FCGR3B基因拷贝数多态性与肾脏疾病相关性和机制探讨
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摘要
前言
移植物的长期带功而不发生排斥反应,是肾移植临床医师和科研人员长期以来梦寐以求的目标。自从免疫抑制剂在临床上的运用以来,移植物的长期存活和受者的生存率都得到很大改善,但只有54.4%的活体供肾和36.4%的尸体供肾,能在10年内肾脏仍然带功。HLA配型、移植前检测移植受者体内的群体反应性抗体(PRA),抗体依赖的补体介导的细胞毒试验(CDC),以及新近发现的抗MHC-Ⅰ类分子相关抗原A(MICA)的抗体,都是影响急性排斥反应发生率的重要因素,并关系到术后移植物的长期生存。然而临床上,在上述影响移植物存活的因素相同,且术后免疫抑制剂用药相似的情况下,移植物结局完全不同的情况并不少见。发现和阐明影响移植物存活的其他的潜在机制,是临床肾移植医师和科研人员多年以来一直努力的方向。
和移植有关的基因多态性研究,一直以来都是影响到移植物结局的热点话题之一,比如编码波形蛋白、血小板特异性抗原的基因,编码产生不同细胞因子以及趋化因子和它们相应的受体的基因,和编码肾素-血管紧张素系统(RAS)分子的基因等。新近的有关基因拷贝数变化(CNVs)的研究,为科研人员提供了一条新的思路:不同种群中与生殖相关的基因UGT2B17缺失与否,其基因活性与睾丸激素的代谢有关,并最终导致前列腺癌的发生;此外,有些疾病例如脊髓性肌萎缩症(Spinal Muscular Atrophy)会因人种的CNVs不同而仅会出先于某些人种中;有研究指出,CCL3L1趋化因子基因拷贝数在基因水平上对HIV感染及艾滋病进程起着重要的决定作用,同一人种中,CCL3L1基因拷贝数低者,HIV-1易感性显著增高,艾滋病进程加快等等。更令我们感兴趣的是,免疫相关基因FCGR3B其拷贝数多态性(CNPs)与系统性红斑狼疮(SLE)患者狼疮性肾炎(LN)的发生相关,低拷贝者更容易发生LN。本研究中,我们探讨了FCGR3B(fcgr3b)基因CNVs与肾移植受体之间的相关性,并分析了该基因CNVs与肾移植受者急性排斥反应发生率和移植物存活之间的关系。
第一部分肾移植受者Fcgr3b基因拷贝数变化与急性排斥和移植物存活之间的关系
目的移植前的HLA配型、群体反应性抗体(PRA)水平、细胞毒实验(CDC),以及新近发现的抗MHC-I类分子相关抗原A(MICA)的抗体,都是影响肾移植术后急性排斥反应发生率和移植物存活的重要因素。然而,即使是上述条件都很理想的肾移植受者,还会有一定的比例术后结果并不十分理想。最近,关于基因拷贝数变化(CNVs)与疾病关系的研究极大地激发了。肾脏病学家的研究兴趣。FCGR3B基因低拷贝的系统性红斑狼疮(SLE)患者,更容易罹患狼疮性肾炎(LN)。由此,我们想到,该基因的拷贝数变化是否会影响到肾移植受者术后急性排斥反应的发生率和移植物的存活?
方法提取869例肾移植受者和761例健康人群的DNA,通过标准曲线方式采用荧光定量PCR的方法,检测他们的FCGR3B基因拷贝数。统计学方法分析该基因CNVs与肾移植术后急性排斥反应发生率,以及与移植物存活之间的关系。所有肾移植患者术后的随访时间中位数为916天,可进行相关的统计学分析。结果来自中国东部人群的健康人群,其FCGR3B基因的拷贝数分布与欧洲(英国)人群的分布类似。健康人群中,单拷贝和双拷贝人群的百分比分别是41%和44%,而在移植人群单拷贝和双拷贝人群的百分比分别是55%和34%(p＜0.01);肾移植术后0,1,2,3,4拷贝数者的急性排斥反应发生率分别是50%,16.8%,8.0%,16.4%和16%(p＜0.001):与两拷贝者相比,0拷贝和1拷贝者急性排斥反应发生的风险分别是9.66(p＜0.001)和2.12(p=0.006);在低拷贝(0和1拷贝)的肾移植受者中,该影响因素对肾移植术后急性排斥反应发生率的影响比HLA配型、供肾热缺血时间和受体的年龄等影响因素更加明显。另外,不同FCGR3B基因拷贝数的肾移植受体之间,移植物的长期存活时间也有显著区别(p＜0.05)。
结论FCGR3B基因不同拷贝数是肾移植术后急性排斥反应发生,以及影响移植物长期存活的独立风险因素之一。
第二部分汉族人群中IgA肾病与FCGR3B基因拷贝数之间的关系
目的IgA肾病(IgAN)是引起中国人群终末期肾病(ESRD)中最主要的原发病;遗传因素与该病的发生有关,我们前期的研究结果发现,肾移植受者FCGR3B基因的拷贝数变化(CNVs)与健康人群不同。本研究试图探讨IgAN患者FCGR3B基因的拷贝数变化与健康人群在该基因分布上的关系,以及IgAN患者FCGR3B基因的拷贝数变化与病理类型之间的关系。
方法本研究共纳入146名IgAN患者和134名健康对照者,提取DNA后通过实时荧光定量PCR的方法,检测他们FCGR3B基因的拷贝数变化,分析IgAN患者与健康人群FCGR3B基因的CNVs,以及IgAN患者中FCGR3B基因的CNVs与病理类型之间的关系。
结果IgAN患者FCGR3B基因的拷贝数分布与健康人群显著不同,前者该基因单拷贝者的比例明显高于健康人群(P=0.028);另外,病理类型比较重的IgAN组,其FCGR3B基因单拷贝的比例也明显高于病理类型较轻组(P=0.021)。
结论FCGR3B基因CNVs与中国人群中IgAN的易感性有关,低拷贝者(0和1拷贝)更容易罹患IgAN,而且该基因CNVs还影响到IgAN患者的病理严重程度。
第三部分FCGR3B基因不同拷贝数者mRNA表达以及对吞噬功能的影响
目的基因拷贝数变化(CNVs)与疾病的关系被很多研究小组所证实,本研究小组前期研究表明,FCGR3B基因CNVs与肾移植受者急性排斥反应的发生率和移植物的长期存活有关;该基因的分布还与中国人群中引起终末期肾病的最常见病因—IgA肾病的发生有显著的相关性。本研究旨在探讨不同FCGR3B基因拷贝数者之间该基因mRNA表达,以及该基因表达产物对抗原物质的吞噬功能的差异。
方法提取不同FCGR3B基因拷贝数者的总RNA,采用实时定量PCR的方法检测该基因mRNA的表达水平。提取不同FCGR3B基因拷贝数的肾移植受者(未发生急性排斥反应者)和健康人新鲜外周血的中性粒细胞,与金葡菌(ATCC25923菌株)在37℃分别混合培养60min和120min后进行菌落计数,检测中性粒细胞对细菌的吞噬百分比。
结果5个单拷贝样本中管家基因的mRNA相对表达量,与来自5个双拷贝的样本比较,采用Student'T检验,P=0.352,说明不同Fcgr3b基因拷贝数者的样本中管家基因GAPDH mRNA表达无显著差异。5个单拷贝样本中FCGR3B基因mRNA相对表达量,与来自5个双拷贝的样本比较,采用Student'T检验,P=0.0001。移植人群(无排斥者)与健康人群相比,不同Fcgr3b基因拷贝数者中性粒细胞对金黄色葡萄球菌的吞噬和杀伤效应无显著差异。
结论不同FCGR3B基因拷贝数的健康人群中,其外周血单个核细胞中该基因的mRNA表达含量有区别,单拷贝者的mRNA表达显著低于双拷贝者;不同FCGR3B基因拷贝数的健康人群和移植人群(未发生排斥反应者)相比,其外周血中性粒细胞对金黄色葡萄球菌的吞噬效应无显著区别。
第四部分浙籍汉族健康人群和肾移植受者FCGR3B基因序列分析
目的很多研究揭示了基因拷贝数变化(CNVs),包括FCGR3B基因与人类疾病易感性之间的关系,然而迄今为止尚无研究探讨每个拷贝基因之间是否存在差异。FCGR3B基因不同拷贝之间,是否存在单个核苷酸的突变(SNP)或是基因片段的缺失,是本研究的目的。
方法本研究共纳入健康对照20例(其中1、2拷贝者分别为10例),肾移植术后发生急性排斥的1拷贝者10例,术后未发生急性排斥的1拷贝者10例,共40例。采用定量PCR的方法扩增这些对象的基因组DNA内,FCGR3B基因外显子5的部分序列,并对整个扩增过程进行跟踪。PCR产物进行测序或者克隆连接载体后测序,研究这些序列的变化。
结果健康人群中1、2拷贝者每组均有9人在Exon 5-204位点发生G/A突变,无排斥组有8人发生突变,而排斥组也有9人发生突变。然而在外显子5的编码序列内未发现SNP现象、基因片段的缺失或插入。编码序列下游的5'UTR 200 bp范围内也未见基因片段的缺失或插入。
结论在浙籍汉族人群中,FCGR3B基因Exon 5的编码序列内可能无高频率的SNP现象,其编码序列下游的5'UTR 300 bp范围内也可能无基因片段的缺失或插入。
Introduction
Great improvement has been made in immunosuppressive therapy, the long-term graft and recipients survival rate has remained static, with only 54.4 percent of kidneys from living donors and 36.4 percent of kidneys from deceased donors functioning 10 years after transplantation. Many efforts had made to achieve an ideal result. HLA matches, pre-transplant PRA, CDC levels and recently MICA are among important factors affect acute rejection rate and hence the long time graft survival for kidney transplantation. However, it is not seldom that despite a similar well handled above factors and a standard immunosuppressive protocol, the clinical outcomes are quite different. The elucidation for the underground mechanisms may give some clues for improving the transplant outcome.
Transplant relevant genes' polymorphisms was once a hot topic that may influence the transplant outcomes, e.g. vimentin, platelet-specific antigens, genes that encode various cytokines, chemokines and their receptors, and molecules of the renin-angiotensin system. Recently, a totally new type of gene polymorphisms due to copy number variations (CNVs) take scientists' eyes: deletions of the UGT2B17 gene contribute to ethnic and inter-individual differences in testosterone metabolism and risk of prostate cancer; increased copy number of the CCL3L1 gene is associated with reduced susceptibility to HIV infection and progression to AIDS. To our interest, reduced FCGR3B copy number was reported to predispose people to lupus nephritis. In the current study, we determined Fcgr3B copy number of kidney transplantation recipient and analyzed its' effect on acute rejection rate and graft survival.
Part I Recipients Fcgr3B copy number variation and acute rejection, graft survival in kidney transplantation
Aims HLA matches, pre-transplant PRA, CDC levels and recently MICA are among important factors affect acute rejection and graft survival for kidney transplantation. Despite well handled above factors, results are not always ideal. Recently, researches on gene copy number variation and its' clinical importance exerted great interest also for nephrologist. Low Fcgr3B copy number predispose to nephritis in SLE patients. We sought to determine if Fcgr3B copy number variation influence acute rejection and graft survival in kidney transplantation.
Methods We determined Fcgr3B copy number of 869 kidney transplantation recipient and 761 unrelated healthy samples with q-PCR. The association between Fcgr3B gene copy number and the acute rejection rate and graft survival were analyzed with corresponding statistical method. The median length of follow-up was 916 days, respectively.
Results Fcgr3B copy number distribution of healthy East Chinese showed a similar result with a report from UK. The main frequency, i.e. one and two copy in healthy control group were 41% and 44%, respectively; while in the kidney transplant group the corresponding frequency were 55% and 34%, respectively (p<0.01). Acute rejection rate of kidney transplant recipients with 0,1,2,3 and 4 copy Fcgr3B was 50%, 16.8%, 8.0%, 16.4% and 16%, respectively (p<0.001). Compared with 2 copy recipient, the hazard ratio for risk of acute rejection of recipients with 0, 1 copy of Fcgr3B were 9.66(p<0.001), 2.12(p=0.006), respectively. In subgroup serial analyses including important factors of HLA match condition, warm ischemia time and recipient age, acute rejection rate difference proved to be more significant in the high risk categories. The cumulative kidney graft survival was different with differentFcgr3B copy (p<0.05).
Conclusions Fcgr3B copy number variation was an independent factor that influencethe acute rejection and graft survival in kidney transplantation.
Part II The relationship between FCGR3B copy number variations and IgA nephrology in Chinese
Aims IgA nephrology (IgAN) was the most common reason for Chinese patients to end stage renal disease (ESRD). Many researchers reported that the heredity was related to the onset of this disease. Our previous study found the distribution of gene FCGR3B copy number variations (CNVs) between healthy blood donors and renal recipients was significantly different. Our current study was to elucidate the relation of FCGR3B CNVs between IgAN patients and healthy blood donors, and if this gene CNVs was involved in the pathological severity of this disease.
Methods 146 IgAN patients and 134 healthy blood donors were included in the study. DNA of the total 280 subjects were extracted from their peripheral blood mononuclear cells, and analyzed by real time PCR.
Results The distribution of gene FCGR3B CNVs was significantly different between healthy donors and IgAN patients in Chinese (P =0.028) . One copy of this gene was easier found in IgAN patients than that of healthy blood donors. In addition, the proportion of single copy gene FCGR3B was observed higher in pathological severe IgAN patients than in pathological slightly changed subjects (P =0.021) .
Conclusions CNVs of gene FCGR3B was related to IgAN in Chinese, low copy number (zero and one copy) was a risk factor for the susceptibility to this disease. Low copy of gene FCGR3B was correlated to severe pathological changes of this disease.
Part III Difference of mRNA Expression and Neutrophil Phagoctyosis in different FCGR3B Gene Copy Number Donors
Aims The relation between gene copy number variation and the susceptibility of diseases were verified by some research groups. Our previous study found that Fcgr3B copy number variation was an independent factor that influence the acute rejection and graft survival in kidney transplantation. Data supporting the hypothesis that low copy number of Fcgr3B gene predispose disease susceptibility of IgAN—the highest morbidity type of nephritis in China, and the possibility to the susceptibility for nephritis of progression to ESRD. The aim of this study was to elucidate the difference of mRNA expression and phagocytosis ability of neutrophil between different FCGR3B copy number renal allo-grafts recipients and healthy blood donors.
Methods Extracting the total RNA of peripheral blood mononuclear cells (PBMC) from different FCGR3B copy number healthy blood donors, and screened the mRNA expression by real time PCR. Extracting the total neutrophil of peripheral blood mononuclear cells (PBMC) from different FCGR3B copy number healthy blood donors and renal allo-grafts recipients (no acute rejecters), and co-cultured with Staphylococcus aureus at 37℃, testing the phagocytosis ratios of neutrophil after 60 minutes and 120 minutes.
Results mRNA expression of housekeeping gene GAPDH between 5 FCGR3B one copy healthy blood donors and 5 FCGR3B two copy healthy blood donors, verified by Student' T test, P = 0.352, that displayed no significant difference of mRNA expression in housekeeping gene between two groups. mRNA expression of gene FCGR3B between 5 one copy healthy blood donors and 5 two copy healthy blood donors, verified by Student' T test, P = 0.0001. There was no significant difference about the phagocytosis ratios of neutrophil after 60 minutes and 120 minutes, in different FCGR3B copy number healthy blood donors and renal allo-grafts recipients (no acute rejecters).
Conclusions There was significant difference of mRNA expression about gene FCGR3B in peripheral blood mononuclear cells (PBMC) from different FCGR3B copy number healthy blood donors. mRNA expression from one copy gene FCGR3B donors was lower than that of two copy donors. No significant difference was observed about the phagocytosis ratios of neutrophil in different FCGR3B copy number healthy blood donors and renal allo-grafts recipients (no acute rejecters).
Part IV Sequencing of Gene FCGR3B Exon 5 in Chinese Renal allograft Recipients and Healthy Donors in Zhejiang Province
Aims Many researchers reported the relation between gene copy number variations (CNVs) including FCGR3B and susceptibilities of some human diseases. This study was to elucidate the single nucleotide polymorphism (SNP), nucleotide segments insertion or deletion of this gene between different copies.
Methods 20 healthy blood donors (10 have one copy and 10 have two copies of gene FCGR3B each), 20 renal allograft recipients with one copy of FCGR3B (10 subjects suffered acute rejection after transplantation and 10 subjects did not). FCGR3B exon 5 part nucleotide sequence of genomic DNA was amplified by real time PCR using SYBR Green I method. PCR products were directly sequenced or after cloning vector by sequencing machine.
Results Exon 5-204 G/A mutation was observed in 9 of 10 subjects with 1 or 2 copies of FCGR3B each. 9 of 10 renal allograft recipients with acute rejection and 8 of 10 renal recipients without rejection were observed the same mutation. No SNP was found in exon 5 coding sequence, and no nucleotide segment insertion or deletion in part nucleotide sequence of 5' un-translated region (5' UTR) of exon 5 in FCGR3B.
Conclusions There was likely no high frequency mutation of SNP in exon 5 coding sequence, and no nucleotide segment insertion or deletion in part nucleotide sequence of 5' UTR in exon 5 of FCGR3B in Chinese from Zhejiang province.
移植物的长期带功而不发生排斥反应,是肾移植临床医师和科研人员长期以来梦寐以求的目标。自从免疫抑制剂在临床上的运用以来,移植物的长期存活和受者的生存率都得到很大改善,但只有54.4%的活体供肾和36.4%的尸体供肾,能在10年内肾脏仍然带功。HLA配型、移植前检测移植受者体内的群体反应性抗体(PRA),抗体依赖的补体介导的细胞毒试验(CDC),以及新近发现的抗MHC-Ⅰ类分子相关抗原A(MICA)的抗体,都是影响急性排斥反应发生率的重要因素,并关系到术后移植物的长期生存。然而临床上,在上述影响移植物存活的因素相同,且术后免疫抑制剂用药相似的情况下,移植物结局完全不同的情况并不少见。发现和阐明影响移植物存活的其他的潜在机制,是临床肾移植医师和科研人员多年以来一直努力的方向。
和移植有关的基因多态性研究,一直以来都是影响到移植物结局的热点话题之一,比如编码波形蛋白、血小板特异性抗原的基因,编码产生不同细胞因子以及趋化因子和它们相应的受体的基因,和编码肾素-血管紧张素系统(RAS)分子的基因等。新近的有关基因拷贝数变化(CNVs)的研究,为科研人员提供了一条新的思路:不同种群中与生殖相关的基因UGT2B17缺失与否,其基因活性与睾丸激素的代谢有关,并最终导致前列腺癌的发生;此外,有些疾病例如脊髓性肌萎缩症(Spinal Muscular Atrophy)会因人种的CNVs不同而仅会出先于某些人种中;有研究指出,CCL3L1趋化因子基因拷贝数在基因水平上对HIV感染及艾滋病进程起着重要的决定作用,同一人种中,CCL3L1基因拷贝数低者,HIV-1易感性显著增高,艾滋病进程加快等等。更令我们感兴趣的是,免疫相关基因FCGR3B其拷贝数多态性(CNPs)与系统性红斑狼疮(SLE)患者狼疮性肾炎(LN)的发生相关,低拷贝者更容易发生LN。本研究中,我们探讨了FCGR3B(fcgr3b)基因CNVs与肾移植受体之间的相关性,并分析了该基因CNVs与肾移植受者急性排斥反应发生率和移植物存活之间的关系。
第一部分肾移植受者Fcgr3b基因拷贝数变化与急性排斥和移植物存活之间的关系
目的移植前的HLA配型、群体反应性抗体(PRA)水平、细胞毒实验(CDC),以及新近发现的抗MHC-I类分子相关抗原A(MICA)的抗体,都是影响肾移植术后急性排斥反应发生率和移植物存活的重要因素。然而,即使是上述条件都很理想的肾移植受者,还会有一定的比例术后结果并不十分理想。最近,关于基因拷贝数变化(CNVs)与疾病关系的研究极大地激发了。肾脏病学家的研究兴趣。FCGR3B基因低拷贝的系统性红斑狼疮(SLE)患者,更容易罹患狼疮性肾炎(LN)。由此,我们想到,该基因的拷贝数变化是否会影响到肾移植受者术后急性排斥反应的发生率和移植物的存活?
方法提取869例肾移植受者和761例健康人群的DNA,通过标准曲线方式采用荧光定量PCR的方法,检测他们的FCGR3B基因拷贝数。统计学方法分析该基因CNVs与肾移植术后急性排斥反应发生率,以及与移植物存活之间的关系。所有肾移植患者术后的随访时间中位数为916天,可进行相关的统计学分析。结果来自中国东部人群的健康人群,其FCGR3B基因的拷贝数分布与欧洲(英国)人群的分布类似。健康人群中,单拷贝和双拷贝人群的百分比分别是41%和44%,而在移植人群单拷贝和双拷贝人群的百分比分别是55%和34%(p＜0.01);肾移植术后0,1,2,3,4拷贝数者的急性排斥反应发生率分别是50%,16.8%,8.0%,16.4%和16%(p＜0.001):与两拷贝者相比,0拷贝和1拷贝者急性排斥反应发生的风险分别是9.66(p＜0.001)和2.12(p=0.006);在低拷贝(0和1拷贝)的肾移植受者中,该影响因素对肾移植术后急性排斥反应发生率的影响比HLA配型、供肾热缺血时间和受体的年龄等影响因素更加明显。另外,不同FCGR3B基因拷贝数的肾移植受体之间,移植物的长期存活时间也有显著区别(p＜0.05)。
结论FCGR3B基因不同拷贝数是肾移植术后急性排斥反应发生,以及影响移植物长期存活的独立风险因素之一。
第二部分汉族人群中IgA肾病与FCGR3B基因拷贝数之间的关系
目的IgA肾病(IgAN)是引起中国人群终末期肾病(ESRD)中最主要的原发病;遗传因素与该病的发生有关,我们前期的研究结果发现,肾移植受者FCGR3B基因的拷贝数变化(CNVs)与健康人群不同。本研究试图探讨IgAN患者FCGR3B基因的拷贝数变化与健康人群在该基因分布上的关系,以及IgAN患者FCGR3B基因的拷贝数变化与病理类型之间的关系。
方法本研究共纳入146名IgAN患者和134名健康对照者,提取DNA后通过实时荧光定量PCR的方法,检测他们FCGR3B基因的拷贝数变化,分析IgAN患者与健康人群FCGR3B基因的CNVs,以及IgAN患者中FCGR3B基因的CNVs与病理类型之间的关系。
结果IgAN患者FCGR3B基因的拷贝数分布与健康人群显著不同,前者该基因单拷贝者的比例明显高于健康人群(P=0.028);另外,病理类型比较重的IgAN组,其FCGR3B基因单拷贝的比例也明显高于病理类型较轻组(P=0.021)。
结论FCGR3B基因CNVs与中国人群中IgAN的易感性有关,低拷贝者(0和1拷贝)更容易罹患IgAN,而且该基因CNVs还影响到IgAN患者的病理严重程度。
第三部分FCGR3B基因不同拷贝数者mRNA表达以及对吞噬功能的影响
目的基因拷贝数变化(CNVs)与疾病的关系被很多研究小组所证实,本研究小组前期研究表明,FCGR3B基因CNVs与肾移植受者急性排斥反应的发生率和移植物的长期存活有关;该基因的分布还与中国人群中引起终末期肾病的最常见病因—IgA肾病的发生有显著的相关性。本研究旨在探讨不同FCGR3B基因拷贝数者之间该基因mRNA表达,以及该基因表达产物对抗原物质的吞噬功能的差异。
方法提取不同FCGR3B基因拷贝数者的总RNA,采用实时定量PCR的方法检测该基因mRNA的表达水平。提取不同FCGR3B基因拷贝数的肾移植受者(未发生急性排斥反应者)和健康人新鲜外周血的中性粒细胞,与金葡菌(ATCC25923菌株)在37℃分别混合培养60min和120min后进行菌落计数,检测中性粒细胞对细菌的吞噬百分比。
结果5个单拷贝样本中管家基因的mRNA相对表达量,与来自5个双拷贝的样本比较,采用Student'T检验,P=0.352,说明不同Fcgr3b基因拷贝数者的样本中管家基因GAPDH mRNA表达无显著差异。5个单拷贝样本中FCGR3B基因mRNA相对表达量,与来自5个双拷贝的样本比较,采用Student'T检验,P=0.0001。移植人群(无排斥者)与健康人群相比,不同Fcgr3b基因拷贝数者中性粒细胞对金黄色葡萄球菌的吞噬和杀伤效应无显著差异。
结论不同FCGR3B基因拷贝数的健康人群中,其外周血单个核细胞中该基因的mRNA表达含量有区别,单拷贝者的mRNA表达显著低于双拷贝者;不同FCGR3B基因拷贝数的健康人群和移植人群(未发生排斥反应者)相比,其外周血中性粒细胞对金黄色葡萄球菌的吞噬效应无显著区别。
第四部分浙籍汉族健康人群和肾移植受者FCGR3B基因序列分析
目的很多研究揭示了基因拷贝数变化(CNVs),包括FCGR3B基因与人类疾病易感性之间的关系,然而迄今为止尚无研究探讨每个拷贝基因之间是否存在差异。FCGR3B基因不同拷贝之间,是否存在单个核苷酸的突变(SNP)或是基因片段的缺失,是本研究的目的。
方法本研究共纳入健康对照20例(其中1、2拷贝者分别为10例),肾移植术后发生急性排斥的1拷贝者10例,术后未发生急性排斥的1拷贝者10例,共40例。采用定量PCR的方法扩增这些对象的基因组DNA内,FCGR3B基因外显子5的部分序列,并对整个扩增过程进行跟踪。PCR产物进行测序或者克隆连接载体后测序,研究这些序列的变化。
结果健康人群中1、2拷贝者每组均有9人在Exon 5-204位点发生G/A突变,无排斥组有8人发生突变,而排斥组也有9人发生突变。然而在外显子5的编码序列内未发现SNP现象、基因片段的缺失或插入。编码序列下游的5'UTR 200 bp范围内也未见基因片段的缺失或插入。
结论在浙籍汉族人群中,FCGR3B基因Exon 5的编码序列内可能无高频率的SNP现象,其编码序列下游的5'UTR 300 bp范围内也可能无基因片段的缺失或插入。
Introduction
Great improvement has been made in immunosuppressive therapy, the long-term graft and recipients survival rate has remained static, with only 54.4 percent of kidneys from living donors and 36.4 percent of kidneys from deceased donors functioning 10 years after transplantation. Many efforts had made to achieve an ideal result. HLA matches, pre-transplant PRA, CDC levels and recently MICA are among important factors affect acute rejection rate and hence the long time graft survival for kidney transplantation. However, it is not seldom that despite a similar well handled above factors and a standard immunosuppressive protocol, the clinical outcomes are quite different. The elucidation for the underground mechanisms may give some clues for improving the transplant outcome.
Transplant relevant genes' polymorphisms was once a hot topic that may influence the transplant outcomes, e.g. vimentin, platelet-specific antigens, genes that encode various cytokines, chemokines and their receptors, and molecules of the renin-angiotensin system. Recently, a totally new type of gene polymorphisms due to copy number variations (CNVs) take scientists' eyes: deletions of the UGT2B17 gene contribute to ethnic and inter-individual differences in testosterone metabolism and risk of prostate cancer; increased copy number of the CCL3L1 gene is associated with reduced susceptibility to HIV infection and progression to AIDS. To our interest, reduced FCGR3B copy number was reported to predispose people to lupus nephritis. In the current study, we determined Fcgr3B copy number of kidney transplantation recipient and analyzed its' effect on acute rejection rate and graft survival.
Part I Recipients Fcgr3B copy number variation and acute rejection, graft survival in kidney transplantation
Aims HLA matches, pre-transplant PRA, CDC levels and recently MICA are among important factors affect acute rejection and graft survival for kidney transplantation. Despite well handled above factors, results are not always ideal. Recently, researches on gene copy number variation and its' clinical importance exerted great interest also for nephrologist. Low Fcgr3B copy number predispose to nephritis in SLE patients. We sought to determine if Fcgr3B copy number variation influence acute rejection and graft survival in kidney transplantation.
Methods We determined Fcgr3B copy number of 869 kidney transplantation recipient and 761 unrelated healthy samples with q-PCR. The association between Fcgr3B gene copy number and the acute rejection rate and graft survival were analyzed with corresponding statistical method. The median length of follow-up was 916 days, respectively.
Results Fcgr3B copy number distribution of healthy East Chinese showed a similar result with a report from UK. The main frequency, i.e. one and two copy in healthy control group were 41% and 44%, respectively; while in the kidney transplant group the corresponding frequency were 55% and 34%, respectively (p<0.01). Acute rejection rate of kidney transplant recipients with 0,1,2,3 and 4 copy Fcgr3B was 50%, 16.8%, 8.0%, 16.4% and 16%, respectively (p<0.001). Compared with 2 copy recipient, the hazard ratio for risk of acute rejection of recipients with 0, 1 copy of Fcgr3B were 9.66(p<0.001), 2.12(p=0.006), respectively. In subgroup serial analyses including important factors of HLA match condition, warm ischemia time and recipient age, acute rejection rate difference proved to be more significant in the high risk categories. The cumulative kidney graft survival was different with differentFcgr3B copy (p<0.05).
Conclusions Fcgr3B copy number variation was an independent factor that influencethe acute rejection and graft survival in kidney transplantation.
Part II The relationship between FCGR3B copy number variations and IgA nephrology in Chinese
Aims IgA nephrology (IgAN) was the most common reason for Chinese patients to end stage renal disease (ESRD). Many researchers reported that the heredity was related to the onset of this disease. Our previous study found the distribution of gene FCGR3B copy number variations (CNVs) between healthy blood donors and renal recipients was significantly different. Our current study was to elucidate the relation of FCGR3B CNVs between IgAN patients and healthy blood donors, and if this gene CNVs was involved in the pathological severity of this disease.
Methods 146 IgAN patients and 134 healthy blood donors were included in the study. DNA of the total 280 subjects were extracted from their peripheral blood mononuclear cells, and analyzed by real time PCR.
Results The distribution of gene FCGR3B CNVs was significantly different between healthy donors and IgAN patients in Chinese (P =0.028) . One copy of this gene was easier found in IgAN patients than that of healthy blood donors. In addition, the proportion of single copy gene FCGR3B was observed higher in pathological severe IgAN patients than in pathological slightly changed subjects (P =0.021) .
Conclusions CNVs of gene FCGR3B was related to IgAN in Chinese, low copy number (zero and one copy) was a risk factor for the susceptibility to this disease. Low copy of gene FCGR3B was correlated to severe pathological changes of this disease.
Part III Difference of mRNA Expression and Neutrophil Phagoctyosis in different FCGR3B Gene Copy Number Donors
Aims The relation between gene copy number variation and the susceptibility of diseases were verified by some research groups. Our previous study found that Fcgr3B copy number variation was an independent factor that influence the acute rejection and graft survival in kidney transplantation. Data supporting the hypothesis that low copy number of Fcgr3B gene predispose disease susceptibility of IgAN—the highest morbidity type of nephritis in China, and the possibility to the susceptibility for nephritis of progression to ESRD. The aim of this study was to elucidate the difference of mRNA expression and phagocytosis ability of neutrophil between different FCGR3B copy number renal allo-grafts recipients and healthy blood donors.
Methods Extracting the total RNA of peripheral blood mononuclear cells (PBMC) from different FCGR3B copy number healthy blood donors, and screened the mRNA expression by real time PCR. Extracting the total neutrophil of peripheral blood mononuclear cells (PBMC) from different FCGR3B copy number healthy blood donors and renal allo-grafts recipients (no acute rejecters), and co-cultured with Staphylococcus aureus at 37℃, testing the phagocytosis ratios of neutrophil after 60 minutes and 120 minutes.
Results mRNA expression of housekeeping gene GAPDH between 5 FCGR3B one copy healthy blood donors and 5 FCGR3B two copy healthy blood donors, verified by Student' T test, P = 0.352, that displayed no significant difference of mRNA expression in housekeeping gene between two groups. mRNA expression of gene FCGR3B between 5 one copy healthy blood donors and 5 two copy healthy blood donors, verified by Student' T test, P = 0.0001. There was no significant difference about the phagocytosis ratios of neutrophil after 60 minutes and 120 minutes, in different FCGR3B copy number healthy blood donors and renal allo-grafts recipients (no acute rejecters).
Conclusions There was significant difference of mRNA expression about gene FCGR3B in peripheral blood mononuclear cells (PBMC) from different FCGR3B copy number healthy blood donors. mRNA expression from one copy gene FCGR3B donors was lower than that of two copy donors. No significant difference was observed about the phagocytosis ratios of neutrophil in different FCGR3B copy number healthy blood donors and renal allo-grafts recipients (no acute rejecters).
Part IV Sequencing of Gene FCGR3B Exon 5 in Chinese Renal allograft Recipients and Healthy Donors in Zhejiang Province
Aims Many researchers reported the relation between gene copy number variations (CNVs) including FCGR3B and susceptibilities of some human diseases. This study was to elucidate the single nucleotide polymorphism (SNP), nucleotide segments insertion or deletion of this gene between different copies.
Methods 20 healthy blood donors (10 have one copy and 10 have two copies of gene FCGR3B each), 20 renal allograft recipients with one copy of FCGR3B (10 subjects suffered acute rejection after transplantation and 10 subjects did not). FCGR3B exon 5 part nucleotide sequence of genomic DNA was amplified by real time PCR using SYBR Green I method. PCR products were directly sequenced or after cloning vector by sequencing machine.
Results Exon 5-204 G/A mutation was observed in 9 of 10 subjects with 1 or 2 copies of FCGR3B each. 9 of 10 renal allograft recipients with acute rejection and 8 of 10 renal recipients without rejection were observed the same mutation. No SNP was found in exon 5 coding sequence, and no nucleotide segment insertion or deletion in part nucleotide sequence of 5' un-translated region (5' UTR) of exon 5 in FCGR3B.
Conclusions There was likely no high frequency mutation of SNP in exon 5 coding sequence, and no nucleotide segment insertion or deletion in part nucleotide sequence of 5' UTR in exon 5 of FCGR3B in Chinese from Zhejiang province.
引文
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