至55.58±20.19 pg/ml(P<0.01).不论在平原或高原,AMS组血浆VEGF浓度均显著高于对照组(P<0.01)。除HSPA4基因的rs35853823位点外,AMS组与对照组的13个SNP位点均存在SNP,且处于Hardy-Weinberg平衡。VEGF基因rs3025039位点中等位基因T与AMS存在关联(P=0.01,比值比(OR),0.62,95%可信区间(CI)0.43-0.90)。该位点基因型CC、CT和TT频率在AMS组与对照组间存在显著性差异(P=0.0297),等位基因T为加性模式时,CT基因型与AMS存在关联(P=0.010,OR,0.56,95%CI0.36～0.87)；等位基因T为显性模式时,CT+TT基因型与AMS存在关联(P=0.008,OR,0.56,95%CI0.37～0.86)。VEGF基因rs3025030位点等位基因C与AMS存在关联(P=0.019,OR,0.64,95%CI0.44～0.93)。该位点等位基因C为显性模式时,CC+CG与AMS显著相关(P=0.0184,OR,1.66,95%CI1.10-2.45)。NOS2基因rs1137933位点等位基因T为加性模式时,TT基因型与AMS显著相关(P=0.049,OR,3.04,95%CI0.96～9.68)。该位点等位基因T为隐性模式时,TT基因型与AMS存在关联(P=0.04,OR,3.13,95%CI0.99-9.87)。ACE基因rs4309位点等位基因C为隐性模式时,CC基因型与AMS存在关联(P=0.049,OR,1.83,95%CI 1.00-3.34)。NOS2基因的rs2297518位点,HIF1A基因的rs8005745、rs2301108和rs10873142位点,GSTP1的rS1695位点,GSTM3的rs7483位点,NOS3的rs1799983. rs3918188和rs7830位点以及HSPA4基因的rs35853823位点等位基因频率和基因型在AMS组和对照组间均不存在显著性差异(P>0.05)。在单体型水平,由VEGFA基因rs3025030(G／C)和rs3025039(C／T)组成的单体型GC／CT频率在AMS组与对照组间存在显著性差异(P=0.029).AMS组与对照组间由HIF1A基因SNP位点rs8005745、rs2301108和rs10873142构成的单体型AGT／TAC／AGC频率分布没有显著性差异(P>0.05)。
结论：1、入伍新兵急进海拔3658米高原(拉萨)后AMS发病率为35.68%。2、高原低氧条件下人体SpO2和血浆VEGF蛋白浓度明显下降,平原和高原条件下AMS患者血浆VEGF浓度均明显高于未发病人群。3、中国汉族人群VEGF基因的rs3025039和rs3025030位点与AMS发病相关联,等位基因T和C是AMS发生的保护因素；4、NOS2基因的rs1137933位点纯合基因型TT和ACE基因的rs4309位点CC基因型与AMS存在关联。携带这2种基因型的个体发生AMS的风险增加。5. NOS2基因的rs2297518位点,HIF1A基因的rs8005745、rs2301108和rs10873142位点,GSTP1的rs1695位点,GSTM3的rs7483位点,NOS3的rs1799983、rs3918188和rs7830位点以及HSPA4基因的rs35853823位点均与AMS发病无关联的依据。
BACKGROUND AND OBJECTIVE:Acute mountain sickness (AMS) is a potentially serious affliction to health in immigrants to Tibetan Plateau above 2500 m. There are no effective treatment and prevention strategy of AMS now.Interindividual variation in acclimatization and adaptation to high altitude suggest that the probability of developing AMS depends on genetic and environmental factors. So we speculated that genetic factors may be associated with AMS susceptivity. The research aimed to explore the association between single nucleotide polymorphism(SNP) of hypoxic gene and AMS by comparing the difference of hypoxic gene SNP betwween AMS-susceptible and acclimatized individuals.
METHODS:The study enrolled Chinese ethnicity soldiers that join the army for the first time flew to high altitude(3658m,Lhasa) from lowland (505m). AMS was diagnosed on the basis of the AMS Questionnaire. Venous blood was collected and then analyzed by ELISA for VEGF and for extraction of genomic DNA and peripheral arterial oxygen saturation (SpO2) was recorded at low altitude and after 24h-48h at high altitude. By case-control study method, we selected 200 cases of AMS as AMS group and 200 individuals which not developed AMS as control group randomly from these soldiers respectively. The selected subjects were genotyped for the fourteen polymorphisms of the hypoxic genes by primer extension of multiplex products with detection by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectroscopy. These hypoxic genes include vascular endothelial growth factor (VEGF), hypoxia inducible factor 1 alpha subunit (HIF1A) Glutathione S-transferase mu 3 (GSTM3), Glutathione S-transferase pi 1 (GSTP1), Nitric oxide synthase 2 (NOS 2) nitric oxide synthase 3 (NOS 3), AngiotensinⅠ converting enzyme (ACE) and heat shock 70kDa protein 4(HSPA4). The association between SNP and AMS was analysed by genetic statistical software.
RESULTS:Morbidity of AMS in the soldiers that join the army for the first time flew to high altitude was 35.68%. SpO2 fell from 98.02±1.69% at 505m to 85.16±5.42% at 3,658 m in subjects with AMS (P＜0.01) and from 98.02±1.40% at 505m to 86.30±4.63% at 3,658 m in subjects without AMS (P＜0.01). SpO2 in subjects with AMS fell signifcantly compared with those wothout AMS at a height of 3658 m(P<0.05). Plasma VEGF concentration decreased at an altitude of 3658 m (16.98±11.61 pg/ml vs 41.03±37.37pg/ml,P<0.01,in group without AMS; 55.58±20.19 pg/ml vs 79.27±27.48 pg/ml, P＜0.01, in group with AMS) compared with the baseline level. The plasma VEGF concentration were significantly higher in group with AMS than in group without AMS at baseline level and at altitude of 3658 m (79.27±27.48 pg/ml vs 41.03±37.37 pg/ml,55.58±20.19 pg/ml vs 16.98±11.61 pg/ml,respectively,P<0.01). All 13 gene locuses exist polymorphisms and were in Hardy-Weinberg equilibrium in both AMS group and controls except for HSPA4 which only have a allelee T. The T allele of rs3025039 of VEGF was significantly associated with AMS(P=0.012, OR=0.62,95% CI 0.43 to 0.90). The rs3025039 of VEGF genotypic frequency distribution differed significantly between AMS and control group (P=0.0297).CT genotype of rs3025039 was significantly associated with AMS (P=0.010, OR=0.56,95% CI 0.36 to 0.87) assuming a additive effect of the T allele; CT+TT genotype of rs3025039 was significantly associated with AMS(P=0.008,OR=0.56,95% CI 0.37 to 0.86) assuming a dominant effect of the T allele. The C allele of rs3025030 of VEGF was significantly associated with AMS (P=0.019,OR=0.64,95% CI 0.44 to 0.93). CC+CG genotype of rs3025030 was significantly associated with AMS (P=0.018, OR=1.66,95% CI 1.10 to 2.45) assuming a dominant effect of the T allele. In terms of NOS2, TT genotype of rs1137933 was significantly associated with AMS (P=0.049,OR=3.045,95% CI 0.96 to 9.68) assuming a additive effect of the T allele. TT genotype of rs1137933 was significantly associated with AMS(P=0.04,OR=3.13,95% CI 0.99 to 9.87) assuming a recessive effect of the T allele. For ACE, CC genotype of rs4309 was significantly associated with AMS (P=0.049, OR=1.83,95% CI 1.00 to 3.34) assuming a recessive effect of the C allele. Genotypic and allelic frequencies of the rs2297518 of NOS2; rs8005745, rs2301108, rs10873142 of HIF1A; rs1695 of GSTP1; rs7483 of GSTM3; rs1799983, rs3918188 and rs7830 of NOS3 and rs35853823 of HSPA4 were not significantly different between AMS and control group (P>0.05). At the haplotype level, a haplotype GC/CT frequencies consisting of rs3025030 (G/C) and rs3025039 (C/T) of VEGF was significantly differences between the AMS group and control group (P=0.029).There were no statistically significant differences in the haplotype AGT/TAC/AGC frequencies consisting of rs8005745,rs2301108 and 10873142 of HIF1A between the AMS group and control group at high altitude (P>0.05).
CONCLUSIONS:1、Morbidity of AMS in the soldiers that join the army for the first time flew to high altitude was 35.68%; 2、SpO2 and VEGF is down-regulated significantly in AMS group and control at athigh altitude, but VEGF level of AMS group still higher significantly than control not only at high altitude but also at sea level; 3、Polymorphism of rs3025039 and rs3025030 in VEGF gene were significantly associated with AMS. Individuals carrying the allele T of rs3025039 and C of rs3025030 significantly decrease the risk of AMS in a Chinese population. 4、Polymorphic loci of rs1137933 in NOS2 and rs4309 in ACE were significantly associated with AMS. Individuals carrying the genotypic TT of rs1137933and genotypic CC rs4309 significantly increase the risk of AMS.5. This study did not provide evidence that SNPs of the rs2297518 of NOS2, rsl799983, rs3918188, rs7830 of NOS3, rsl695 of GSTP1, rs7483 of GSTM3, rs8005745, rs2301108, rs10873142 of HIF1A and rs35853823 of HSPA4 gene are associated with susceptibility to AMS in a Chinese population.
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