非缺失型遗传性持续性胎儿血红蛋白综合征对不同基因型β-地中海贫血的影响
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摘要
目的:探讨非缺失型遗传性持续性胎儿血红蛋白综合征(nd-HPFH)对β-地中海贫血杂合子血液学表型的影响。方法:选取2017年10月至2018年6月在广西医科大学第一附属医院行地中海贫血筛查及基因诊断的患者。对患者行血常规检测及血红蛋白(Hb)分析。应用荧光定量PCR法对β-地中海贫血基因型进行检测,应用DNA测序法对γ-珠蛋白基因启动子序列进行分析。结果:nd-HPFH复合β-地中海贫血杂合子组红细胞平均容积(MCV)、红细胞平均血红蛋白(MCH)、胎儿Hb(HbF)、HbA_2较单纯β-地中海贫血杂合子组升高(P<0.05)。nd-HPFH复合β~+-地中海贫血杂合子组MCV、MCH、HbF和HbA_2较单纯β~+-地中海贫血杂合子组升高;nd-HPFH复合β~0-地中海贫血杂合子组MCV、MCH、HbF较单纯β~0-地中海贫血杂合子组升高;nd-HPFH复合β~+-地中海贫血杂合子组Hb、MCV、MCH、HbA_2较nd-HPFH复合β~0-地中海贫血杂合子组升高,差异均有统计学意义(均P<0.05)。结论:nd-HPFH复合β-地中海贫血杂合子的血液学特征与单纯β-地中海贫血杂合子存在明显差异,nd-HPFH对不同基因突变类型的β-地中海贫血均有显著影响。
Objective:To investigate the effects of non-deletion hereditary persistent of fetal hemoglobin(nd-HPFH) on the hematologic features of β-thalassemia heterozygotes.Methods:Cases for thalassemia screening and diagnosis were requested from October 2017 to June 2018 in our hospital.The hematologic data and hemoglobin level were obtained by routine blood test and hemoglobin(Hb) analysis.The β-thalassemia genotypes were detected by qPCR.The γ-globin gene promoter sequences was analyzed by DNA sequencing.Results:The mean red blood cell hemoglobin(MCH),mean red blood cell volume(MCV),fetal hemoglobin(Hb F) and HbA_2 in nd-HPFH compound β-thalassemia patients were higher than those of simple β-thalassemia heterozygous group including β~0-thalassemia heterozygotes and β~+-thalassemia heterozygotes(P<0.05).nd-HPFH compound β~0-thalassemia heterozygotes had higher MCV,MCH and HbF than simple β~0-thalassemia heterozygotes,and nd-HPFH compound β~+-thalassemia heterozygotes had higher Hb,MCV,MCH and HbA_2 than simple β~+-thalassemia heterozygotes(P<0.05).nd-HPFH compound β~+-thalassemia heterozygotes had higher Hb,MCV,MCH and HbA_2 than nd-HPFH compound β~0-thalassemia heterozygotes(P<0.05).Conclusion:The hematological characteristics of nd-HPFH compound β-thalassemia heterozygotes were significantly different from those of simple β-thalassemia heterozygotes.nd-HPFH had significant effects on different genotypes of β-thalassemia.
Objective:To investigate the effects of non-deletion hereditary persistent of fetal hemoglobin(nd-HPFH) on the hematologic features of β-thalassemia heterozygotes.Methods:Cases for thalassemia screening and diagnosis were requested from October 2017 to June 2018 in our hospital.The hematologic data and hemoglobin level were obtained by routine blood test and hemoglobin(Hb) analysis.The β-thalassemia genotypes were detected by qPCR.The γ-globin gene promoter sequences was analyzed by DNA sequencing.Results:The mean red blood cell hemoglobin(MCH),mean red blood cell volume(MCV),fetal hemoglobin(Hb F) and HbA_2 in nd-HPFH compound β-thalassemia patients were higher than those of simple β-thalassemia heterozygous group including β~0-thalassemia heterozygotes and β~+-thalassemia heterozygotes(P<0.05).nd-HPFH compound β~0-thalassemia heterozygotes had higher MCV,MCH and HbF than simple β~0-thalassemia heterozygotes,and nd-HPFH compound β~+-thalassemia heterozygotes had higher Hb,MCV,MCH and HbA_2 than simple β~+-thalassemia heterozygotes(P<0.05).nd-HPFH compound β~+-thalassemia heterozygotes had higher Hb,MCV,MCH and HbA_2 than nd-HPFH compound β~0-thalassemia heterozygotes(P<0.05).Conclusion:The hematological characteristics of nd-HPFH compound β-thalassemia heterozygotes were significantly different from those of simple β-thalassemia heterozygotes.nd-HPFH had significant effects on different genotypes of β-thalassemia.
引文
[1] 朱恒莹,陈萍.非缺失型遗传性持续性胎儿血红蛋白综合征复合β地中海贫血的研究进展[J].实用医学杂志,2016,32(19):3268-3270.
[2] 雷蓓蓓,陈萍,肖璇,等.非缺失型遗传性持续性胎儿血红蛋白综合征的研究[J].广西医科大学学报,2013,30(1):61-64.
[3] SRIPICHAI O,FUCHAROEN S.Fetal hemoglobin reg-ulation in beta-thalassemia: heterogeneity,modifiers and therapeutic approaches[J].Expert Review of Hematology,2016,9(12):1129-1137.
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[7] 蒋南华,梁徐,金琪,等.广西地区β-地中海贫血的基因型与临床型的关系[J].中国小儿血液,1996(2):49-53.
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[9] 曾小红,朱宝生.遗传性持续性胎儿血红蛋白增高症(HPFH)的分子机制[J].中国产前诊断杂志,2012,4(2):26-31.
[10] AMATO A,CAPPABIANCA M P,PERRI M,et al.Interpreting elevated fetal hemoglobin in pathology and health at the basic laboratory level: new and known γ- gene mutations associated with hereditary persistence of fetal hemoglobin[J].International Journal of Laboratory Hematology,2014,36(1):13-19.
[11] MUSALLAM K M,TAHER A T,CAPPELLINI M D,et al.Clinical experience with fetal hemoglobin induction therapy in patients with beta-thalassemia[J].Blood,2013,121(12):2199-2212.
[12] EL-BESHLAWY A,HAMDY M,EL GHAMRAWY M.Fetal globin induction in beta-thalassemia[J].Hemoglobin,2009,33(Suppl 1):S197-S203.
[13] 朱恒莹,陈萍,林伟雄,等.Aγ-225～-222缺失复合β地中海贫血的研究[J].广西医科大学学报,2015,32(2):196-200.
[14] 黄欣,陈萍,林伟雄,等.珠蛋白基因～Gγ-158C>T纯合子突变导致nd-HPFH的研究[J].广西医科大学学报,2017,34(5):698-702.
[15] KOLLIA P, KALAMARAS A, CHASSANIDIS C, et al.Compound heterozygosity for the Cretan type of non-deletional hereditary persistence of fetal hemoglobin and beta-thalassemia or Hb Sabine confirms the functional role of the Agamma -158 C>T mutation in gamma-globin gene transcription[J].Blood Cells Molecules & Diseases,2008,41(3):263-264.
[16] DEDOUSSIS G V,SINOPOULOU K,GYPARAKI M,et al.Fetal hemoglobin expression in the compound heterozygous state for -117(G-->A) Agamma HPFH and IVSII-745(C-->G) beta+ thalassemia: a case study[J].American Journal of Hematology,1999,61(2):139-43.
[17] GARNER C,DEW T K,SHERWOOD R,ET A L.Heterocellular hereditary persistence of fetal haemoglobin affects the haematological parameters of beta-thalassaemia trait[J].British Journal of Haematology,2015,123(2):353-358.
[18] BAUER D E,ORIKIN S H.Update on fetal hemoglobin gene regulation in hemoglobinopathies[J].Current Opinion in Pediatrics,2011,23(1):1-8.
[19] GALANELLO R,CAO A.Beta-thalassemia[J].Genetics in Medicine Official Journal of the American College of Medical Genetics,2010,12(2):61-76.
[2] 雷蓓蓓,陈萍,肖璇,等.非缺失型遗传性持续性胎儿血红蛋白综合征的研究[J].广西医科大学学报,2013,30(1):61-64.
[3] SRIPICHAI O,FUCHAROEN S.Fetal hemoglobin reg-ulation in beta-thalassemia: heterogeneity,modifiers and therapeutic approaches[J].Expert Review of Hematology,2016,9(12):1129-1137.
[4] THEIN S L.The molecular basis of beta-thalassemia[J].Cold Spring Harbor Perspectives in Medicine,2013,3(5):a011700.
[5] 张莉,徐酉华.地中海贫血的临床表现与鉴别[J].国际检验医学杂志,2013,34(21):2875,933.
[6] TATHER A T,WEATHERALL D J,CAPPELLINI M D.Thalassaemia[J].Lancet,2017,391(10116):S0140673617318226.
[7] 蒋南华,梁徐,金琪,等.广西地区β-地中海贫血的基因型与临床型的关系[J].中国小儿血液,1996(2):49-53.
[8] PEREIRA C,RELVASL,BENTO C,et al.Polymorphic variations influencing fetal hemoglobin levels: association study in beta-thalassemia carriers and in normal individuals of Portuguese origin[J].Blood Cells Mol Dis,2015,54(4):315-320.
[9] 曾小红,朱宝生.遗传性持续性胎儿血红蛋白增高症(HPFH)的分子机制[J].中国产前诊断杂志,2012,4(2):26-31.
[10] AMATO A,CAPPABIANCA M P,PERRI M,et al.Interpreting elevated fetal hemoglobin in pathology and health at the basic laboratory level: new and known γ- gene mutations associated with hereditary persistence of fetal hemoglobin[J].International Journal of Laboratory Hematology,2014,36(1):13-19.
[11] MUSALLAM K M,TAHER A T,CAPPELLINI M D,et al.Clinical experience with fetal hemoglobin induction therapy in patients with beta-thalassemia[J].Blood,2013,121(12):2199-2212.
[12] EL-BESHLAWY A,HAMDY M,EL GHAMRAWY M.Fetal globin induction in beta-thalassemia[J].Hemoglobin,2009,33(Suppl 1):S197-S203.
[13] 朱恒莹,陈萍,林伟雄,等.Aγ-225～-222缺失复合β地中海贫血的研究[J].广西医科大学学报,2015,32(2):196-200.
[14] 黄欣,陈萍,林伟雄,等.珠蛋白基因～Gγ-158C>T纯合子突变导致nd-HPFH的研究[J].广西医科大学学报,2017,34(5):698-702.
[15] KOLLIA P, KALAMARAS A, CHASSANIDIS C, et al.Compound heterozygosity for the Cretan type of non-deletional hereditary persistence of fetal hemoglobin and beta-thalassemia or Hb Sabine confirms the functional role of the Agamma -158 C>T mutation in gamma-globin gene transcription[J].Blood Cells Molecules & Diseases,2008,41(3):263-264.
[16] DEDOUSSIS G V,SINOPOULOU K,GYPARAKI M,et al.Fetal hemoglobin expression in the compound heterozygous state for -117(G-->A) Agamma HPFH and IVSII-745(C-->G) beta+ thalassemia: a case study[J].American Journal of Hematology,1999,61(2):139-43.
[17] GARNER C,DEW T K,SHERWOOD R,ET A L.Heterocellular hereditary persistence of fetal haemoglobin affects the haematological parameters of beta-thalassaemia trait[J].British Journal of Haematology,2015,123(2):353-358.
[18] BAUER D E,ORIKIN S H.Update on fetal hemoglobin gene regulation in hemoglobinopathies[J].Current Opinion in Pediatrics,2011,23(1):1-8.
[19] GALANELLO R,CAO A.Beta-thalassemia[J].Genetics in Medicine Official Journal of the American College of Medical Genetics,2010,12(2):61-76.