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Lanlan Wang - One of the best experts on this subject based on the ideXlab platform.
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polymorphisms in sodium taurocholate cotransporting polypeptide are not associated with hepatitis b virus clearance in chinese Tibetans and uygurs
Infection Genetics and Evolution, 2016Co-Authors: Yun Liao, Jie Chen, Bei Cai, Binwu Ying, Chuanmin Tao, Min Zhao, Zhaoxia Zhang, Junlong Zhang, Lanlan WangAbstract:Abstract An association between polymorphisms in the sodium taurocholate cotransporting polypeptide (NTCP) and the natural course of hepatitis B virus (HBV) infection in the Chinese Han population has been noted. However, it is not known whether these polymorphisms are associated with the risk of developing chronic HBV infection in other racial or ethnic populations. Accordingly, we conducted a candidate single nucleotide polymorphism (SNP) association study in Tibetan and Uygur HBV-infected patients. A total of 1302 subjects including 871 Tibetans and 431 Uygurs were recruited. According to their serological and clinical characteristics, each ethnic group was divided into two groups comprising spontaneous clearance individuals and persistently infected patients. Three SNPs were genotyped by a high resolution melting curve methodology. Among the SNPs, rs2296651 exhibited a minor allele frequency of p p = 0.002). Irrespective of race, no significant differences in the frequency distributions of the three SNP alleles or genotypes were observed between the case and clearance groups. Moreover, none of the NTCP haplotypes were statistically different between the two groups. Data from the Tibetan patients could be grouped by HBeAg status, viral load and HBV genotype; however, no significant differences were found in the SNP genotype distribution for each characteristic. In conclusion, the NTCP polymorphisms we identified tended to be ethnicity-dependent. For Tibetans and Uygurs, no association of the three SNPs (rs7154439, rs4646287 and rs2296651) and their haplotypes with HBV chronicity was observed. Examination of SNPs in NTCP for their specific associations with the course of HBV infection in other ethnic minority groups is now required.
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association of hla dp dq stat4 and il 28b variants with hbv viral clearance in Tibetans and uygurs in china
Liver International, 2015Co-Authors: Yun Liao, Jie Chen, Bei Cai, Binwu Ying, Chuanmin Tao, Min Zhao, Zhaoxia Zhang, Lanlan WangAbstract:Background & Aims Several genome-wide association studies have revealed that HLA-DP/DQ, STAT4 and IL-28B associated with liver diseases. But because of population heterogeneity, different races would have different causative polymorphisms. Therefore, in this study, we included Chinese Tibetans and Uygurs to examine the roles of these genes on HBV natural clearance. Methods A total of 1341 subjects including 908 Tibetans and 433 Uygurs were recruited. Seven single nucleotide polymorphisms (SNP) were genotyped. Results HLA-DP/DQ polymorphisms associated with HBV natural clearance in both ethnicities (Tibetans, rs3077, OR = 0.61, 95% CI = 0.46–0.82; rs9277535, OR = 0.56, 95% CI = 0.41–0.75; rs7453920, OR = 0.64, 95%CI = 0.47–0.85; Uygurs, rs3077, OR = 0.48, 95% CI = 0.24–0.96; rs9277535, OR = 0.43, 95% CI = 0.20–0.91; rs7453920, OR = 0.62, 95% CI = 0.39–0.99), whereas no significant association was observed between IL-28B with HBV natural clearance in neither ethnicities (P > 0.05). STAT4 rs7574865 seemed to be Tibetan specific in HBV natural clearance (OR = 0.76, 95% CI = 0.58–0.99). Moreover, in Tibetan patients, HLA-DQ rs7453920 GG had a higher frequency in HBeAg positive patients (P = 0.032) and STAT4 rs7574865 GG genotype appeared more frequently in Genotype C virus infected patients (P = 0.005). In addition, Uygurs have higher frequencies of HLA-DP/DQ protective alleles (72.5% for rs3077, 76.6% for rs9277535 and 26.8% for rs7453920) than Tibetans (51.7% for rs3077, 52.5% for rs9277535 and 18.5% for rs7453920)(all P < 0.05), and a lower prevalence of HBV infection as previously reported. Conclusions HLA-DP/DQ but not IL-28B polymorphisms correlate with HBV natural clearance, irrespective of race, and HLA-DP/DQ would be causative genes attributing to varying prevalence in different regions. STAT4 rs7574865 seemed to be population specific in Tibetans and it might synergistically interact with virus contributing to disease progression.
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Association of HLA-DP/DQ, STAT4 and IL-28B variants with HBV viral clearance in Tibetans and Uygurs in China.
Liver International, 2014Co-Authors: Yun Liao, Jie Chen, Bei Cai, Binwu Ying, Chuanmin Tao, Min Zhao, Zhaoxia Zhang, Lanlan WangAbstract:Background & Aims Several genome-wide association studies have revealed that HLA-DP/DQ, STAT4 and IL-28B associated with liver diseases. But because of population heterogeneity, different races would have different causative polymorphisms. Therefore, in this study, we included Chinese Tibetans and Uygurs to examine the roles of these genes on HBV natural clearance. Methods A total of 1341 subjects including 908 Tibetans and 433 Uygurs were recruited. Seven single nucleotide polymorphisms (SNP) were genotyped. Results HLA-DP/DQ polymorphisms associated with HBV natural clearance in both ethnicities (Tibetans, rs3077, OR = 0.61, 95% CI = 0.46–0.82; rs9277535, OR = 0.56, 95% CI = 0.41–0.75; rs7453920, OR = 0.64, 95%CI = 0.47–0.85; Uygurs, rs3077, OR = 0.48, 95% CI = 0.24–0.96; rs9277535, OR = 0.43, 95% CI = 0.20–0.91; rs7453920, OR = 0.62, 95% CI = 0.39–0.99), whereas no significant association was observed between IL-28B with HBV natural clearance in neither ethnicities (P > 0.05). STAT4 rs7574865 seemed to be Tibetan specific in HBV natural clearance (OR = 0.76, 95% CI = 0.58–0.99). Moreover, in Tibetan patients, HLA-DQ rs7453920 GG had a higher frequency in HBeAg positive patients (P = 0.032) and STAT4 rs7574865 GG genotype appeared more frequently in Genotype C virus infected patients (P = 0.005). In addition, Uygurs have higher frequencies of HLA-DP/DQ protective alleles (72.5% for rs3077, 76.6% for rs9277535 and 26.8% for rs7453920) than Tibetans (51.7% for rs3077, 52.5% for rs9277535 and 18.5% for rs7453920)(all P
Cynthia M Beall - One of the best experts on this subject based on the ideXlab platform.
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admixture facilitates genetic adaptations to high altitude in tibet
Nature Communications, 2014Co-Authors: Choongwon Jeong, Cynthia M Beall, Gorka Alkortaaranburu, Buddha Basnyat, Maniraj Neupane, David B Witonsky, Jonathan K Pritchard, Anna Di RienzoAbstract:Admixture is recognized as a widespread feature of human populations, renewing interest in the possibility that genetic exchange can facilitate adaptations to new environments. Studies of Tibetans revealed candidates for high-altitude adaptations in the EGLN1 and EPAS1 genes, associated with lower haemoglobin concentration. However, the history of these variants or that of Tibetans remains poorly understood. Here we analyse genotype data for the Nepalese Sherpa, and find that Tibetans are a mixture of ancestral populations related to the Sherpa and Han Chinese. EGLN1 and EPAS1 genes show a striking enrichment of high-altitude ancestry in the Tibetan genome, indicating that migrants from low altitude acquired adaptive alleles from the highlanders. Accordingly, the Sherpa and Tibetans share adaptive haemoglobin traits. This admixture-mediated adaptation shares important features with adaptive introgression. Therefore, we identify a novel mechanism, beyond selection on new mutations or on standing variation, through which populations can adapt to local environments.
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natural selection on epas1 hif2α associated with low hemoglobin concentration in Tibetan highlanders
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Cynthia M Beall, Gianpiero L Cavalleri, Mark Mccormack, Yu Liang, Libin Deng, Robert C Elston, Yang Gao, Jo Knight, Hugh Montgomery, Hao PanAbstract:By impairing both function and survival, the severe reduction in oxygen availability associated with high-altitude environments is likely to act as an agent of natural selection. We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200–3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2α, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. Second, in a separate cohort of Tibetans residing at 4,200 m, we identified 31 EPAS1 SNPs in high linkage disequilibrium that correlated significantly with hemoglobin concentration. The sex-adjusted hemoglobin concentration was, on average, 0.8 g/dL lower in the major allele homozygotes compared with the heterozygotes. These findings were replicated in a third cohort of Tibetans residing at 4,300 m. The alleles associating with lower hemoglobin concentrations were correlated with the signal from the GWADS study and were observed at greatly elevated frequencies in the Tibetan cohorts compared with the Han. High hemoglobin concentrations are a cardinal feature of chronic mountain sickness offering one plausible mechanism for selection. Alternatively, as EPAS1 is pleiotropic in its effects, selection may have operated on some other aspect of the phenotype. Whichever of these explanations is correct, the evidence for genetic selection at the EPAS1 locus from the GWADS study is supported by the replicated studies associating function with the allelic variants.
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andean Tibetan and ethiopian patterns of adaptation to high altitude hypoxia
Integrative and Comparative Biology, 2006Co-Authors: Cynthia M BeallAbstract:Synopsis Research on humans at high-altitudes contributes to understanding the processes of human adaptation to the environment and evolution. The unique stress at high altitude is hypobaric hypoxia caused by the fall in barometric pressure with increasing altitude and the consequently fewer oxygen molecules in a breath of air, as compared with sea level. The natural experiment of human colonization of high-altitude plateaus on three continents has resulted in two—perhaps three—quantitatively different arterial-oxygen-content phenotypes among indigenous Andean, Tibetan and Ethiopian high-altitude populations. This paper illustrates these contrasting phenotypes by presenting evidence for higher hemoglobin concentration and percent of oxygen saturation of hemoglobin among Andean highlanders as compared with Tibetans at the same altitude and evidence that Ethiopian highlanders do not differ from sea-level in these two traits. Evolutionary processes may have acted differently on the colonizing populations to cause the different patterns of adaptation. Hemoglobin concentration has significant heritability in Andean and Tibetan samples. Oxygen saturation has no heritability in the Andean sample, but does among Tibetans where an autosomal dominant major gene for higher oxygen saturation has been detected. Women estimated with high probability to have high oxygen saturation genotypes have more surviving children than women estimated with high probability to have the low oxygen saturation genotype. These findings suggest the hypothesis that ongoing natural selection is increasing the frequency of the high saturation allele at this major gene locus.
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percent of oxygen saturation of arterial hemoglobin among bolivian aymara at 3 900 4 000 m
American Journal of Physical Anthropology, 1999Co-Authors: Cynthia M Beall, Kingman P Strohl, John Blangero, Sarah Williamsblangero, Laura Almasy, Michael J Decker, Enrique Vargas, Mercedes Villena, Gary M Brittenham, Rudy SoriaAbstract:A range of variation in percent of oxygen saturation of arterial hemoglobin (SaO2) among healthy individuals at a given high altitude indicates differences in physiological hypoxemia despite uniform ambient hypoxic stress. In populations native to the Tibetan plateau, a significant portion of the variance is attributable to additive genetic factors, and there is a major gene influencing SaO2. To determine whether there is genetic variance in other high-altitude populations, we designed a study to test the hypothesis that additive genetic factors contribute to phenotypic variation in SaO2 among Aymara natives of the Andean plateau, a population geographically distant from the Tibetan plateau and with a long, separate history of high-altitude residence. The average SaO2 of 381 Aymara at 3,900-4,000 m was 92 6 0.15% (SEM) with a range of 84-99%. The average was 2.6% higher than the average SaO2 of a sample of Tibetans at 3,800-4,065 m measured with the same techniques. Quantitative genetic analyses of the Aymara sample detected no significant variance attributable to genetic factors. The presence of genetic variance in SaO2 in the Tibetan sample and its absence in the Aymara sample indicate there is potential for natural selection on this trait in the Tibetan but not the Aymara population. Am J Phys Anthropol 108:41-51, 1999. r 1999 Wiley-Liss, Inc.
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ventilation and hypoxic ventilatory response of Tibetan and aymara high altitude natives
American Journal of Physical Anthropology, 1997Co-Authors: Cynthia M Beall, Melvyn C. Goldstein, Kingman P Strohl, John Blangero, Sarah Williamsblangero, Laura Almasy, Michael J Decker, Carol M Worthman, Enrique Vargas, Mercedes VillenaAbstract:Newcomers acclimatizing to high altitude and adult male Tibetan high altitude natives have increased ventilation relative to sea level natives at sea level. However, Andean and Rocky Mountain high altitude natives have an intermediate level of ventilation lower than that of newcom- ers and Tibetan high altitude natives although generally higher than that of sea level natives at sea level. Because the reason for the relative hypoventila- tion of some high altitude native populations was unknown, a study was designed to describe ventilation from adolescence through old age in samples of Tibetan and Andean high altitude natives and to estimate the relative genetic and environmental influences. This paper compares resting ventila- tion and hypoxic ventilatory response (HVR) of 320 Tibetans 9-82 years of age and 542 Bolivian Aymara 13-94 years of age, native residents at 3,800-4,065 m. Tibetan resting ventilation was roughly 1.5 times higher and Tibetan HVR was roughly double that of Aymara. Greater duration of hypoxia (older age) was not an important source of variation in resting ventilation or HVR in either sample. That is, contrary to previous studies, neither sample acquired hypoventilation in the age ranges under study. Within populations, greater severity of hypoxia (lower percent of oxygen saturation of arterial hemoglo- bin) was associated with slightly higher resting ventilation among Tibetans and lower resting ventilation and HVR among Aymara women, although the associations accounted for just 2-7% of the variation. Between populations, the Tibetan sample was more hypoxic and had higher resting ventilation and HVR. Other systematic environmental contrasts did not appear to elevate Tibetan or depress Aymara ventilation. There was more intrapopulation genetic variation in these traits in the Tibetan than the Aymara sample. Thirty-five percent of the Tibetan, but none of the Aymara, resting ventilation variance was due to genetic differences among individuals. Thirty-one percent of the Tibetan HVR, but just 21% of the Aymara, HVR variance was due to
Yun Liao - One of the best experts on this subject based on the ideXlab platform.
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polymorphisms in sodium taurocholate cotransporting polypeptide are not associated with hepatitis b virus clearance in chinese Tibetans and uygurs
Infection Genetics and Evolution, 2016Co-Authors: Yun Liao, Jie Chen, Bei Cai, Binwu Ying, Chuanmin Tao, Min Zhao, Zhaoxia Zhang, Junlong Zhang, Lanlan WangAbstract:Abstract An association between polymorphisms in the sodium taurocholate cotransporting polypeptide (NTCP) and the natural course of hepatitis B virus (HBV) infection in the Chinese Han population has been noted. However, it is not known whether these polymorphisms are associated with the risk of developing chronic HBV infection in other racial or ethnic populations. Accordingly, we conducted a candidate single nucleotide polymorphism (SNP) association study in Tibetan and Uygur HBV-infected patients. A total of 1302 subjects including 871 Tibetans and 431 Uygurs were recruited. According to their serological and clinical characteristics, each ethnic group was divided into two groups comprising spontaneous clearance individuals and persistently infected patients. Three SNPs were genotyped by a high resolution melting curve methodology. Among the SNPs, rs2296651 exhibited a minor allele frequency of p p = 0.002). Irrespective of race, no significant differences in the frequency distributions of the three SNP alleles or genotypes were observed between the case and clearance groups. Moreover, none of the NTCP haplotypes were statistically different between the two groups. Data from the Tibetan patients could be grouped by HBeAg status, viral load and HBV genotype; however, no significant differences were found in the SNP genotype distribution for each characteristic. In conclusion, the NTCP polymorphisms we identified tended to be ethnicity-dependent. For Tibetans and Uygurs, no association of the three SNPs (rs7154439, rs4646287 and rs2296651) and their haplotypes with HBV chronicity was observed. Examination of SNPs in NTCP for their specific associations with the course of HBV infection in other ethnic minority groups is now required.
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association of hla dp dq stat4 and il 28b variants with hbv viral clearance in Tibetans and uygurs in china
Liver International, 2015Co-Authors: Yun Liao, Jie Chen, Bei Cai, Binwu Ying, Chuanmin Tao, Min Zhao, Zhaoxia Zhang, Lanlan WangAbstract:Background & Aims Several genome-wide association studies have revealed that HLA-DP/DQ, STAT4 and IL-28B associated with liver diseases. But because of population heterogeneity, different races would have different causative polymorphisms. Therefore, in this study, we included Chinese Tibetans and Uygurs to examine the roles of these genes on HBV natural clearance. Methods A total of 1341 subjects including 908 Tibetans and 433 Uygurs were recruited. Seven single nucleotide polymorphisms (SNP) were genotyped. Results HLA-DP/DQ polymorphisms associated with HBV natural clearance in both ethnicities (Tibetans, rs3077, OR = 0.61, 95% CI = 0.46–0.82; rs9277535, OR = 0.56, 95% CI = 0.41–0.75; rs7453920, OR = 0.64, 95%CI = 0.47–0.85; Uygurs, rs3077, OR = 0.48, 95% CI = 0.24–0.96; rs9277535, OR = 0.43, 95% CI = 0.20–0.91; rs7453920, OR = 0.62, 95% CI = 0.39–0.99), whereas no significant association was observed between IL-28B with HBV natural clearance in neither ethnicities (P > 0.05). STAT4 rs7574865 seemed to be Tibetan specific in HBV natural clearance (OR = 0.76, 95% CI = 0.58–0.99). Moreover, in Tibetan patients, HLA-DQ rs7453920 GG had a higher frequency in HBeAg positive patients (P = 0.032) and STAT4 rs7574865 GG genotype appeared more frequently in Genotype C virus infected patients (P = 0.005). In addition, Uygurs have higher frequencies of HLA-DP/DQ protective alleles (72.5% for rs3077, 76.6% for rs9277535 and 26.8% for rs7453920) than Tibetans (51.7% for rs3077, 52.5% for rs9277535 and 18.5% for rs7453920)(all P < 0.05), and a lower prevalence of HBV infection as previously reported. Conclusions HLA-DP/DQ but not IL-28B polymorphisms correlate with HBV natural clearance, irrespective of race, and HLA-DP/DQ would be causative genes attributing to varying prevalence in different regions. STAT4 rs7574865 seemed to be population specific in Tibetans and it might synergistically interact with virus contributing to disease progression.
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Association of HLA-DP/DQ, STAT4 and IL-28B variants with HBV viral clearance in Tibetans and Uygurs in China.
Liver International, 2014Co-Authors: Yun Liao, Jie Chen, Bei Cai, Binwu Ying, Chuanmin Tao, Min Zhao, Zhaoxia Zhang, Lanlan WangAbstract:Background & Aims Several genome-wide association studies have revealed that HLA-DP/DQ, STAT4 and IL-28B associated with liver diseases. But because of population heterogeneity, different races would have different causative polymorphisms. Therefore, in this study, we included Chinese Tibetans and Uygurs to examine the roles of these genes on HBV natural clearance. Methods A total of 1341 subjects including 908 Tibetans and 433 Uygurs were recruited. Seven single nucleotide polymorphisms (SNP) were genotyped. Results HLA-DP/DQ polymorphisms associated with HBV natural clearance in both ethnicities (Tibetans, rs3077, OR = 0.61, 95% CI = 0.46–0.82; rs9277535, OR = 0.56, 95% CI = 0.41–0.75; rs7453920, OR = 0.64, 95%CI = 0.47–0.85; Uygurs, rs3077, OR = 0.48, 95% CI = 0.24–0.96; rs9277535, OR = 0.43, 95% CI = 0.20–0.91; rs7453920, OR = 0.62, 95% CI = 0.39–0.99), whereas no significant association was observed between IL-28B with HBV natural clearance in neither ethnicities (P > 0.05). STAT4 rs7574865 seemed to be Tibetan specific in HBV natural clearance (OR = 0.76, 95% CI = 0.58–0.99). Moreover, in Tibetan patients, HLA-DQ rs7453920 GG had a higher frequency in HBeAg positive patients (P = 0.032) and STAT4 rs7574865 GG genotype appeared more frequently in Genotype C virus infected patients (P = 0.005). In addition, Uygurs have higher frequencies of HLA-DP/DQ protective alleles (72.5% for rs3077, 76.6% for rs9277535 and 26.8% for rs7453920) than Tibetans (51.7% for rs3077, 52.5% for rs9277535 and 18.5% for rs7453920)(all P
Jie Chen - One of the best experts on this subject based on the ideXlab platform.
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genetic signatures of high altitude adaptation in Tibetans
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Jian Yang, Zibing Jin, Jie Chen, Xiufeng Huang, Yuanbo Liang, Jianyang Mao, Xin Chen, Zhili Zheng, Andrew Bakshi, Dongdong ZhengAbstract:Indigenous Tibetan people have lived on the Tibetan Plateau for millennia. There is a long-standing question about the genetic basis of high-altitude adaptation in Tibetans. We conduct a genome-wide study of 7.3 million genotyped and imputed SNPs of 3,008 Tibetans and 7,287 non-Tibetan individuals of Eastern Asian ancestry. Using this large dataset, we detect signals of high-altitude adaptation at nine genomic loci, of which seven are unique. The alleles under natural selection at two of these loci [methylenetetrahydrofolate reductase (MTHFR) and EPAS1] are strongly associated with blood-related phenotypes, such as hemoglobin, homocysteine, and folate in Tibetans. The folate-increasing allele of rs1801133 at the MTHFR locus has an increased frequency in Tibetans more than expected under a drift model, which is probably a consequence of adaptation to high UV radiation. These findings provide important insights into understanding the genomic consequences of high-altitude adaptation in Tibetans.
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polymorphisms in sodium taurocholate cotransporting polypeptide are not associated with hepatitis b virus clearance in chinese Tibetans and uygurs
Infection Genetics and Evolution, 2016Co-Authors: Yun Liao, Jie Chen, Bei Cai, Binwu Ying, Chuanmin Tao, Min Zhao, Zhaoxia Zhang, Junlong Zhang, Lanlan WangAbstract:Abstract An association between polymorphisms in the sodium taurocholate cotransporting polypeptide (NTCP) and the natural course of hepatitis B virus (HBV) infection in the Chinese Han population has been noted. However, it is not known whether these polymorphisms are associated with the risk of developing chronic HBV infection in other racial or ethnic populations. Accordingly, we conducted a candidate single nucleotide polymorphism (SNP) association study in Tibetan and Uygur HBV-infected patients. A total of 1302 subjects including 871 Tibetans and 431 Uygurs were recruited. According to their serological and clinical characteristics, each ethnic group was divided into two groups comprising spontaneous clearance individuals and persistently infected patients. Three SNPs were genotyped by a high resolution melting curve methodology. Among the SNPs, rs2296651 exhibited a minor allele frequency of p p = 0.002). Irrespective of race, no significant differences in the frequency distributions of the three SNP alleles or genotypes were observed between the case and clearance groups. Moreover, none of the NTCP haplotypes were statistically different between the two groups. Data from the Tibetan patients could be grouped by HBeAg status, viral load and HBV genotype; however, no significant differences were found in the SNP genotype distribution for each characteristic. In conclusion, the NTCP polymorphisms we identified tended to be ethnicity-dependent. For Tibetans and Uygurs, no association of the three SNPs (rs7154439, rs4646287 and rs2296651) and their haplotypes with HBV chronicity was observed. Examination of SNPs in NTCP for their specific associations with the course of HBV infection in other ethnic minority groups is now required.
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association of hla dp dq stat4 and il 28b variants with hbv viral clearance in Tibetans and uygurs in china
Liver International, 2015Co-Authors: Yun Liao, Jie Chen, Bei Cai, Binwu Ying, Chuanmin Tao, Min Zhao, Zhaoxia Zhang, Lanlan WangAbstract:Background & Aims Several genome-wide association studies have revealed that HLA-DP/DQ, STAT4 and IL-28B associated with liver diseases. But because of population heterogeneity, different races would have different causative polymorphisms. Therefore, in this study, we included Chinese Tibetans and Uygurs to examine the roles of these genes on HBV natural clearance. Methods A total of 1341 subjects including 908 Tibetans and 433 Uygurs were recruited. Seven single nucleotide polymorphisms (SNP) were genotyped. Results HLA-DP/DQ polymorphisms associated with HBV natural clearance in both ethnicities (Tibetans, rs3077, OR = 0.61, 95% CI = 0.46–0.82; rs9277535, OR = 0.56, 95% CI = 0.41–0.75; rs7453920, OR = 0.64, 95%CI = 0.47–0.85; Uygurs, rs3077, OR = 0.48, 95% CI = 0.24–0.96; rs9277535, OR = 0.43, 95% CI = 0.20–0.91; rs7453920, OR = 0.62, 95% CI = 0.39–0.99), whereas no significant association was observed between IL-28B with HBV natural clearance in neither ethnicities (P > 0.05). STAT4 rs7574865 seemed to be Tibetan specific in HBV natural clearance (OR = 0.76, 95% CI = 0.58–0.99). Moreover, in Tibetan patients, HLA-DQ rs7453920 GG had a higher frequency in HBeAg positive patients (P = 0.032) and STAT4 rs7574865 GG genotype appeared more frequently in Genotype C virus infected patients (P = 0.005). In addition, Uygurs have higher frequencies of HLA-DP/DQ protective alleles (72.5% for rs3077, 76.6% for rs9277535 and 26.8% for rs7453920) than Tibetans (51.7% for rs3077, 52.5% for rs9277535 and 18.5% for rs7453920)(all P < 0.05), and a lower prevalence of HBV infection as previously reported. Conclusions HLA-DP/DQ but not IL-28B polymorphisms correlate with HBV natural clearance, irrespective of race, and HLA-DP/DQ would be causative genes attributing to varying prevalence in different regions. STAT4 rs7574865 seemed to be population specific in Tibetans and it might synergistically interact with virus contributing to disease progression.
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Association of HLA-DP/DQ, STAT4 and IL-28B variants with HBV viral clearance in Tibetans and Uygurs in China.
Liver International, 2014Co-Authors: Yun Liao, Jie Chen, Bei Cai, Binwu Ying, Chuanmin Tao, Min Zhao, Zhaoxia Zhang, Lanlan WangAbstract:Background & Aims Several genome-wide association studies have revealed that HLA-DP/DQ, STAT4 and IL-28B associated with liver diseases. But because of population heterogeneity, different races would have different causative polymorphisms. Therefore, in this study, we included Chinese Tibetans and Uygurs to examine the roles of these genes on HBV natural clearance. Methods A total of 1341 subjects including 908 Tibetans and 433 Uygurs were recruited. Seven single nucleotide polymorphisms (SNP) were genotyped. Results HLA-DP/DQ polymorphisms associated with HBV natural clearance in both ethnicities (Tibetans, rs3077, OR = 0.61, 95% CI = 0.46–0.82; rs9277535, OR = 0.56, 95% CI = 0.41–0.75; rs7453920, OR = 0.64, 95%CI = 0.47–0.85; Uygurs, rs3077, OR = 0.48, 95% CI = 0.24–0.96; rs9277535, OR = 0.43, 95% CI = 0.20–0.91; rs7453920, OR = 0.62, 95% CI = 0.39–0.99), whereas no significant association was observed between IL-28B with HBV natural clearance in neither ethnicities (P > 0.05). STAT4 rs7574865 seemed to be Tibetan specific in HBV natural clearance (OR = 0.76, 95% CI = 0.58–0.99). Moreover, in Tibetan patients, HLA-DQ rs7453920 GG had a higher frequency in HBeAg positive patients (P = 0.032) and STAT4 rs7574865 GG genotype appeared more frequently in Genotype C virus infected patients (P = 0.005). In addition, Uygurs have higher frequencies of HLA-DP/DQ protective alleles (72.5% for rs3077, 76.6% for rs9277535 and 26.8% for rs7453920) than Tibetans (51.7% for rs3077, 52.5% for rs9277535 and 18.5% for rs7453920)(all P
Josef T Prchal - One of the best experts on this subject based on the ideXlab platform.
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High altitude genetic adaptation in Tibetans: no role of increased hemoglobin-oxygen affinity.
Blood cells molecules & diseases, 2014Co-Authors: Tsewang Tashi, Tang Feng-lin, Parvaiz Koul, Ricardo Amaru, Dottie Hussey, Ge Rili, Felipe R Lorenzo, Josef T PrchalAbstract:High altitude exerts selective evolutionary pressure primarily due to its hypoxic environment, resulting in multiple adaptive responses. High hemoglobin-oxygen affinity is postulated to be one such adaptive change, which has been reported in Sherpas of the Himalayas. Tibetans have lived on the Qinghai-Tibetan plateau for thousands of years and have developed unique phenotypes, such as protection from polycythemia which has been linked to PDH2 mutation, resulting in the downregulation of the HIF pathway. In order to see if Tibetans also developed high hemoglobin-oxygen affinity as a part of their genetic adaptation, we conducted this study assessing hemoglobin-oxygen affinity and their fetal hemoglobin levels in Tibetan subjects from 3 different altitudes. We found normal hemoglobin-oxygen affinity in all subjects, fetal hemoglobin levels were normal in all except one and no hemoglobin variants in any of the subjects. We conclude that increased hemoglobin-oxygen affinity or increased fetal hemoglobin are not adaptive phenotypes of the Tibetan highlanders.
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high altitude genetic adaptation in Tibetans does not include increased hemoglobin oxygen affinity
Blood, 2013Co-Authors: Tsewang Tashi, Parvaiz Koul, Dottie Hussey, Felipe R Lorenzo, Josef T PrchalAbstract:Increased hemoglobin-oxygen affinity has been shown to be an adaptive response to hypoxia in many high altitude animals such as the Andean goose, guinea pig and llamas (Reynafarje C. 1975; Hebbel R. 1978). It has been reported that people living in a high altitude, hypoxic environment have also developed a similar adaptation. Native Tibetans are known to have lived at an average of 3000-5000 meters on the Tibetan Plateau for more than 20,000 years, and have undergone genetic adaptations that have enabled them to thrive in this reduced oxygen environment. Most Tibetans are thus protected from polycythemia and other features of chronic mountain sickness. Several studies have reported higher arterial oxygen saturations among Tibetans as part of their genetic adaptation (Beall C. 1994; Moore L. 2001; Niermeyer S. 1995), thereby concluding that they have higher hemoglobin-oxygen affinity. Further, recent genomic studies have reported that beta-globin haplotypes (HBB and HBG2) have been selected in Tibetans, suggesting the presence of hemoglobin variants as a beneficial factor of Tibetan adaptation (Yi. 2010). However, some of the reports of increased hemoglobin-oxygen affinity are based on single readings of arterial oxygen measurements. Hemoglobin-oxygen affinity is more optimally measured by deriving the P50 value, which is the partial pressure of oxygen at which hemoglobin is 50% saturated with oxygen. A decreased P50 can be due to mutated globin genes resulting in high oxygen affinity hemoglobins, low 2,3 BPG, high pH or low temperature. The hemoglobin-oxygen dissociation is optimally derived by hemoximeter measurements of the percent saturation of hemoglobin at various partial pressures of oxygen. The resultant curve has a sigmoid shape due to the cooperative binding of oxygen to the four globins in the hemoglobin tetramer; this cooperative interaction can be enumerated as a Hill coefficient “n”. If a hemoximeter is not readily available, the P50 can be estimated from the venous blood gas using the measured pO2, hemoglobin oxygen percent saturation O2%, and pH (Lichtman M. 1976); however the Hill coefficient “n” cannot be derived by this method. To definitely establish whether the Tibetan adaptation to high altitude hypoxia involves increased hemoglobin-oxygen affinity, we conducted the following study of direct and indirect oxygen-hemoglobin affinity among Tibetans living at two different altitudes. We enrolled 14 healthy ethnic Tibetans and one closely related Nepalese Sherpa. There were 8 males and 7 females ages ranging 35-75 years. The first group consisted of 5 ethnic Tibetans living in Srinagar, India (1,600 meters), on whom venous blood gases were done and the P50 was derived using pH, PO2 and O2 saturation using the formula described by Lichtman and colleagues. Three were born in Tibet and two were offspring of Tibet-born parents. The second group consisted of 10 volunteers (9 Tibetans and one Nepalese Sherpa) residing in Salt Lake City, UT, (1,300 meters) whose peripheral blood was evaluated by Hemox Analyzer for obtaining P50 values and “n” Hill coefficients for hemoglobin oxygen binding. All the ethnic Tibetans in Salt Lake City were born in Tibet except for one, and the Nepalese Sherpa was born in Nepal. The results are depicted in Table. The P50 measured by venous blood gases on the Tibetan volunteers from Srinagar, India and those measured by Hemox Analyzer on the 10 volunteers from Salt Lake City, UT were normal, with values in the normal range (22-28 mmHg). No hemoglobin variants were detected by high pressure liquid chromatography in these 15 Tibetan volunteers. We report no evidence for the presence of high hemoglobin-oxygen affinity in Tibetans as a constituent of their genetic adaptation. Our data rule out the existence of hemoglobin variants and aberrant 2,3 BPG metabolism as possible features of Tibetan high-altitude adaptation; however acquired transient metabolic alterations at high altitudes, cannot be excluded to account for possible changes in hemoglobin-oxygen affinity but these are not evolved persistent features of Tibetan genetic adaptation. Studies of Tibetans living in these extreme hypoxic environment (>4,000m) are now planned. Disclosures: No relevant conflicts of interest to declare.
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the Tibetan phd2 polymorphism asp4glu is associated with hypersensitivity of erythroid progenitors to epo and upregulation of hif 1 regulated genes hexokinase hk1 and glucose transporter 1 slc2a glut1
Blood, 2011Co-Authors: Felipe R Lorenzo, Sabina Swierczek, Chad D Huff, Josef T PrchalAbstract:Abstract 3388 The hypoxic response, mediated by hypoxia inducible transcription factors (HIFs), is central to the control and development of many essential biological functions, including erythropoiesis. As a high-altitude population, many Tibetans have developed a remarkable ability to protect against several hypoxic complications, including polycythemia and other harmful responses exhibited by non-adapted populations upon exposure to severe hypoxia. We have identified 10 genes involved in high-altitude adaptation in Tibetans, including a principal negative regulator of HIF-1a and HIF-2 a peptides, i.e. PHD2 (EGLN1), as well as HIF2A (EPAS1) (Simonson, Science 2010). At this meeting last year (Lorenzo, Abstract# 2602 ASH 2010), we reported a novel PHD2 Asp4Glu mutation that we found in 57 of 94 Tibetan, 2 of 88 Asian and 0 of 38 Caucasian chromosomes. In most Tibetan samples, this variant is associated with a previously reported, unvalidated PHD2 polymorphism, Cys127Ser (found in 70 of 94 Tibetan, 27 of 88 Asian and 4 of 38 Caucasian chromosomes). To study the functional consequences of this PHD2 Asp4Glu mutation, we recruited five Tibetan volunteers living in Utah, four of whom were homozygous and 1 heterozygous for PHD2 Asp4Glu and Cys127Ser. We unexpectedly found that homozygotes for the exon 1 PHD2 mutation had markedly hypersensitive erythroid BFU-E (Fig.1) compared to the range of normal controls we have standardized over several decades. Interestingly, erythroid progenitors from individuals with Chuvash polycythemia or a HIF-2a gain-of-function mutation also have hypersensitive BFU-E. To determine if the Tibetan erythroid hypersensitivity data may be explained by increased HIF activity, we have quantified HIF target gene expression in subject granulocytes and found a significant increase in hexokinase (HK1) and glucose transporter (GLUT1/SLC2A) mRNA levels. These data report the first molecular defect with functional consequences that is associated with the complex Tibetan adaptation to extreme hypoxia. Disclosures: No relevant conflicts of interest to declare.
