WT1基因多态性与多发性骨髓瘤易感的相关性
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摘要
目的:分析168例患者的WT1基因多态性与多发性骨髓瘤(multiple myeloma,MM)易感的相关性。方法:以河北省中医院及河北省人民医院2013年1月至2017年12月住院的168名MM患者为研究对象,中位年龄62.4岁(36岁～83岁),其中男性121例(72%)、女性47例(28%),采用SSP-PCR和SBT-PCR对样本WT1基因的多态性进行检测分析。结果:MM患者中有11种WT1等位基因被检测出,WT1*010、WT1*012两等位基因在MM组中占有较高频率(WT1*010:OR=6.13,95%CI:3.5～10.75,PC<0.000;WT1*012:OR=2.06,95%CI:1.23～1.44,PC<0.051)。WT1*A5的STR基因频率检测量到明显增多(OR=1.62,95%CI:1.18～2.23,PC<0.05)。基因型频率检测到WT1*010/010的频率明显增多(OR=6.28,95%CI:1.81～21.76,PC<0.05)。结论:WT1等位基因在MM患者中具有高度多态性,WT1*010/010纯合子是MM的易感基因型,这表明MM的发生发展与WT1基因的多态性相关。
Objective: To analyze the correlation between WT1 gene polymorphism and multiple myeloma(MM) susceptibility in 168 patients. Methods: One hundred and sixty eight MM patients, who were hospitalized in our hospital and Hebei Provincial People's Hospital from January 2013 to December 2017, were researched in this study. There were 121 males(72%) and 47 females(28%) with a median age of 62.4 years old(36～83 years old). Polymorphism of WT1 gene of the samples was detected and analyzed by SSP-PCR and SBT-PCR. Results: Eleven WT1 alleles were detected in MM patients, WT1*010 and WT1*012 alleles occupied a higher frequency in MM group(WT1*010: OR=6.13, 95%CI:3.5～10.75, PC<0.000; WT1*012: OR=2.06, 95%CI:1.23～1.44, PC<0.051). STR genotype frequency of WT1*A5 markedly increased(OR=1.62, 95%CI:1.18～2.23, PC<0.05). Genotype frequency of WT1*010/010 also obviously increased(OR=6.28, 95%CI:1.81～21.76, PC<0.05). Conclusion: WT1 allele is highly polymorphic in MM patients and homozygote WT1*010/010 is a susceptible genotype of MM, indicating that the occurrence and development of MM are related to the polymorphism of WT1 gene.
Objective: To analyze the correlation between WT1 gene polymorphism and multiple myeloma(MM) susceptibility in 168 patients. Methods: One hundred and sixty eight MM patients, who were hospitalized in our hospital and Hebei Provincial People's Hospital from January 2013 to December 2017, were researched in this study. There were 121 males(72%) and 47 females(28%) with a median age of 62.4 years old(36～83 years old). Polymorphism of WT1 gene of the samples was detected and analyzed by SSP-PCR and SBT-PCR. Results: Eleven WT1 alleles were detected in MM patients, WT1*010 and WT1*012 alleles occupied a higher frequency in MM group(WT1*010: OR=6.13, 95%CI:3.5～10.75, PC<0.000; WT1*012: OR=2.06, 95%CI:1.23～1.44, PC<0.051). STR genotype frequency of WT1*A5 markedly increased(OR=1.62, 95%CI:1.18～2.23, PC<0.05). Genotype frequency of WT1*010/010 also obviously increased(OR=6.28, 95%CI:1.81～21.76, PC<0.05). Conclusion: WT1 allele is highly polymorphic in MM patients and homozygote WT1*010/010 is a susceptible genotype of MM, indicating that the occurrence and development of MM are related to the polymorphism of WT1 gene.
引文
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[19]GAMBELUNGHE G,GERLI R,BOCCI E B,et al.Contribution of MHC class I chain-related A(WT1)gene polymorphism to genetic susceptibility forsystemic lupus erythematosus[J].Rheumatology(Oxford),2005,44(3):287-292.DOI:10.1093/rheumatology/keh459.
[20]邢永华,杨生,吕同德,等.青海汉族、回族、藏族WT1-TM基因多态性与胃癌相关性[J].青海医学院学报,2011,32(1):1-4.
[21]ZHAO J,JIANG Y,LEI Y,et al.Functional WT1-129polymorphism and serum levels of soluble WT1 arecorrelated with ulcerative colitis in Chinese patients[J].Gastroenterol Hepatol,2011,26(3):593-598.DOI:10.1111/j.1440-1746.2010.06524.x.
[22]LONG J,FANG S,DAI Q,et al.The wilms tumor-1(WT1)rs16754polymorphism is a prognostic factor in acute myeloid leukemia(AML):ameta-analysis[J].Oncotarget,2016,7(22):32079-32087.DOI:10.18632/oncotarget.8117.
[23]JUNGHANNS A S,WOEHLECKE C W,LEHMANN T,et al.Wilms tumor gene single nucleotide polymorphism rs16754 predicts a favorable outcomein children with acute lymphoblastic leukemia[J].Cancer Res Clin Oncol,2015,141(12):2221-2228.DOI:10.1007/s00432-015-2018-y.
[2]ZOU Y,HAN M,WANG Z,et al.WT1 allele-level typingby sequencebased typing with computerizedassignment of polymorphic sites and short tandemrepeats within the transmembrane region[J].Hum Immunol,2006,67(3):145-151.DOI:10.1016/j.humimm.2006.02.016.
[3]HABER D A,BUCKLER A J,CLASER T,et al.An intemal deletion within an 11p13 zinc finger gene contrihutes to the development of Wilms'tumor[J].Cell,1990,61(7):1257-1269.DOI:10.1016/0092-8674(90)90690-g.
[4]RAMPAL R,FIGUEROA M E.Wilms tumor 1 mutations in the pathogen-esis of acute myeloid leukemia[J].Haematologica,2016,101(6):672-679.DOI:10.3324/haematol.2015.141796.
[5]TOSKA E,ROBERTS S G.Mechanisms of transcriptional regulation by WT1(Wilms'tumour 1)[J].Biochem J,2014,461(1):15-32.DOI:10.1042/bj20131587.
[6]LUO S,YU K,YAN Q X,et al.Analysis of WT1 mutations,expression levels and single nucleotide polymorphism rs16754 in de novo non-M3 acute myeloid leukemia[J].Lymphoma,2014,55(2):349-357.DOI:10.3109/10428194.2013.791985.
[7]LAUHAKIRTI N,SRITANA C,BOONTHIMAT O,PROMSUWI-CHA C U,et al.WT1 mutations and polymorphisms in Southeast Asian acute myeloid leukemia[J].Exp Mol Pathol,2011,91(3):682-686.DOI:10.1016/j.yexmp.2011.06.009.
[8]QI X W,ZHENG X D,ZONG B G,et al.Association between WT1polymorphisms and susceptibility to breast cancer:resultsfromacasecontrol studyina Southwestern Chinese population[J].Cancer,2015,5(3):1234-1250.DOI:10.1097/01.md.0000481302.82879.cc.
[9]SHIINA T,TAMIYA G,OKA A,et al.Molecular dynamicsof MHCgenesis unraveled by sequence analysis of the1,796,938-bp HLAclass I region[J].Proc Natl AcadSci U S A,1999,96(23):13282-13287.DOI:10.1073/pnas.96.23.13282.
[10]CHEN E,LIN L,CHEN C J,et al.MIC gene polymorphismand haplotype diversity in Zhuang nationality of Southern China[J].Hum Immunol,2014,75(9):953-959.DOI:10.1016/j.humimm.2014.08.203.
[11]LI Z,ZHANG Z,HE Z,et al.A partition-ligationcombination-subdivision EM algorithm for haplotypeinference with multiallelic markers:update of theSHEsis[J].Cell Res,2009,19(4):519-523.DOI:10.1038/cr.2009.33.
[12]LOPEZ-CIMA M F,GONZALEZ-ARRIAGA P,GARCIA-CAS-TROL,et al.Polymorphisms in XPC,XPD,XRCC1,and XRCC3DNA repair genes and multiple myeloma risk in a population of northern Spain[J].BMC Cancer,2007,16(7):162.DOI:10.1186/1471-2407-7-162.
[13]黄萌,陈星,邱月锋,等.XRCC3基因多态性与MM的关联[J].卫生研究,2011,6(2):187-190.
[14]王渊渊,王伟,杨颉,等.GSTT1和GSTM1基因多态性和PAH-DNA加合物与多发性骨髓瘤发病的关系研究[J].中国实验血液学杂志,2015,23(3):728-732.DOI:10.7534/j.issn.1009-2137.2015.03.025.
[15]WANG Z Y,QIU Q Q,DEUEL T F.The Wilms’tumor geneproduct WT1 activates or supresses transcription throughseparate functional domains[J].J Biol Chem,1993,268(13):9172-9175.
[16]PHELAN S A,LINDBERG C,CALL K M,et al.Wilms’tumor gene WT1 m RNA is down regulated during induction of erythroid and megakaryocytic differentiation of K562 cells[J].Cell Growth Differ,1994,5(6):677-686.
[17]SEKIYA M,ADACHI M,HINODA Y,et al.Downregula-tion of Wilms’tumor gene(WT1)during myelomoonocytic differentiation in HL-60 cells[J].Blood,1994,83(7):1876-1882.
[18]MELDI K M,FIGUEROA M E.Cytosine modifications in myeloid malignancies[J].Pharmacol Ther,2015,152(1):42-53.DOI:10.1016/j.pharmthera.2015.05.002.
[19]GAMBELUNGHE G,GERLI R,BOCCI E B,et al.Contribution of MHC class I chain-related A(WT1)gene polymorphism to genetic susceptibility forsystemic lupus erythematosus[J].Rheumatology(Oxford),2005,44(3):287-292.DOI:10.1093/rheumatology/keh459.
[20]邢永华,杨生,吕同德,等.青海汉族、回族、藏族WT1-TM基因多态性与胃癌相关性[J].青海医学院学报,2011,32(1):1-4.
[21]ZHAO J,JIANG Y,LEI Y,et al.Functional WT1-129polymorphism and serum levels of soluble WT1 arecorrelated with ulcerative colitis in Chinese patients[J].Gastroenterol Hepatol,2011,26(3):593-598.DOI:10.1111/j.1440-1746.2010.06524.x.
[22]LONG J,FANG S,DAI Q,et al.The wilms tumor-1(WT1)rs16754polymorphism is a prognostic factor in acute myeloid leukemia(AML):ameta-analysis[J].Oncotarget,2016,7(22):32079-32087.DOI:10.18632/oncotarget.8117.
[23]JUNGHANNS A S,WOEHLECKE C W,LEHMANN T,et al.Wilms tumor gene single nucleotide polymorphism rs16754 predicts a favorable outcomein children with acute lymphoblastic leukemia[J].Cancer Res Clin Oncol,2015,141(12):2221-2228.DOI:10.1007/s00432-015-2018-y.