中国汉族CHC患者病程及对规范化治疗反应性与KIR2DL2基因相关性的群体分析
摘要
目的
1、通过观察中国汉族人群中CHC患者和健康人之间KIR基因、HLA-C基因的频率变化,深入探讨中国汉族人群中KIR基因、HLA-C基因与CHC病程的相关性;
2、通过观察中国汉族人群中CHC患者经规范化治疗后不同反应者的KIR基因HLA-C基因的频率变化,寻找对CHC治疗反应有影响力的基因；
3、经荟萃分析(Meta-analysis)对pubmed上多个CHC治疗效果研究资料进行分析和概括,并结合本次研究结果对KIR2DL2对CHC治疗反应的影响；
4、通过调节KIR2DL2基因的表达,观察其对NK细胞功能影响的特点,分析KIR2DL2影响CHC治疗反应的可能机制,为CHC治疗以及预后判断提供可能途径和新的治疗靶点。
方法
1.入选中国汉族人群中CHC病例通过生化指标检测ALT, ELISA检测HCV抗体,Realtime-PCR定量检测HCV RNA。ELISA检测排除入选病例HAV、HBV、HDV、 HEV、HIV、病毒感染。
2.通过饱和盐析的方法从研究对象的抗凝血中提取DNA,采用序列特异性引物扩增技术(PCR—Sequence Specific Primer, PCR-SSP)对样本进行KIR和HLA-C分型,读取结果后计算基因频率,并统计分析比较中国汉族人群CHC患者和健康对照者之间的差异。
3.中国汉族人群中CHC患者接受规范化治疗,即聚乙二醇干扰素-α(1.5微克/公斤体重/周)和利巴韦林(0.9g/天)。所有患者进行至少6个月治疗后按照与以前报道的病毒学标准分为两个治疗结果：持续病毒学应答(sustained virological responders,SVR)和无应答(nonresponders, NR),提取研究对象DNA,采用PCR-SSP对样本进行KIR和HLA-C分型,统计分析比较SVR和NR之间的差异。
4.引入配对分析方法,将KIR2DL1与HLA-C2、KIR2DL2与HLA-C1配对,统计配对频率,比较中国汉族人群CHC患者和健康对照者之间、SVR和NR之间的差异。
5.在pubmed数据库(1995.11-2013.4)中,以‘'KIR2DL2"和“HCV”为关键词搜索文献,并按照需要英文书写、与国际标准相同的CHC诊断标准和治疗方法及结果判断、PCR-SSP检测KIR基因并含有KIR2DL2频率数据,患者除HCV感染外无其他疾病等筛选条件,选出合适的文献用于Meta分析,确定文献异质性、发表偏倚,选择固定效应模型计算总体风险系数。
6.使用经5-Aza-dc处理后的NK92细胞,该细胞表面可高表达KIR2DL2分子,观察不同抗体浓度抗体封闭KIR2DL2受体后,NK细胞对K562细胞的杀伤活性。
7. SPSS17.0对数据进行统计分析。
结果
1.基因分型结果表明：KIR2DL2、KIR2DS3计算的OR值均大于1,提示在CHC患者中这两种基因的频率高于健康对照组,这可能是CHC发生的危险因素；同时,HLA-Cw*06, HLA-Cw*15, KIR2DS4计算的OR值小于1,提示在CHC患者中这些基因的频率低于健康对照组,这些基因的存在可能可以抑制CHC的发生。
2.在SVR与NR患者的分型结果中,我们可以看到KIR2DL2和HLA-Cw*03计算的OR值仍然大于1,提示在治疗效果较差的CHC患者(NR)中KIR2DL2基因的频率高于SVR组,携带有该基因的CHC患者的治疗反应要弱。
3. KIR/HLA-C配对分析显示,KIR2DL2+HLA-C group1配对OR值大于1,同时该组合在NR患者中的频率要高于SVR,提示在CHC中这种组合的存在可能有利于CHC的发生以及不利于CHC的治疗；KIR2DL1+HLA-C group2配对OR值小于1,提示这种组合的存在可能对抑制CHC的发生有一定作用。
4. Meta分析结果同样提示KIR2DL2对CHC治疗的负面影响。
5.经5-Aza-dc处理后的NK92细胞,该细胞表面可高表达KIR2DL2分子,在使用抗体浓度20μg/ml封闭KIR2DL2受体后,NK细胞对K562细胞的杀伤活性明显增强。
结论
1.KIR2DL2可以抑制NK细胞活性；
2. KIR2DL2和它的受体HLA-C groupl可能有利于中国汉族人群中CHC的发生以及对PeglFN-a与利巴韦林联合治疗的反应不佳；
3. KIR2DS3在中国汉族人群CHC患者中的频率高于健康对照组,这可能是中国汉族人群中CHC发生的危险因素；
4. HLA-Cw*06, HLA-Cw*15, KIR2DS4CHC患者中的频率低于健康对照组,这些基因的存在可能可以抑制CHC的发生。
本研究的创新点
1.目前,在高加索人群中有关于KIR与CHC相关性的报道,但在中国汉族人群中未见相关报道,本研究主要通过PCR-SSP检测中国汉族人群CHC患者中KIR频率与疾病以及治疗的相关性。
2.通过研究结果及Meta分析,首次提出在中国汉族人群中KIR2DL2为CHC发生以及治疗的负面因子。
本研究的意义
1.通过研究,发现在中国汉族人群中KIR2DL2的存在具有较强的NK细胞抑制能力,使得KIR2DL2的存在可能不利于HCV的清除,导致HCV感染规范化治疗效果差,进而有利于HCV持续性感染发生。
2. K1R2DL2可成为一种HCV治疗效果预判指标,也是中国汉族人群中CHC发生流行病学危险因素,在后期研究中,KIR2DL2可成为免疫治疗CHC的重要靶点。
Objects
1. Observing the changes of KIR gene and KIR ligand gene HLA-C frequency between CHC patients and healthy person in Chinese Han population, we hope to find the relationship between KIR gene, KIR ligand gene HLA-C and HCV persistent infection.
2. Aiming to study the influence on the therapeutic effect of CHC gene in Chinese Han population, the variation of KIR gene and KIR ligand gene HLA-C frequency for different effects of treatment were observed after standard therapy.
3. The meta-analysis of KIR2DL2on CHC treatment effection were analyzed and summarized, combining the research results on the effects of CHC therapeutic response by Pub-Med data.
4. Through regulating the expression of KIR2DL2gene, and observing the characteristics of its effect on NK cell function, the analysis will be draw that how the treatment response of CHC was down-regulated by KIR2DL2. It provided the possible ways and new therapeutic target for CHC treatment and prognosis judgment.
Methods
1. In Chinese Han population, the CHC patients were defined by ALT detected by biochemical test, anti-hepatitis C virus ELISA, and quantified HCV RNA by realtime-PCR. Those patients excluding HAV, HBV, HDV, HEV, HIV virus infection, were detected by ELISA.
2. Extracting DNA from anticoagulant of study subject by saturated salt method, amplifing KIR and HLA-C genotyping of samples with sequence specific primer PCR technology (PCR-SSP), and calculating gene frequency, the results were dealed with by statistical analysis and comparison of differences between CHC patients and healthy controls in Chinese Han population.
3. After CHC patients in Chinese Han population received standard treatment at least6months, that is pegylated interferon-α (1.5g/kg body weight/week) and ribavirin (0.9g/day), All patients were divided into two outcome according to previous reported:sustained virological responders(SVR) and nonresponders(NR). Then we extracted DNA, used PCR-SSP to classific KIR and HLA-C, and analysed the differences between SVR and NR more by statistic method.
4. The joint analysis of KIR-HLA ligands pairs (i.e., KIR2DL1and C2, KIR2DL2and Cl) revealed an association of both combinations with HCV infection and therapeutic response in Chinese Han population.
5. In the PubMed database (1995.11-2013.4), we searched literature with "KIR2DL2" and "HCV" as a keyword, and flited by English writing, the same CHC diagnosis standard and international standard treatment methods, the same results judgment, reported the KIR2DL2genotype frequencies, Hepatitis C patients without other disease. The proper documents for Meta-analysis were determined by heterogeneity, publication bias; calculate the overall risk coefficient selection of the fixed effect model.
6. After treating NK92cells with5-Aza-dc, those cells can express KIR2DL2molecules. Observing the effects of different concentration of antibody blocking KIR2DL2receptor, it was detected that NK cell killing ability of K562cells.
7. Data are analysed by Statistical Package for Social Sciences (SPSS) version17.0.
Results
1. As genotyping results showed, the OR values of KIR2DL2, KIR2DS3are greater than1. It indicated two genes frequency of CHC patients are higher than the healthy control group in Chinese Han population, which may be the risk factors for CHC. Moreover, the OR values of HLA-Cw*06, HLA-Cw*15, are less than1. It suggested these genes in Chinese Han patients with CHC frequency is lower than that of healthy controls, these genes are likely to inhibit CHC.
2. Accroding from the genotyping results of SVR and NR, it was implied that patients who carry KIR2DL2and HLA-Cw*03have poor effect for tratment of CHC in Chinese Han population.
3. As KIR/HLA-C paired analysis described, the OR values of KIR2DL2/HLA-C group1matching was greater than1, while the frequency of the combination in patients with NR is higher than SVR. It suggested this combination could be conducive to the occurrence of CHC and treatment against CHC. However, KIR2DL1/HLA-C group1was on the contrary.
4. The Meta analysis results also suggested negative effects of KIR2DL2on CHC therapy.
5. After treatment of5-Aza-dc NK92cells, the cells can express higer KIR2DL2molecules. Blocking with20μg/ml KIR2DL2receptor antibody, NK cell killing activity of K562cells increased significantly.
Conclusions
1. KIR2DL2can inhibit the activity of NK cells;
2. KIR2DL2and its receptor HLA-C group1might contribute to the occurrence of CHC and poor response of Peg1FN-alpha and ribavirin combination therapy;
3. The frequency of KIR2DS3in CHC patients is higher than the healthy control group; this may be the risk factors of CHC;
4. The frequency of HLA-Cw*06, HLA-Cw*15, KIR2DS4in CHC patients is lower than that of healthy controls; these genes are likely to inhibit CHC.
1、通过观察中国汉族人群中CHC患者和健康人之间KIR基因、HLA-C基因的频率变化,深入探讨中国汉族人群中KIR基因、HLA-C基因与CHC病程的相关性;
2、通过观察中国汉族人群中CHC患者经规范化治疗后不同反应者的KIR基因HLA-C基因的频率变化,寻找对CHC治疗反应有影响力的基因；
3、经荟萃分析(Meta-analysis)对pubmed上多个CHC治疗效果研究资料进行分析和概括,并结合本次研究结果对KIR2DL2对CHC治疗反应的影响；
4、通过调节KIR2DL2基因的表达,观察其对NK细胞功能影响的特点,分析KIR2DL2影响CHC治疗反应的可能机制,为CHC治疗以及预后判断提供可能途径和新的治疗靶点。
方法
1.入选中国汉族人群中CHC病例通过生化指标检测ALT, ELISA检测HCV抗体,Realtime-PCR定量检测HCV RNA。ELISA检测排除入选病例HAV、HBV、HDV、 HEV、HIV、病毒感染。
2.通过饱和盐析的方法从研究对象的抗凝血中提取DNA,采用序列特异性引物扩增技术(PCR—Sequence Specific Primer, PCR-SSP)对样本进行KIR和HLA-C分型,读取结果后计算基因频率,并统计分析比较中国汉族人群CHC患者和健康对照者之间的差异。
3.中国汉族人群中CHC患者接受规范化治疗,即聚乙二醇干扰素-α(1.5微克/公斤体重/周)和利巴韦林(0.9g/天)。所有患者进行至少6个月治疗后按照与以前报道的病毒学标准分为两个治疗结果：持续病毒学应答(sustained virological responders,SVR)和无应答(nonresponders, NR),提取研究对象DNA,采用PCR-SSP对样本进行KIR和HLA-C分型,统计分析比较SVR和NR之间的差异。
4.引入配对分析方法,将KIR2DL1与HLA-C2、KIR2DL2与HLA-C1配对,统计配对频率,比较中国汉族人群CHC患者和健康对照者之间、SVR和NR之间的差异。
5.在pubmed数据库(1995.11-2013.4)中,以‘'KIR2DL2"和“HCV”为关键词搜索文献,并按照需要英文书写、与国际标准相同的CHC诊断标准和治疗方法及结果判断、PCR-SSP检测KIR基因并含有KIR2DL2频率数据,患者除HCV感染外无其他疾病等筛选条件,选出合适的文献用于Meta分析,确定文献异质性、发表偏倚,选择固定效应模型计算总体风险系数。
6.使用经5-Aza-dc处理后的NK92细胞,该细胞表面可高表达KIR2DL2分子,观察不同抗体浓度抗体封闭KIR2DL2受体后,NK细胞对K562细胞的杀伤活性。
7. SPSS17.0对数据进行统计分析。
结果
1.基因分型结果表明：KIR2DL2、KIR2DS3计算的OR值均大于1,提示在CHC患者中这两种基因的频率高于健康对照组,这可能是CHC发生的危险因素；同时,HLA-Cw*06, HLA-Cw*15, KIR2DS4计算的OR值小于1,提示在CHC患者中这些基因的频率低于健康对照组,这些基因的存在可能可以抑制CHC的发生。
2.在SVR与NR患者的分型结果中,我们可以看到KIR2DL2和HLA-Cw*03计算的OR值仍然大于1,提示在治疗效果较差的CHC患者(NR)中KIR2DL2基因的频率高于SVR组,携带有该基因的CHC患者的治疗反应要弱。
3. KIR/HLA-C配对分析显示,KIR2DL2+HLA-C group1配对OR值大于1,同时该组合在NR患者中的频率要高于SVR,提示在CHC中这种组合的存在可能有利于CHC的发生以及不利于CHC的治疗；KIR2DL1+HLA-C group2配对OR值小于1,提示这种组合的存在可能对抑制CHC的发生有一定作用。
4. Meta分析结果同样提示KIR2DL2对CHC治疗的负面影响。
5.经5-Aza-dc处理后的NK92细胞,该细胞表面可高表达KIR2DL2分子,在使用抗体浓度20μg/ml封闭KIR2DL2受体后,NK细胞对K562细胞的杀伤活性明显增强。
结论
1.KIR2DL2可以抑制NK细胞活性；
2. KIR2DL2和它的受体HLA-C groupl可能有利于中国汉族人群中CHC的发生以及对PeglFN-a与利巴韦林联合治疗的反应不佳；
3. KIR2DS3在中国汉族人群CHC患者中的频率高于健康对照组,这可能是中国汉族人群中CHC发生的危险因素；
4. HLA-Cw*06, HLA-Cw*15, KIR2DS4CHC患者中的频率低于健康对照组,这些基因的存在可能可以抑制CHC的发生。
本研究的创新点
1.目前,在高加索人群中有关于KIR与CHC相关性的报道,但在中国汉族人群中未见相关报道,本研究主要通过PCR-SSP检测中国汉族人群CHC患者中KIR频率与疾病以及治疗的相关性。
2.通过研究结果及Meta分析,首次提出在中国汉族人群中KIR2DL2为CHC发生以及治疗的负面因子。
本研究的意义
1.通过研究,发现在中国汉族人群中KIR2DL2的存在具有较强的NK细胞抑制能力,使得KIR2DL2的存在可能不利于HCV的清除,导致HCV感染规范化治疗效果差,进而有利于HCV持续性感染发生。
2. K1R2DL2可成为一种HCV治疗效果预判指标,也是中国汉族人群中CHC发生流行病学危险因素,在后期研究中,KIR2DL2可成为免疫治疗CHC的重要靶点。
Objects
1. Observing the changes of KIR gene and KIR ligand gene HLA-C frequency between CHC patients and healthy person in Chinese Han population, we hope to find the relationship between KIR gene, KIR ligand gene HLA-C and HCV persistent infection.
2. Aiming to study the influence on the therapeutic effect of CHC gene in Chinese Han population, the variation of KIR gene and KIR ligand gene HLA-C frequency for different effects of treatment were observed after standard therapy.
3. The meta-analysis of KIR2DL2on CHC treatment effection were analyzed and summarized, combining the research results on the effects of CHC therapeutic response by Pub-Med data.
4. Through regulating the expression of KIR2DL2gene, and observing the characteristics of its effect on NK cell function, the analysis will be draw that how the treatment response of CHC was down-regulated by KIR2DL2. It provided the possible ways and new therapeutic target for CHC treatment and prognosis judgment.
Methods
1. In Chinese Han population, the CHC patients were defined by ALT detected by biochemical test, anti-hepatitis C virus ELISA, and quantified HCV RNA by realtime-PCR. Those patients excluding HAV, HBV, HDV, HEV, HIV virus infection, were detected by ELISA.
2. Extracting DNA from anticoagulant of study subject by saturated salt method, amplifing KIR and HLA-C genotyping of samples with sequence specific primer PCR technology (PCR-SSP), and calculating gene frequency, the results were dealed with by statistical analysis and comparison of differences between CHC patients and healthy controls in Chinese Han population.
3. After CHC patients in Chinese Han population received standard treatment at least6months, that is pegylated interferon-α (1.5g/kg body weight/week) and ribavirin (0.9g/day), All patients were divided into two outcome according to previous reported:sustained virological responders(SVR) and nonresponders(NR). Then we extracted DNA, used PCR-SSP to classific KIR and HLA-C, and analysed the differences between SVR and NR more by statistic method.
4. The joint analysis of KIR-HLA ligands pairs (i.e., KIR2DL1and C2, KIR2DL2and Cl) revealed an association of both combinations with HCV infection and therapeutic response in Chinese Han population.
5. In the PubMed database (1995.11-2013.4), we searched literature with "KIR2DL2" and "HCV" as a keyword, and flited by English writing, the same CHC diagnosis standard and international standard treatment methods, the same results judgment, reported the KIR2DL2genotype frequencies, Hepatitis C patients without other disease. The proper documents for Meta-analysis were determined by heterogeneity, publication bias; calculate the overall risk coefficient selection of the fixed effect model.
6. After treating NK92cells with5-Aza-dc, those cells can express KIR2DL2molecules. Observing the effects of different concentration of antibody blocking KIR2DL2receptor, it was detected that NK cell killing ability of K562cells.
7. Data are analysed by Statistical Package for Social Sciences (SPSS) version17.0.
Results
1. As genotyping results showed, the OR values of KIR2DL2, KIR2DS3are greater than1. It indicated two genes frequency of CHC patients are higher than the healthy control group in Chinese Han population, which may be the risk factors for CHC. Moreover, the OR values of HLA-Cw*06, HLA-Cw*15, are less than1. It suggested these genes in Chinese Han patients with CHC frequency is lower than that of healthy controls, these genes are likely to inhibit CHC.
2. Accroding from the genotyping results of SVR and NR, it was implied that patients who carry KIR2DL2and HLA-Cw*03have poor effect for tratment of CHC in Chinese Han population.
3. As KIR/HLA-C paired analysis described, the OR values of KIR2DL2/HLA-C group1matching was greater than1, while the frequency of the combination in patients with NR is higher than SVR. It suggested this combination could be conducive to the occurrence of CHC and treatment against CHC. However, KIR2DL1/HLA-C group1was on the contrary.
4. The Meta analysis results also suggested negative effects of KIR2DL2on CHC therapy.
5. After treatment of5-Aza-dc NK92cells, the cells can express higer KIR2DL2molecules. Blocking with20μg/ml KIR2DL2receptor antibody, NK cell killing activity of K562cells increased significantly.
Conclusions
1. KIR2DL2can inhibit the activity of NK cells;
2. KIR2DL2and its receptor HLA-C group1might contribute to the occurrence of CHC and poor response of Peg1FN-alpha and ribavirin combination therapy;
3. The frequency of KIR2DS3in CHC patients is higher than the healthy control group; this may be the risk factors of CHC;
4. The frequency of HLA-Cw*06, HLA-Cw*15, KIR2DS4in CHC patients is lower than that of healthy controls; these genes are likely to inhibit CHC.
引文
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15. Ravetch JV, Lanier LL:Immune inhibitory receptors. Science 2000, 290(5489):84-89.
16. Hamerman JA, Tchao NK, Lowell CA, Lanier LL:Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. Nature immunology 2005, 6(6):579-586.
17. Norman PJ, Carrington CV, Byng M, Maxwell LD, Curran MD, Stephens HA, Chandanayingyong D, Verity DH, Hameed K, Ramdath DD et al: Natural killer cell immunoglobulin-like receptor (KIR) locus profiles in African and South Asian populations. Genes and immunity 2002,3(2):86-95.
18. Becker S, Tonn T, Fussel T, Uhrberg M, Bogdanow M, Seifried E, Seidl C: Assessment of killer cell immunoglobulinlike receptor expression and corresponding HLA class I phenotypes demonstrates heterogenous KIR expression independent of anticipated HLA class I ligands. Human immunology 2003, 64(2):183-193.
19. Jones DC, Edgar RS, Ahmad T, Cummings JR, Jewell DP, Trowsdale J, Young NT: Killer Ig-like receptor (KIR) genotype and HLA ligand combinations in ulcerative colitis susceptibility. Genes and immunity 2006,7(7):576-582.
20. Single RM, Martin MP. Gao X, Meyer D, Yeager M, Kidd JR, Kidd KK, Carrington M:Global diversity and evidence for coevolution of KIR and HLA. Nature genetics 2007,39(9):1114-1119.
21. Toneva M, Lepage V, Lafay G, Dulphy N, Busson M, Lester S, Vu-Trien A, Michaylova A, Naumova E, McCluskey J et al: Genomic diversity of natural killer cell receptor genes in three populations. Tissue antigens 2001,57(4):358-362.
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25. Khakoo SI, Thio CL, Martin MP, Brooks CR, Gao X, Astemborski J, Cheng J, Goedert JJ, Vlahov D, Hilgartner M et al: HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 2004,305(5685):872-874.
26. Boyington JC, Motyka SA, Schuck P, Brooks AG, Sun PD:Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature 2000,405(6786):537-543.
27. Carneiro VL, Lemaire DC, Bendicho MT, Souza SL, Cavalcante LN, Angelo AL, Freire SM, Mendes CM, Santana N, Lyra LG et al: Natural killer cell receptor and HLA-C gene polymorphisms among patients with hepatitis C:a comparison between sustained viro logical responders and non-responders. Liver international: official journal of the International Association for the Study of the Liver 2010, 30(4):567-573.
28. Hsu KC, Liu XR, Selvakumar A, Mickelson E, O'Reilly RJ, Dupont B:Killer Ig-like receptor haplotype analysis by gene content:evidence for genomic diversity with a minimum of six basic framework haplotypes, each with multiple subsets. Journal of immunology 2002,169(9):5118-5129.
29. Lu Z, Zhang B, Chen S, Gai Z, Feng Z, Liu X, Liu Y, Wen X, Li L, Jiao Y et al: Association of KIR genotypes and haplotypes with susceptibility to chronic hepatitis B virus infection in Chinese Han population. Cellular & molecular immunology 2008,5(6):457-463.
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31. Sung PS, Choi HB, Kim SY, Hong SW, Park CH, Song MJ, Lee SW, Yoo CR, Choi SW, Han NI et al: Frequency of killer cell immunoglobulin-like receptors (KIRs) in Korean patients with chronic HCV infection. Journal of Korean medical science 2011,26(11):1483-1488.
32. Westergren A, Karlsson S, Andersson P, Ohlsson O, Hallberg IR:Eating difficulties, need for assisted eating, nutritional status and pressure ulcers in patients admitted for stroke rehabilitation. Journal of clinical nursing 2001,10(2):257-269.
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35. Winter CC, Gumperz JE, Parham P, Long EO, Wagtmann N:Direct binding and functional transfer of NK cell inhibitory receptors reveal novel patterns of HLA-C allotype recognition. Journal of immunology 1998,161(2):571-577.
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27. Carneiro VL, Lemaire DC, Bendicho MT, Souza SL, Cavalcante LN, Angelo AL, Freire SM, Mendes CM, Santana N, Lyra LG et al: Natural killer cell receptor and HLA-C gene polymorphisms among patients with hepatitis C:a comparison between sustained viro logical responders and non-responders. Liver international: official journal of the International Association for the Study of the Liver 2010, 30(4):567-573.
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