中国输血协会人类组织抗原专业委员会kir hla研究与临床应用国际研讨会hlakir深圳

1、HLA/KIR基因变异对性肝炎及的影响医学科学院医学生物学研究所2017.06.06主要内容n HLA/KIR基因系统n HLA/KIR基因系统在HCV慢染中的作用分析n HLA/KIR基因系统与非小细胞肺癌的相关性研究n 小结性疾病的是和宿主相互作用的结果病原体在病原体方面，必须具备宿毒力的差异耐药基因 基因变异 基因型等等主免疫反应的能快速遗传的适应能力来逃避宿主强大的免疫监视，找到适合生存的空间。宿主从宿主方面来看，经过数百万年的进化形成了适合于自身免疫防御的完整的免疫基因组结构，在病原体侵袭时通过天然免疫和获得性免疫应答来有效清除病原体 。基础疾病个体遗传背景相互适应相互斗争同HCV相

2、关的宿主遗传因素Ø 人类白细胞抗原（human leucocyte HLA）gen,细胞免疫球蛋白样受体（killer cellØimmunoglobulin-like receptors, KIR）Ø TOLL样受体(Toll like receptor):TLR7Ø 细胞因子和趋化因子:IL-10, IL-12, TGF, CCR5Ø 干扰素:IL-28BØ 干扰素诱导基因:ISGs人类白细胞抗原（human leucocytegen, HLA）系统，是重要的免疫遗传体系，是目前已知多态性最丰富的基因系统，在机体免疫应答和器官移植

3、中发挥着重要的作用，其高度的多态性赋予机体巨大潜力以适应多变的内外环境。细胞免疫球蛋白样受体(Killer cell immunoglobulin-like receptors, KIR)基因位于Ø19q13.4，长约100200kb。因组成和等位基因2种多态性。ØCited from: Seminars in Immunology 20 (2008) 343352HLA/KIR基因系统Autoimmune diseaseGenetic BackgroundImmune response to vaccineInfectious diseaseCancer群体背景性疾病 /

4、Population StudyInfectious Disease Association StudyVaccineEvaluation and DesignHLA/KIR associated with HCV infectionAlleles/HaplotypesSusceptibleProtectivePopulationPersistanceClearanceDRB3+BraziliansDQB1*02+DRB1*01+DQB1*03+DRB1*07+Brazilian CaucasianC*05+Midwestern AmericanA*03+DRB1*01+DQB1*05+DRB

5、1*01-DQB1*05+DQB1*02+DRB1*07-DQB1*02+B*07+JapaB*46+DRB1*01+B*52+DQB1*0501+AmericanDQB1*02:01+DRB1*03:01+DRB1*11+BrazilianDQB1*03+DRB1*01:01+U.S. womenB*57:01+B*57:03+C*01:02+DRB1*03:01+DRB1*15+EgyptianB27+German CaucasianDRB1*04:03+Northern European CaucasianDQA1*03+DQB1*03:02+DPB1*0402+Alleles/Hapl

6、otypesSusceptibleProtectivePopulationpersistenceClearanceDelay HCVKIR2DL2/2DL3+Puerto Rican(European, African, American Indian)KIR2DL2/2DL3+2DS4+KIR2DS4+HLA-C1C1+KIR2DS4+2DL2/2DL3+HLA-C1C1+HLA-C1C1+UK Caucasion USA Caucasian, USA African-AmericanHLA-C2C2+KIR2DL3+HLA-C1C1+HLA-C1C1-Switzerland Caucasi

7、anHLA-C2C2-KIR2DL3+HLA-C1C1-HLA-Bw4(I80)+CaucasianKIR3DS1+HLA-Bw4(I80)+KIR2DL3+HLA-C1C1CaucasianHLA-DQB1*0501+AmericanKIR2DL3/2DL3+HLA-C1C1+KIR2DL3+HLA-DRB1*12:01+KIR2DL2+Spain CaucasiansKIR2DL3+KIR2DL2/KIR2DL2+HLA-C1C2+KIR2DL3/KIR2DL3+HLA-C1C1+HLA-C1C2+ThaiKIR2DL2/2DL3+KIR2DL2/2DL3+HLA-C1C1+KIR2DL3

8、+HLA-C1+london CaucasianKIR3DS1+HLA-Bw4(I80)+SpanishKIR2DS2/2DL2+Caucasian与HCV相关的HLA基因的全球分布群体背景研究开展了民族群体HLA、KIR以及HLA相关基因相关基因的研究。构建了不同民族群体HLA、KIR及其相关基因数据库。0.70001.00000.800Bulang WaDai Maonan Zhuang Hani Jinuo Lishu NuTu Yugu Han_YNBulang WaDai Maonan Zhuang Hani Jinuo Lisu NuTu YuguHan_YunnanBulang

9、WaDai Maonan Zhuang Hani Jinuo Lisu NuTu Yugu Han YN0.90000.80000.70000.60000.50000.40000.30000.20000.10000.00000.7000.60000.6000.50000.5000.40000.4000.30000.3000.20000.2000.1000.10000.0000.000012482DS12DS22DS32DS42DS53DS1A*02:01A*02:03A*02:07A*11:01A*24:02KIR GenotypeActivating KIR genesCommon HLA-

10、A Alleles0 9000 8000 7000 6000 5000 4000 3000 2000 1000 000Haplotype A Haplotype BPopulationsAllele FrequenciesFrequenciesFrequenciesFrequenciesPart 1HCV特点Ø 由丙型肝炎Ø 全球2亿HCV（Hepatitis C, HCV）所致。者，每年新发病例3.5万。HCV阳性患者约有3千万，直接医疗费用约为117.26215.59亿元/年。ØHCV后，Ø 约2030%的急Ø 70发展为慢性持续染者可自发

11、清除HCV；染，其中：1520最终进展为肝硬化， 14进展为肝细胞癌；Ø 慢染进程也不一，临床表现不一。HCV HCV属单股正链RNA, 属于黄科 Simmonds 命名：根据C区、E1区和NS5区的核苷酸序列将HCV分为6型11亚型,表示为1a,1b,2a等。云南的特殊地理位置-HCV技术路线样本收集慢性HCV组健康对照组PCR-SSP KIR基因分型NGSHLA基因分型HLA, KIR, KIR-HLA与HCV关联分析Pypop，PyHLA, SPSS, GraphPad Prism 4.0直接计数法, SPSS GraphPad Prism 4.0HLA等位基因与HCV慢染的相

12、关性0.1600.3000.1400.2500.120*0.1000.2000.0800.1500.0600.0400.1000.0200.0500.0000.000*0.2500.2500.2000.2000.1500.150*0.1000.100*0.0500.0500.0000.000C*01C*02 C*03C*04 C*05 C*06 C*07 C*08 C*12 C*14 C*15CaseControlCaseControlHLA residue与HCV慢染的相关性P5.0E-024.5E-024.0E-023.5E-023.0E-022.5E-022.0E-021.5E-021.

13、0E-025.0E-030.0E+00OR121086420IDHom_PHet_PZyg_PHom_ORHet_ORZyg_ORA_94_H0.4510.0510.0150.8631.7020.507A_121_M1.0000.0780.1980.9671.4060.688A_176_V0.2270.1400.0180.7701.4150.545B_118_T0.4730.0790.0321.1460.4832.374B_176_E0.8160.0600.0661.0740.6811.578B_237_F1.0000.0371.0000.0770.0950.811C_25_G0.8770.0

14、130.2221.0991.6020.686C_45_H0.6260.0270.5191.1981.5210.787C_97_A0.2300.0210.5400.7490.6391.172C_118_I0.4580.0120.7141.3581.6210.838C_119_I0.1600.0210.6471.9911.5791.260C_127_V0.5570.0130.7031.3321.6290.817C_176_T1.0000.0001.0000.5450.3641.498C_187_L0.5570.0130.7031.3321.6290.817C_197_K0.5570.0130.70

15、31.3321.6290.817C_243_R0.4330.0120.0041.2050.5962.023C_299_G1.0000.0450.5151.0220.6321.617HLA单倍型与HCV慢染的相关性0.0800.0700.0600.0500.0400.0300.0200.0100.000CaseControlOR14.00012.00010.0008.0006.0004.0002.0000.000KIR基因与HCV慢染的相关性0.6001.0000.9000.8000.7000.6000.5000.5000.4000.3000.4000.3000.2000.1000.000*0.

16、200*0.100*79 200 2020.00012345689 13 14 15 23 44 64 69 75CaseControlCaseControlHLA-KIR与HCV慢染的相关性CaseControlNone2DL1+HLA-C2None2DL1+HLA-C22DL2/3+HLA-C12DS1+HLA-C22DL2/3+HLA-C12DS1+HLA-C22DL1+HLA-C2,2DL2/3+HLA-C12DL1+HLA-C2,2DL2/3+HLA-C1,2DS1+HLA-C22DL1+HLA-C2,2DS1+HLA-C22DL1+HLA-C2,2DL2/3+HLA-C12DL1+

17、HLA-C2,2DS1+HLA-C22DL1+HLA-C2,2DL2/3+HLA-C1,2DS1+HLA-C2HLA与肝硬化相关性0.3000.2500.2000.1500.1000.0500.0000.1400.1200.1000.0800.0600.0400.0200.000Hepatocirrhosis CaseNon-Hepatocirrhosis CaseHNHA*02:07- A*02:07- A*02:07- A*02:07- A*11:01- A*11:01- A*11:01- A*11:01- A*11:01- A*33:03- A*33:03- A*33:03- B*15:

18、02- B*38:02- B*40:01- B*40:01- B*46:01- B*58:01-肝硬化与KIR基因型的相关性0.50.450.4肝硬化组非肝硬化组0.350.30.250.2 *0.15* *0.1*0.05KIR0Genotype ID123456891011131418233132374458646972757989 200 384 393 427HaplotypeFrequency(%)AABx吸毒人群和普通人群HCV基因特点IDUs(%)GP(%)1a2.001b10.028.32a0.010.03a12.019.23b29.029.26a15.03.36n30.08.

19、36k01.76u1.006v1.00Compare of HCV genotype diversity in general population and IDUs in southeast AsianHCV in general populationHCV inIDUsA route of HCV 6a and 6n subtype in Southeastern AsiaHCV基因型与HLA/KIR0.5000.4500.4000.3500.3000.2500.2000.1500.1000.0500.000HCV-1bHCV-2aHCV-3aHCV-3bHCV-6a0.5000.4500

20、.4000.3500.3000.2500.2000.1500.1000.0500.000HCV-1bHCV-2aHCV-3aHCV-3bHCV-6a0.6000.5000.4000.3000.2000.1000.000HCV-1bHCV-2aHCV-3aHCV-3bHCV-6aPart 2非小细胞肺癌HLA单倍型与NSCLC的相关性0.0900.0800.0700.0600.0500.0400.0300.0200.0100.0000.1600.1400.1200.1000.0800.0600.0400.0200.000NSCLCControlNSCLCControlKIR基因型与NSCLC的相关性1.2000.6001.0000.5000.8000.4000.6000.3000.4000.2000.2000.1000.0000.0003DL1 2DL1 2DL3 2DS4 2DL2 2DL5 3DS12DS12DS22DS32DS5 2DL4 3DL2 3DL32DP13DP11234581315236468NSCLCControlNSCLCControlHLA/KIR与NSCLC的相关性NSCLCControlNone2DL2/3+HLA-C12DL1+HLA-C22DS1+HLA-C2None2DL2/3+HLA-C12DL1+HLA-C2,2DL2/3+H