云南汉族人群CCR5基因启动子多态性与HCV慢性感染的关系
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摘要
目的:研究云南汉族人群CCR5基因启动子单核苷酸多态性位点(SNPs)与丙型肝炎病毒(HCV)慢性感染的关系。方法:选取356例云南汉族HCV慢性感染者作为病例组,353例健康体检者作为对照组,采用PCR法扩增受检者CCR5基因启动子区基因序列;然后采用Sanger法对扩增序列进行测序并与Gen Bank(NC_000003.12)序列比较获得与云南省汉族人群具有多态性的SNPs位点,对获得的SNPs位点进行基因分型,计算这些SNPs位点的等位基因频率和基因型频率;构建单倍型并分析遗传模式进行,比较两组间的分布差异。结果:在CCR5基因启动子区域有9个SNPs位点,其中rs2227010(A>G)、rs2734648(T>G)、rs1799987 (G>A)、rs1799988 (T>C)、rs1800023 (G>A)及1800024 (C>T) 6个位点在云南省汉族人群中具有多态性;这6个SNPs位点的基因型频率、等位基因频率及单倍型频率在病例组与对照组比较,差异均无统计学意义(P>0.05)。结论:CCR5基因启动子中的rs2227010(A>G)、rs2734648(T>G)、rs1799987 (G>A)、rs1799988 (T>C)、rs1800023 (G>A)及1800024 (C>T) SNPs位点与云南汉族人群HCV慢性感染无关。
Objective:To investigate the association of single nucleotide polymorphisms(SNPs) in CCR5 gene promoter with chronic HCV infection in Yunnan Han population.Methods:Among Chinese Han population in Yunnan Province,363 patients with HCV chronic infection were recruited as a case group,and 354 healthy individuals as control group.The CCR5 promoter sequences were amplified by PCR.Sanger sequencing was used to detect six SNPs including rs2227010(A>G),rs2734648(T>G),rs1799987(G>A),rs1799988(T>C),rs1800023(G>A) and rs180024(C>T)) in CCR5 promoter region.We compared these six SNPs with the GenBank(NC_000003.12) sequence to obtain SNP sites in the Han population of Yunnan Province.The obtained SNPs were genotyped and calculated for allele frequency and genotype frequency;the haplotype was constructed to analyze the genetic model and the distribution difference between the two groups.Results:Among nine SNPs sites in the CCR5 gene promoter,six SNPs including rs2227010(A>G),rs2734648(T>G),rs1799987(G>A),rs1799988(T>C),rs1800023(G>A),rs41355345(C>G) and 1800024(C>T)have polymorphisms in Yunnan Han population.However,there is not statistically significant difference in the frequencies of allele,genotype,haplotype and inheritance patterns of these six SNPs between HCV infection group and healthy control group(P>0.05).Conclusion:These six SNP locus in CCR5 gene promoter region may not be associated with the susceptibility of HCV chronic infection in Han population of Yunnan provience.
Objective:To investigate the association of single nucleotide polymorphisms(SNPs) in CCR5 gene promoter with chronic HCV infection in Yunnan Han population.Methods:Among Chinese Han population in Yunnan Province,363 patients with HCV chronic infection were recruited as a case group,and 354 healthy individuals as control group.The CCR5 promoter sequences were amplified by PCR.Sanger sequencing was used to detect six SNPs including rs2227010(A>G),rs2734648(T>G),rs1799987(G>A),rs1799988(T>C),rs1800023(G>A) and rs180024(C>T)) in CCR5 promoter region.We compared these six SNPs with the GenBank(NC_000003.12) sequence to obtain SNP sites in the Han population of Yunnan Province.The obtained SNPs were genotyped and calculated for allele frequency and genotype frequency;the haplotype was constructed to analyze the genetic model and the distribution difference between the two groups.Results:Among nine SNPs sites in the CCR5 gene promoter,six SNPs including rs2227010(A>G),rs2734648(T>G),rs1799987(G>A),rs1799988(T>C),rs1800023(G>A),rs41355345(C>G) and 1800024(C>T)have polymorphisms in Yunnan Han population.However,there is not statistically significant difference in the frequencies of allele,genotype,haplotype and inheritance patterns of these six SNPs between HCV infection group and healthy control group(P>0.05).Conclusion:These six SNP locus in CCR5 gene promoter region may not be associated with the susceptibility of HCV chronic infection in Han population of Yunnan provience.
引文
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[21]HOLTE S,LEE J,KAUPP N,et al.Analysis of genetic polymorphisms in CCR5,CCR2,stromal cell-derived factor-1,RANTES,and dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin in seronegative individuals repeatedly exposed to HIV-1[J].Journal of Infectious Diseases,2004,190(6):1055-1058.
[22]CHANG H Y,AHN S H,KIM D Y,et al.Association between CCR5 promoter polymorphisms and hepatitis Bvirus infection[J].Korean Journal of Hepatology,2005,11(2):116-124.
[23]MCDERMOTT D H,ZIMMERMAN P A,GUIGNARDF,et al.CCR5 promoter polymorphism and HIV-1 disease progression[J].Lancet,1998,352(9131):866-870.
[24]SHIEH B,LIAU Y E,HSIEH P S,et al.Influence of nucleotide polymorphisms in the CCR2 gene and the CCR5 promoter on the expression of cell surface CCR5and CXCR4[J].International Immunology,2000,12(9):1311-1318.
[25]KONISHI I,HORIIKE N,HIASA Y,et al.CCR5 promoter polymorphism influences the interferon response of patients with chronic hepatitis C in Japan[J].Intervirology,2004,47(2):114-120.
[26]KALLEL A,SEDIRI Y,MOURALI M S,et al.296 CCchemokine receptors(CCR5 and CCR2)polymorphisms in Tunisian patients with myocardial infarction[J].Archives of Cardiovascular Diseases Supplements,2012,4(1):94.
[27]MUMMIDI S,AHUJA S S,MCDANIEL B L,et al.The human CC chemokine receptor 5(CCR5)gene.Multiple transcripts with 5'-end heterogeneity,dual promoter usage,and evidence for polymorphisms within the regulatory regions and noncoding exons[J].Journal of Biological Chemistry,1997,272(49):30662-30671.
[28]CATANO G,CHYKARENKO Z A,MANGANO A,et al.Concordance of CCR5 genotypes that influence cellmediated immunity and HIV-1 disease progression rates[J].Journal of Infectious Diseases,2011,203(2):263-272.
[29]PARCZEWSKI M,URBA?SKA A,MACIEJEWSKA K,et al.Association of chemokine receptor gene variants with HIV-1 genotype predicted tropism[J].Hiv Medicine,2015,15(10):577-586.
[30]CARRINGTON M,DEAN M,MARTIN M P,et al.Genetics of HIV-1 infection:chemokine receptor CCR5 polymorphism and its consequences[J].Human Molecular Genetics,1999,8(10):1939-1945.
[31]JIAPENG L,AIJUAN S,YOUXIN W,et al.The genetic associations and epistatic effects of the CCR5 promoter and CCR2-V64I polymorphisms on susceptibility to HIV-1infection in a Northern Han Chinese population[J].Genetic Testing&Molecular Biomarkers,2012,16(12):1369.
[32]MARTIN M P,DEAN M,SMITH M W,et al.Genetic Acceleration of AIDS Progression by a Promoter Variant of CCR5[J].Science,1998,282(5395):1907-1911.
[33]JOSHI A,PUNKE E B,SEDANO M,et al.CCR5 promoter activity correlates with HIV disease progression by regulating CCR5 cell surface expression and CD4 T cell apoptosis[J].Scientific Reports,2017,7(1):232.
[34]COENEN M,NATTERMANN J,FELDMANN G,et al.The role of CCR5 in HCV infection[J].European Journal of Medical Research,2010,15(3):97-101.
[2]SEBASTIANI G,GKOUVATSOS K,PANTOPOULOS K.Chronic hepatitis C and liver fibrosis.[J].World Journal of Gastroenterology,2014,20(32):11033-11053.
[3]LISTED N A.New hepatitis data highlight need for urgent global response[J].Saudi Medical Journal,2017,38(6):672-675.
[4]CAMPBELL C,CANARY L,SMITH N,et al.State HCV incidence and policies related to HCV preventive and treatment services for persons who inject drugs-United States,2015-2016.[J].American Journal of Transplantation,2017,17(7):1945-1948.
[5]LECHNER F,GRUENER N H,URBANI S,et al.CD8+T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained[J].European Journal of Immunology,2015,30(9):2479-2487.
[6]KUMAR U,MONJARDINO J,THOMAS H C.Hypervariable region of hepatitis C virus envelope glycoprotein(E2/NS1)in an agammaglobulinemic patient[J].Gastroenterology,1994,106(4):1072-1075.
[7]HE X S,REHERMANN B,LóPEZLABRADOR F X,et al.Quantitative analysis of hepatitis C virus-specific CD8+T cells in peripheral blood and liver using peptideMHC tetramers[J].Proceedings of the National Academy of Sciences of the United States of America,1999,96(10):5692-5697.
[8]SURUKI R Y,MUELLER N,HAYASHI K,et al.Host immune status and incidence of hepatocellular carcinoma among subjects infected with hepatitis C virus:a nested case-control study in Japan.[J].Cancer Epidemiology Biomarkers&Prevention,2006,15(12):2521-2525.
[9]ZHANG S,BAKSHI R K,SUNEETHA P V,et al.Frequency,private specificity,and cross-reactivity of preexisting hepatitis c virus(HCV)-Specific CD8+T cells in hcv-seronegative individuals:implications for vaccine responses[J].Journal of Virology,2015,89(16):8304-8317.
[10]MUMMIDI S,BAMSHAD M,AHUJA S S,et al.Evolution of human and non-human primate CC chemokine receptor 5 gene and mRNA.Potential roles for haplotype and mRNA diversity,differential haplotype-specific transcriptional activity,and altered transcription factor binding to polymorphic nucleotides[J].Journal of Biological Chemistry,2000,275(25):18946-18961.
[11]PATERLINI M G.Structure modeling of the chemokine receptor CCR5:implications for ligand binding and selectivity[J].Biophysical Journal,2002,83(6):3012-3031.
[12]FUKADA K,SOBAO Y,TOMIYAMA H,et al.Functional expression of the chemokine receptor CCR5 on virus epitope-specific memory and effector CD8+T cells[J].Journal of Immunology,2002,168(5):2225-2232.
[13]XIANG J,GEORGE S L,WüNSCHMANN S,et al.Inhibition of HIV-1 replication by GB virus C infection through increases in RANTES,MIP-1alpha,MIP-1beta,and SDF-1.[J].Lancet,2004,363(9426):2040-2046.
[14]MONIKA R,KATHARINA B,ANDREAS G,et al.Host genetic variants in the pathogenesis of hepatitis C[J].Viruses,2012,4(12):3281-3302.
[15]GILLIAM B L,RIEDEL D J,REDFIELD R R,et al.Clinical use of CCR5 inhibitors in HIV and beyond[J].Journal of Translational Medicine,2011,9(Suppl 1):S9.
[16]HERSBERGER M,MARTI J J E,SPECK R F.Rapid detection of the CCR2-V64I,CCR5-A59029G and SDF1-G801A polymorphisms by tetra-primer PCR[J].Clinical Biochemistry,2002,35(5):399-403.
[17]SHI Y Y,HE L.SHEsis,a powerful software platform for analyses of linkage disequilibrium,haplotype construction,and genetic association at polymorphism loci[J].Cell Research,2005,15(2):97-98.
[18]SOLX,GUINE,VALLS J,et al.SNPStats:a web tool for the analysis of association studies[J].Bioinformatics,2006,22(15):1928-1929.
[19]VILELA M C,LIMA G K,RODRIGUES D H,et al.Absence of CCR5 increases neutrophil recruitment in severe herpetic encephalitis[J].Bmc Neuroscience,2013,14(1):19.
[20]JAVAD S,NIMA S,MOHAMMAD K A,et al.CCR5plays important roles in hepatitis B infection[J].Viral Immunology,2014,27(1):2-6.
[21]HOLTE S,LEE J,KAUPP N,et al.Analysis of genetic polymorphisms in CCR5,CCR2,stromal cell-derived factor-1,RANTES,and dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin in seronegative individuals repeatedly exposed to HIV-1[J].Journal of Infectious Diseases,2004,190(6):1055-1058.
[22]CHANG H Y,AHN S H,KIM D Y,et al.Association between CCR5 promoter polymorphisms and hepatitis Bvirus infection[J].Korean Journal of Hepatology,2005,11(2):116-124.
[23]MCDERMOTT D H,ZIMMERMAN P A,GUIGNARDF,et al.CCR5 promoter polymorphism and HIV-1 disease progression[J].Lancet,1998,352(9131):866-870.
[24]SHIEH B,LIAU Y E,HSIEH P S,et al.Influence of nucleotide polymorphisms in the CCR2 gene and the CCR5 promoter on the expression of cell surface CCR5and CXCR4[J].International Immunology,2000,12(9):1311-1318.
[25]KONISHI I,HORIIKE N,HIASA Y,et al.CCR5 promoter polymorphism influences the interferon response of patients with chronic hepatitis C in Japan[J].Intervirology,2004,47(2):114-120.
[26]KALLEL A,SEDIRI Y,MOURALI M S,et al.296 CCchemokine receptors(CCR5 and CCR2)polymorphisms in Tunisian patients with myocardial infarction[J].Archives of Cardiovascular Diseases Supplements,2012,4(1):94.
[27]MUMMIDI S,AHUJA S S,MCDANIEL B L,et al.The human CC chemokine receptor 5(CCR5)gene.Multiple transcripts with 5'-end heterogeneity,dual promoter usage,and evidence for polymorphisms within the regulatory regions and noncoding exons[J].Journal of Biological Chemistry,1997,272(49):30662-30671.
[28]CATANO G,CHYKARENKO Z A,MANGANO A,et al.Concordance of CCR5 genotypes that influence cellmediated immunity and HIV-1 disease progression rates[J].Journal of Infectious Diseases,2011,203(2):263-272.
[29]PARCZEWSKI M,URBA?SKA A,MACIEJEWSKA K,et al.Association of chemokine receptor gene variants with HIV-1 genotype predicted tropism[J].Hiv Medicine,2015,15(10):577-586.
[30]CARRINGTON M,DEAN M,MARTIN M P,et al.Genetics of HIV-1 infection:chemokine receptor CCR5 polymorphism and its consequences[J].Human Molecular Genetics,1999,8(10):1939-1945.
[31]JIAPENG L,AIJUAN S,YOUXIN W,et al.The genetic associations and epistatic effects of the CCR5 promoter and CCR2-V64I polymorphisms on susceptibility to HIV-1infection in a Northern Han Chinese population[J].Genetic Testing&Molecular Biomarkers,2012,16(12):1369.
[32]MARTIN M P,DEAN M,SMITH M W,et al.Genetic Acceleration of AIDS Progression by a Promoter Variant of CCR5[J].Science,1998,282(5395):1907-1911.
[33]JOSHI A,PUNKE E B,SEDANO M,et al.CCR5 promoter activity correlates with HIV disease progression by regulating CCR5 cell surface expression and CD4 T cell apoptosis[J].Scientific Reports,2017,7(1):232.
[34]COENEN M,NATTERMANN J,FELDMANN G,et al.The role of CCR5 in HCV infection[J].European Journal of Medical Research,2010,15(3):97-101.
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