基因单核苷酸多态性与IgA肾病及系统性红斑狼疮的相关性研究
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摘要
IgA肾病(IgA nephropathy,IgAN)是一种肾小球系膜增生性肾小球肾炎,指IgA或以IgA为主的免疫球蛋白在肾小球系膜区以及毛细血管袢呈弥漫颗粒状或团块状沉积所引起的一系列临床及病理变化。在20年以内,15～40%的IgA肾病患者会逐渐发展成终末期肾功能衰竭。经鉴定用于预测IgA肾病进展的方法包括有高血压、严重的蛋白尿、上升的血清肌酐酸水平,以及肾小球硬化和间质性纤维化的组织学标记。最近,也有资料把IgA肾病患者中的高甘油三酸酯、高尿酸血症和其他部分代谢综合征归因于肾功能衰退。可是IgA肾病进展的多变过程也表明还有其他因素参与了IgA肾病的发生与发展。为了更好地治疗和控制IgA肾病,有必要进一步阐明IgA肾病的病因学及发病机制,加深对这种疾病病因的理解。IgA肾病是由多重生理学调节系统之间的相互作用所引起的,而且很可能涉及到多种基因,这些基因是导致遗传学研究上出现相互矛盾结果的主要原因。
系统性红斑狼疮(Systemic lupus erythematosus,SLE)是一种原发性自身免疫风湿性疾病,主要发生于分娩期的妇女。在过去的40年中,系统性红斑狼疮患者的预后水平得到了很大的提高,10年存活率大约达到了90%。这可能得益于早期诊断和中期诊断的结合,也有部分是因为多种SLE血清学实验的使用、类固醇和其他免疫抑制剂的应用,以及肾透析和肾移植的应用。尽管如此,在部分敏感或抗治疗性的疾病患者中仍能存在显著性的发病率和死亡率。为了更好地治疗和控制系统性红斑狼疮,有必要进一步阐明SLE的病因学及发病机制,加深对这种疾病病因的理解。有资料显示,系统性红斑狼疮的发生和发展很可能涉及到多种基因,这些基因是导致遗传学研究上出现相互矛盾结果的主要原因。
为了研究基因单核苷酸多态性与IgA肾病及系统性红斑狼疮的关联性,本研究挑选了14个疾病候选基因中的23种单核苷酸,使用Sequenom? MassARRAY? SNP基因分型技术来研究这些候选基因与疾病发生/发展的关联性。寻找和研究SNP已成为人类基因组计划的内容和目标之一。本研究将有助于进一步阐明IgA肾病及系统性红斑狼疮的病因学及发病机制,加深对这两种疾病病因的理解,可能为发展新的IgA肾病及系统性红斑狼疮诊断提供一个非常重要的线索。
研究发现,CTLA4rs231726和CR2rs1048971与IgA肾病的发生有显著的关联性,STAT4rs7574865和TYK2rs12720270与系统系统性红斑狼疮的发生存在显著性的相关性。在系统性红斑狼疮与正常对照组的等位基因分析中,还发现了两种具有显著性差异的单核苷酸位点,分别为rs7574865和rs294183。这些发现证实了IgA肾病和系统性红斑狼疮病因学中的多基因性质,也为后续基因之间相互作用研究提供了一个潜在的模型。
IgA nephropathy (IgAN) is a mesangial proliferative glomerulonephritis characterized by diffuse or glaebule deposition of immunoglobulin A (IgA, mainly IgA 1) or IgA-containing immune complexes (IgA-ICs) in mesangium and capillary loop. The proportion of 15-40 % patients with IgAN develop end-stage renal failure (ESRF) within twenty years. Strong predictors of progression of IgAN have been identified and include hypertension, severe proteinuria, elevated serum creatinine level as well as histological signs of glomerular sclerosis and interstitial fibrosis. Recently, hypertriglyceridaemia, hyperuricaemia and other components of metabolic syndrome have been incriminated in the process of deterioration of renal function in IgAN. However, a variable course of IgAN progression indicates involvement of other factors as well. In order to elevate the effectiveness of therapia and manipulation in IgAN, it is necessity to elucidate the etiology and pathogenesy of IgAN. IgAN is a complex trait regulated by the interaction among multiple physiologic regulatory systems and likely involving numerous genes which leads to inconsistent findings in genetic studies.
Systemic lupus erythematosus (SLE) is a prototypical autoimmune rheumatic disease principally affecting women during childbearing years. In the past 40 years, prognosis for patients with systemic lupus erythematosus (SLE) has improved, with 10-year survival now approximately 90%. This is due probably to a combination of earlier disease diagnosis and diagnosis of milder disease, due in part to availability of multiple serological tests for SLE, use of steroids and other immunosuppressive agents, and availability of renal dialysis and transplantation. Despite this, however, the potential for significant morbidity and mortality remains in the group of patients with partially responsive or treatment resistant disease. In order to elevate the effectiveness of therapia and manipulation in SLE, it is necessity to elucidate the etiology and pathogenesy of SLE. Some investigation had shown that SLE likely involving numerous genes which leads to inconsistent findings in genetic studies.
In our study, in order to investigate the association between Polymorphism and IgA nephropathy as well as Systemic lupus erythematosus, a large-scale evaluation of 22 Single Nucleotide Polymorphisms of 14 candidate genes was undertaken using the Sequenom? MassARRAY? system in Chinese southern Han’s males. investigation of SNPs have been the contents and objective of the human genome project. Our study will contribute effects to elevate the effectiveness of therapia and manipulation in IgAN and SLE. At the same time, it may provid an important clue for the diagnosticate of IgAN and SLE.
In this experiment, CTLA4rs231726 and CR2rs1048971 revealed a significant association with IgA nephropathy, and STAT4rs7574865 and TYK2rs12720270 revealed a significant association with SLE. In addition, there were two significant differences in allele frequency between SLE and the matched controls for all of the 22 SNPs(rs7574865 and rs294183, separately). These findings support the multigenic nature of the etiology of IgA nephropathy and propose a potential gene–gene interactive model for future studies.
系统性红斑狼疮(Systemic lupus erythematosus,SLE)是一种原发性自身免疫风湿性疾病,主要发生于分娩期的妇女。在过去的40年中,系统性红斑狼疮患者的预后水平得到了很大的提高,10年存活率大约达到了90%。这可能得益于早期诊断和中期诊断的结合,也有部分是因为多种SLE血清学实验的使用、类固醇和其他免疫抑制剂的应用,以及肾透析和肾移植的应用。尽管如此,在部分敏感或抗治疗性的疾病患者中仍能存在显著性的发病率和死亡率。为了更好地治疗和控制系统性红斑狼疮,有必要进一步阐明SLE的病因学及发病机制,加深对这种疾病病因的理解。有资料显示,系统性红斑狼疮的发生和发展很可能涉及到多种基因,这些基因是导致遗传学研究上出现相互矛盾结果的主要原因。
为了研究基因单核苷酸多态性与IgA肾病及系统性红斑狼疮的关联性,本研究挑选了14个疾病候选基因中的23种单核苷酸,使用Sequenom? MassARRAY? SNP基因分型技术来研究这些候选基因与疾病发生/发展的关联性。寻找和研究SNP已成为人类基因组计划的内容和目标之一。本研究将有助于进一步阐明IgA肾病及系统性红斑狼疮的病因学及发病机制,加深对这两种疾病病因的理解,可能为发展新的IgA肾病及系统性红斑狼疮诊断提供一个非常重要的线索。
研究发现,CTLA4rs231726和CR2rs1048971与IgA肾病的发生有显著的关联性,STAT4rs7574865和TYK2rs12720270与系统系统性红斑狼疮的发生存在显著性的相关性。在系统性红斑狼疮与正常对照组的等位基因分析中,还发现了两种具有显著性差异的单核苷酸位点,分别为rs7574865和rs294183。这些发现证实了IgA肾病和系统性红斑狼疮病因学中的多基因性质,也为后续基因之间相互作用研究提供了一个潜在的模型。
IgA nephropathy (IgAN) is a mesangial proliferative glomerulonephritis characterized by diffuse or glaebule deposition of immunoglobulin A (IgA, mainly IgA 1) or IgA-containing immune complexes (IgA-ICs) in mesangium and capillary loop. The proportion of 15-40 % patients with IgAN develop end-stage renal failure (ESRF) within twenty years. Strong predictors of progression of IgAN have been identified and include hypertension, severe proteinuria, elevated serum creatinine level as well as histological signs of glomerular sclerosis and interstitial fibrosis. Recently, hypertriglyceridaemia, hyperuricaemia and other components of metabolic syndrome have been incriminated in the process of deterioration of renal function in IgAN. However, a variable course of IgAN progression indicates involvement of other factors as well. In order to elevate the effectiveness of therapia and manipulation in IgAN, it is necessity to elucidate the etiology and pathogenesy of IgAN. IgAN is a complex trait regulated by the interaction among multiple physiologic regulatory systems and likely involving numerous genes which leads to inconsistent findings in genetic studies.
Systemic lupus erythematosus (SLE) is a prototypical autoimmune rheumatic disease principally affecting women during childbearing years. In the past 40 years, prognosis for patients with systemic lupus erythematosus (SLE) has improved, with 10-year survival now approximately 90%. This is due probably to a combination of earlier disease diagnosis and diagnosis of milder disease, due in part to availability of multiple serological tests for SLE, use of steroids and other immunosuppressive agents, and availability of renal dialysis and transplantation. Despite this, however, the potential for significant morbidity and mortality remains in the group of patients with partially responsive or treatment resistant disease. In order to elevate the effectiveness of therapia and manipulation in SLE, it is necessity to elucidate the etiology and pathogenesy of SLE. Some investigation had shown that SLE likely involving numerous genes which leads to inconsistent findings in genetic studies.
In our study, in order to investigate the association between Polymorphism and IgA nephropathy as well as Systemic lupus erythematosus, a large-scale evaluation of 22 Single Nucleotide Polymorphisms of 14 candidate genes was undertaken using the Sequenom? MassARRAY? system in Chinese southern Han’s males. investigation of SNPs have been the contents and objective of the human genome project. Our study will contribute effects to elevate the effectiveness of therapia and manipulation in IgAN and SLE. At the same time, it may provid an important clue for the diagnosticate of IgAN and SLE.
In this experiment, CTLA4rs231726 and CR2rs1048971 revealed a significant association with IgA nephropathy, and STAT4rs7574865 and TYK2rs12720270 revealed a significant association with SLE. In addition, there were two significant differences in allele frequency between SLE and the matched controls for all of the 22 SNPs(rs7574865 and rs294183, separately). These findings support the multigenic nature of the etiology of IgA nephropathy and propose a potential gene–gene interactive model for future studies.
引文
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[2]李贵森,张宏,吕继成,等. MUC20基因串联重复片段多态性及其对IgA肾病的影响.中华医学杂志, 2005, 85: 1333-1338.
[3] Hsu SI,Bamirez SB,Winn MP,et a1.Evidence for genetic factors in the development and progreesion of IgA nephropathy . Kidney Int. 2000;57: 1818-1835.
[4] D. Maixnerová, M. Mertá, J. Reiterová, et al. The Influence of Three Endothelin-1 Polymorphisms on the Progression of IgA Nephropathy. Folia Biologica (Praha) 2007; 53: 27-32 .
[5] Narita, I., Goto, S., Saito, N., et al., Gejyo, F. Interaction between ACE and ADD1 gene polymorphisms in the progression of IgA nephropathy in Japanese patients. Hypertension 2003;42:304-309.
[6] Merta M, Tesar V,Maixnerova D, et al. The influence of three endothelin-1 polymorphisms on the progression of IgA nephropathy. Folia Biol(Praha). 2007;53(1):27-32.
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[2]李贵森,张宏,吕继成,等. MUC20基因串联重复片段多态性及其对IgA肾病的影响.中华医学杂志, 2005, 85: 1333-1338.
[3] Hsu SI,Bamirez SB,Winn MP,et a1.Evidence for genetic factors in the development and progreesion of IgA nephropathy . Kidney Int. 2000;57: 1818-1835.
[4] D. Maixnerová, M. Mertá, J. Reiterová, et al. The Influence of Three Endothelin-1 Polymorphisms on the Progression of IgA Nephropathy. Folia Biologica (Praha) 2007; 53: 27-32 .
[5] Narita, I., Goto, S., Saito, N., et al., Gejyo, F. Interaction between ACE and ADD1 gene polymorphisms in the progression of IgA nephropathy in Japanese patients. Hypertension 2003;42:304-309.
[6] Merta M, Tesar V,Maixnerova D, et al. The influence of three endothelin-1 polymorphisms on the progression of IgA nephropathy. Folia Biol(Praha). 2007;53(1):27-32.
[7]李江涛,李素. IgA肾病发病机制的研究进展.同济大学学报(医学版).2002,23(5):442—444.
[8] Peschken CA, Esdaile JM. Systemic lupus erythematosus in North American Indians: a population based study. J Rheumatol. 2000; 27:1884–91.
[9] Moss KE. Isenberg DA. Comparison of renal disease severity and outcome in patients with primary antiphospholipid syndrome, antiphospholipid syndrome secondary to systemic lupus erythematosus (SLE) and SLE alone. Rheumatology (Oxford). 2001; 40:863–867.
[10] Rahman A, Giles I, Haley J, Isenberg D. Systematic analysis of sequences of anti-DNA antibodies– relevance to theories of origin and pathogenicity. Lupus. 2002; 11:807–823.
[11] Okamura M, Kanayama Y, Amastu K, et al. Significance of enzyme linked immunosorbent assay (ELISA) for antibodies to double stranded and single stranded DNA in patients with lupus nephritis: correlation with severity of renal histology. Ann Rheum Dis. 1993; 52:14–20.
[12] Sachidanandam R, Weissman D, Schmidt SC, et al. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature. 2001; 409:928–933.
[13] Collins FS, Brooks LD, Chakravarti A. A DNA polymorphism discovery resource for research on human genetic variation. Genome Res. 1998; 8:1229–1231.
[14] Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature. 2001; 409:860–921.
[15] I.H.G.S. Consortium Finishing the euchromatic sequence of the human genome. Nature. 2004; 431:931–945.
[16] Collins, F.S., Guyer, M.S., and Charkravarti, A. Variations on a theme: cataloging human DNA sequence. Science. 1997; 278:1580-1581.
[17] Ponomarenko JV, Orlova GV, Merkulova TI, et al. rSNP_Guide: an integrated database-tools system for studying SNPs and site-directed mutations in transcription factor binding sites. Hum Mutat. 2002; 20:239–248.
[18] Wang X, Tomso DJ, Liu X, Bell DA. Single nucleotide polymorphism in transcriptional regulatory regions and expression of environmentally responsive genes. Toxicol Appl Pharmacol. 2005; 207:84–90.
[19] Wang X, Tomso DJ, Chorley BN, et al. Identification of polymorphic antioxidant response elements in the human genome. Hum Mol Genet. 2007; 16:1188–1200.
[20] Knight JC. Functional implications of genetic variation in non-coding DNA for disease susceptibility and gene regulation. Clin Sci (Lond). 2003; 104:493–501.
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