目的:采用两样本孟德尔随机化分析法,探讨EPAS1与2型糖尿病(T2DM)的因果关联,以期为T2DM的防治提供新思路。方法:利用全基因组关联研究(GWAS)的数据,将EPAS1作为暴露因素,以T2DM为结局变量,进行孟德尔随机化分析。本研究以逆方差加权(I...目的:采用两样本孟德尔随机化分析法,探讨EPAS1与2型糖尿病(T2DM)的因果关联,以期为T2DM的防治提供新思路。方法:利用全基因组关联研究(GWAS)的数据,将EPAS1作为暴露因素,以T2DM为结局变量,进行孟德尔随机化分析。本研究以逆方差加权(IVW)法作为主要的MR分析手段,将单核苷酸多态性(SNP)的因果效应估计进行汇总合并,同时结合MR-Egger回归、加权中位数、加权模式作为补充方法分析二者之间的潜在因果关联。利用Cochran’s Q检验、MR-Egger回归截距、留一法进行敏感性分析。结果:IVW分析结果显示,EPAS1与T2DM之间存在显著的正向因果关联(OR: 1.055, 95% CI: 1.044~1.067, P = 6.96e−22)。敏感性分析显示不存在多效性,但异质性显著,结果相对可靠。结论:EPAS1与T2DM之间存在显著的正向因果关联,但需进行进一步验证。Aim: To explore the cause-and-effect relationship between EPAS1 and Type 2 Diabetes Mellitus (T2DM), a two-sample Mendelian randomization analysis was used to provide new ideas for the prevention and treatment of T2DM. Method: Using data from the Genome-Wide Association Study (GWAS), mendelian randomization analysis was performed with EPAS1 as an exposure factor and T2DM as an outcome variable. In this paper, Inverse Variance Weighting (IVW) was used as the primary analysis method to pool and combine the causal effect estimates of Single Nucleotide Polymorphisms (SNPs), and MR-Egger regression, weighted median, and weighted model were used as supplementary methods to analyze the potential causal association between the two. Cochran’s Q test, MR-Egger regression intercept, and leave-one-out method were used for sensitivity analysis. Results: IVW analysis showed that EPAS1 and T2DM had a significant positive causal relationship (OR: 1.055, 95% CI: 1.044~1.067, P = 6.96e–22). Sensitivity analysis showed no pleiotropy but significant heterogeneity, and the results were relatively reliable. Conclusion: EPAS1 and T2DM have a significant positive causal relationship, but further verification is needed.展开更多
AIM: To evaluate the prognostic signif icance of HIF- 2α/EPAS1 expression in hepatocellular carcinoma (HCC). METHODS: Surgical specimens from 315 patients with HCC as well as 196 adjacent noncancerous lesions and 22 ...AIM: To evaluate the prognostic signif icance of HIF- 2α/EPAS1 expression in hepatocellular carcinoma (HCC). METHODS: Surgical specimens from 315 patients with HCC as well as 196 adjacent noncancerous lesions and 22 cases of normal liver tissue were investigated by immunohistochemistry (IHC) for HIF-2α/EPAS1 using a standard detection system. Correlations with clinicopathological factors, VEGF, microvessel density (MVD), and prognosis were analyzed. RESULTS: Immunoreactivity of HIF-2α/EPAS1 was positive in 69.5% of HCC, 55.6% of adjacent noncancerous tissue, and 0% of normal liver tissue. And it was significantly correlated with tumor grade, venous invasion, intrahepatic metastasis, necrosis, and capsule infiltration. Correlation analysis of HIF-2α/EPAS1 with angiogenic factor VEGF (P < 0.001), and MVD (P = 0.016) was also noted. HIF-2α/EPAS1 protein was less frequently expressed in low MVD cases, whereas a high rate of expression was noted in cases with both medium and high MVD (P = 0.042). By Kaplan-Meier analysis, strong HIF-2α/EPAS1 staining (> 50% of tumor cells) in HCC correlated with a shortened survival in patients (Cox's regression, P < 0.001, r = 3.699). CONCLUSION: We conclude that HIF-2α/EPAS1 expression may play an important role in tumor progression and prognosis of HCC. Assessment of HIF-2α/EPAS1 expression in HCC may be used as a diagnostic tool and possibly a target in the treatment of HCC.展开更多
Endothelial PAS domain protein 1 gene （EPAS1） is a key transcription factor that activates the expression of oxygen-regu- lated genes. In this study, in order to better understand the effects of EPAS1 gene on hemato...Endothelial PAS domain protein 1 gene （EPAS1） is a key transcription factor that activates the expression of oxygen-regu- lated genes. In this study, in order to better understand the effects of EPAS1 gene on hematologic parameters in yak, we firstly quantified the tissue expression patterns for EPASl mRNA of yak, identified polymorphism in this gene and evaluated its association with hematologic parameters. Expression of EPAS1 mRNA was detected in all eight tissues （heart, liver, lung, spleen, pancreas, kidney, muscles and ovary）. The expressions of EPAS1 in lung and pancreas were extremely higher than other tissues examined. Three novel single nucleotide polymorphisms （SNPs） （g.83052 C〉T, g.83065 G〉A and g.83067 C〉A） within the EPAS1 were identified and genotyped in Pali （PL）, Gannan （GN） and Tianzhu White （TZW） yak breeds. Significant higher frequencies of the AA and GA genotypes and A allele of the g.83065 G〉A were observed in the PL and GN breeds than that in the TZW breed （P〈0.01）. Association analysis of the PL breed indicated that the g.83065 G〉A polymorphism was significantly associated with hemoglobin （HGB） concentration in yaks （P〈0.05）. Individuals with genotype AA had significantly higher HGB concentration （P〈0.05） than those with genotype GA and GG. All these results will help our further understanding of biological functional of yak EPAS1 gene in responding to hypoxia and also indicate EPAS1 might contribute to the hypoxia adaptation of the yak.展开更多
文摘目的:采用两样本孟德尔随机化分析法,探讨EPAS1与2型糖尿病(T2DM)的因果关联,以期为T2DM的防治提供新思路。方法:利用全基因组关联研究(GWAS)的数据,将EPAS1作为暴露因素,以T2DM为结局变量,进行孟德尔随机化分析。本研究以逆方差加权(IVW)法作为主要的MR分析手段,将单核苷酸多态性(SNP)的因果效应估计进行汇总合并,同时结合MR-Egger回归、加权中位数、加权模式作为补充方法分析二者之间的潜在因果关联。利用Cochran’s Q检验、MR-Egger回归截距、留一法进行敏感性分析。结果:IVW分析结果显示,EPAS1与T2DM之间存在显著的正向因果关联(OR: 1.055, 95% CI: 1.044~1.067, P = 6.96e−22)。敏感性分析显示不存在多效性,但异质性显著,结果相对可靠。结论:EPAS1与T2DM之间存在显著的正向因果关联,但需进行进一步验证。Aim: To explore the cause-and-effect relationship between EPAS1 and Type 2 Diabetes Mellitus (T2DM), a two-sample Mendelian randomization analysis was used to provide new ideas for the prevention and treatment of T2DM. Method: Using data from the Genome-Wide Association Study (GWAS), mendelian randomization analysis was performed with EPAS1 as an exposure factor and T2DM as an outcome variable. In this paper, Inverse Variance Weighting (IVW) was used as the primary analysis method to pool and combine the causal effect estimates of Single Nucleotide Polymorphisms (SNPs), and MR-Egger regression, weighted median, and weighted model were used as supplementary methods to analyze the potential causal association between the two. Cochran’s Q test, MR-Egger regression intercept, and leave-one-out method were used for sensitivity analysis. Results: IVW analysis showed that EPAS1 and T2DM had a significant positive causal relationship (OR: 1.055, 95% CI: 1.044~1.067, P = 6.96e–22). Sensitivity analysis showed no pleiotropy but significant heterogeneity, and the results were relatively reliable. Conclusion: EPAS1 and T2DM have a significant positive causal relationship, but further verification is needed.
基金Supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of China
文摘AIM: To evaluate the prognostic signif icance of HIF- 2α/EPAS1 expression in hepatocellular carcinoma (HCC). METHODS: Surgical specimens from 315 patients with HCC as well as 196 adjacent noncancerous lesions and 22 cases of normal liver tissue were investigated by immunohistochemistry (IHC) for HIF-2α/EPAS1 using a standard detection system. Correlations with clinicopathological factors, VEGF, microvessel density (MVD), and prognosis were analyzed. RESULTS: Immunoreactivity of HIF-2α/EPAS1 was positive in 69.5% of HCC, 55.6% of adjacent noncancerous tissue, and 0% of normal liver tissue. And it was significantly correlated with tumor grade, venous invasion, intrahepatic metastasis, necrosis, and capsule infiltration. Correlation analysis of HIF-2α/EPAS1 with angiogenic factor VEGF (P < 0.001), and MVD (P = 0.016) was also noted. HIF-2α/EPAS1 protein was less frequently expressed in low MVD cases, whereas a high rate of expression was noted in cases with both medium and high MVD (P = 0.042). By Kaplan-Meier analysis, strong HIF-2α/EPAS1 staining (> 50% of tumor cells) in HCC correlated with a shortened survival in patients (Cox's regression, P < 0.001, r = 3.699). CONCLUSION: We conclude that HIF-2α/EPAS1 expression may play an important role in tumor progression and prognosis of HCC. Assessment of HIF-2α/EPAS1 expression in HCC may be used as a diagnostic tool and possibly a target in the treatment of HCC.
基金supported by the Special Fund for Agro-scientific Research in the Public Interest,China (201003061)the Key Technologies R&D Program of China during the 12thFive-Year Plan period (2012BAD13B05)+1 种基金the Great Project of Science and Technology of Gansu Province in China (1102NKDA027)the National Natural Science Foundation of China (31101702)
文摘Endothelial PAS domain protein 1 gene （EPAS1） is a key transcription factor that activates the expression of oxygen-regu- lated genes. In this study, in order to better understand the effects of EPAS1 gene on hematologic parameters in yak, we firstly quantified the tissue expression patterns for EPASl mRNA of yak, identified polymorphism in this gene and evaluated its association with hematologic parameters. Expression of EPAS1 mRNA was detected in all eight tissues （heart, liver, lung, spleen, pancreas, kidney, muscles and ovary）. The expressions of EPAS1 in lung and pancreas were extremely higher than other tissues examined. Three novel single nucleotide polymorphisms （SNPs） （g.83052 C〉T, g.83065 G〉A and g.83067 C〉A） within the EPAS1 were identified and genotyped in Pali （PL）, Gannan （GN） and Tianzhu White （TZW） yak breeds. Significant higher frequencies of the AA and GA genotypes and A allele of the g.83065 G〉A were observed in the PL and GN breeds than that in the TZW breed （P〈0.01）. Association analysis of the PL breed indicated that the g.83065 G〉A polymorphism was significantly associated with hemoglobin （HGB） concentration in yaks （P〈0.05）. Individuals with genotype AA had significantly higher HGB concentration （P〈0.05） than those with genotype GA and GG. All these results will help our further understanding of biological functional of yak EPAS1 gene in responding to hypoxia and also indicate EPAS1 might contribute to the hypoxia adaptation of the yak.
