IgA肾病和紫癜性肾炎患者白细胞介素—1受体拮抗剂基因多态性？…

目的 阐明白细胞介素－１受体拮抗剂基因多态性对其功能的影响。论证ＩＬ－１ｒａ基因型与ＩｇＡ肾病及紫癜性肾炎临床表型之间联系的机理。方法 用ＰＣＲ方法对ＩｇＡＮ和ＨＳＰＮ患者ＩＬ－１ｒａ基因型进行分析，从ＩＬ－１ｒａ不同基因型患者获取外周血单细胞，观察单核细胞经单核巨噬细胞集落刺激因子刺激后，ＩＬ－１ｒａ，ＩＬ－１α和ＩＬ－１β的产生能力。     

白细胞介素1受体拮抗剂等位基因与紫癜性肾炎和IgA肾病的相关…

目的为了进一步阐明紫癜性肾炎（ＨＳＰＮ）及ＩｇＡ肾病（ＩｇＡＮ）二者在发病机理上可能存在的联系，方法用ＰＣＲ方法对４３例ＨＳＰＮ，９７例ＩｇＡＮ患乾和９８名正常人ＩＬ－１受体拮剂（ＩＬ＿１ｒａ）基因数目可变的串联重复（ＶＮＴＲ）多态性进行了分析。结果ＨＳＰＮ患者白细胞介素１受体拮抗剂等位基因（ＩＬＲＮ２）的携带率明显高于正常人（Ｐ〈０．０２）和ＩｇＡＮ患乾中表现为反复发作性肉眼血尿患者戎ＩＬＩＲＡ     

淋巴细胞CD28通路活化后Th1/Th2细胞因子mRNA表达及CsA的抑制作用

采用ＲＴＰＣＲ方法，观察ＣＤ２８通路活化后淋巴细胞Ｔｈ１／Ｔｈ２细胞因子ｍＲＮＡ表达水平及ＣｓＡ的抑制作用。取正常人外周血淋巴细胞，培养过程中分别给予抗ＣＤ３ｍＡｂ单独刺激或抗ＣＤ３ｍＡｂ＋抗ＣＤ２８ｍＡｂ共同刺激。提取细胞总ＲＮＡ并逆转录成ｃＤＮＡ，对Ｔｈ１细胞因子（ＩＦＮγ、ＩＬ２）和Ｔｈ２细胞因子（ＩＬ４、ＩＬ１０）ｃＤＮＡ进行扩增。结果显示：共刺激信号可使Ｔｈ１细胞因子基因ｍＲＮＡ转录增加，且对ＣｓＡ的抑制作用产生抵抗；而对Ｔｈ２细胞因子则不产生明显影响。研究表明：ＣＤ２８共刺激信号主要增强淋巴细胞Ｔｈ１细胞因子基因ｍＲＮＡ表达，并可能参与其分化调节；这一活化通路不被ＣｓＡ阻断。     

白介素1β对肾小球系膜细胞表达纤维蛋白溶解酶原激活物抑制物-1和纤维连接蛋白的影响

目的探讨白介素１β（ＩＬ１β）对人肾小球系膜细胞表达纤维蛋白溶解酶原（纤溶酶原）激活物抑制物１（ＰＡＩ１）和纤维连接蛋白（ＦＮ）的影响。方法应用Ｎｏｒｔｈｅｒｎ杂交检测体外培养的肾小球系膜细胞在ＩＬ１β刺激后ＰＡＩ１和ＦＮ的ｍＲＮＡ表达,采用纤维蛋白平板法检测系膜细胞培养上清中ＰＡＩ１的活性,利用ＥＬＩＳＡ法检测ＦＮ的水平。结果ＩＬ１β刺激组系膜细胞ＰＡＩ１和ＦＮｍＲＮＡ的表达显著增高（与对照组比,Ｐ＜００５）,细胞培养上清中ＰＡＩ１的活性和ＦＮ的水平亦明显增加（与对照组比,Ｐ＜００１）。结论ＩＬ１β可以上调系膜细胞ＰＡＩ１和ＦＮ蛋白质及ｍＲＮＡ的表达,提示ＩＬ１β可能通过抑制细胞外基质降解和增加细胞外基质合成而导致细胞外基质的积聚。     

食管癌术后肠外营养支持早期机体免疫功能的变化(附30例临床分析)

目的观察食管癌术后肠外营养支持早期机体免疫功能的变化。方法对３０例食管癌病人根治术后,随机分为ＰＮ组和非ＰＮ组进行对比观察,分别在手术前、术后１天及术后８天检测ＩｇＧ、ＩｇＡ、ＩｇＭ、Ｃ３、Ｔ细胞亚群、ＮＫ细胞活性和ＩＬ－２等的改变。结果食管癌病人术前均有不同程度的免疫功能低下,术后第１天,ＩｇＧ、ＩｇＡ、ＩｇＭ、Ｃ３较术前显著下降,术后１周ＰＮ组ＩｇＧ、ＩｇＡ、Ｃ３恢复较快,达到或超过术前水平,与非ＰＮ组比较差异有显著意义（Ｐ＜００１）。ＣＤ＋３、ＣＤ＋４、ＣＤ＋４／ＣＤ＋８比值术后第１天下降明显,而ＰＮ组术后１周迅速恢复并明显超过术前水平,与非ＰＮ组相比差异有显著意义（Ｐ＜００１）。ＮＫ细胞活性术后第１天也明显降低,ＩＬ－２显著减少。术后１周ＮＫ细胞活性ＩＬ－２ＰＮ组较非ＰＮ组恢复较快,差异有显著意义（Ｐ＜００１）。结论食管癌病人术后早期免疫功能低下,应用ＰＮ包括脂肪乳剂可以有效地改善机体的免疫功能,并相应降低术后并发症和病死率。     

白介素1β对肾小球系膜细胞表达纤维蛋白溶解酶原激活物抑？…

目的 探讨白介素１β（ＩＬ－１β）对人肾小球系膜细胞表达纤维蛋白溶解酶原（纤溶酶原）激活物抑制物－１（ＰＡＩ－１）和纤维连接蛋白（ＦＮ）的影响。方法 应用Ｎｏｒｔｈｅｒｎ杂交检测体外培养的肾小球系膜细胞在ＩＬ－１β刺激后ＰＡＩ－１和ＦＮ的ｍＲＮＡ表达，采用纤维蛋白平板法检测系膜细胞培养上清中ＰＡＩ－１的活性，利用ＥＬＩＳＡ法检测ＦＮ的水平。结果 ＩＬ－１β刺激组系膜细胞ＰＡＩ－１和ＦＮ ｍＲＮＡ的     

白细胞介素10抑制核因子кB介导的肾小管上皮细胞表达细胞间黏附分子1

目的研究白细胞介素１０（ＩＬ－１０）对人近端肾小管上皮细胞（ＨＫ－２细胞）在促炎症因子肿瘤坏死因子α（ＴＮＦα）作用下表达细胞间黏附分子１（ＩＣＡＭ－ｌ）及其相关核转录途径的影响。方法 用ＨＫ－２细胞作靶细胞，用细胞酶联免疫吸附法（ＥＩＪＳＡ）和Ｎｏｒｔｈｅｒｎ杂交观察ＩＣＡＭ－１的蛋白和基因的表达，以电泳迁移率变动法测定转录因子核因子ｋＢ （ＮＦｋＢ）和激活蛋白 Ｉ（ＡＰ－１）的活性。结果ＴＮＦα呈剂量依赖地诱导ＨＫ－２细胞ＮＦｋＢ的活化及ＩＣＡＭ－１的基因和蛋白表达，这些作用可以被ＮＦｋＢ的抑制剂对甲苯磺－Ｌ－苯丙氨酸氯甲基甲酮（ＴＰＣＫ）所抑制，但ＴＮＦα对ＨＫ－２细胞的ＡＰ－１活性无影响。 ＩＬ－１０（１～ ２０ｎｇ／ｍｌ）可抑制 ＴＮＦα诱导的 ＨＫ－２细胞 ＩＣＡＭ－ｌ基因和蛋白表达及 ＮＦｋＢ的活化。结论ＴＮＦα诱导人肾小管上皮细胞ＨＫ－２的ＮＦｋＢ活化，进而促进ＩＣＡＭ－ｌ基因和蛋白表达，ＩＬ－１０可抑制ＴＮＦα诱导的上述炎症效应。     

单核细胞趋化蛋白-1在肾小球内皮细胞中表达的实验研究

目的探讨肿瘤坏死因子α（ＴＮＦα）对培养的人肾小球内皮细胞（ＨＵＧＥＣ）表达单核细胞趋化蛋白１（ＭＣＰ１）的影响以及ＨＵＧＥＣ的条件培养基对单核细胞（ＭＣ）的趋化作用及抗ＭＣＰ１抗体对单核细胞迁移的影响。方法（１）采用原位杂交技术、免疫细胞化学、细胞ＥＬＩＳＡ法观察ＭＣＰ１基因及蛋白表达。（２）用改良的Ｂｏｙｄｅｎ小室微孔滤膜法测定ＴＮＦα刺激ＨＣＧＥＣ后的条件培养基对ＭＣ的趋化作用及抗ＭＣＰ１抗体对ＭＣ迁移的影响。结果（１）在不加刺激条件下培养的ＨＵＧＥＣ弱表达ＭＣＰ１基因及蛋白,５０ｎｇ／ｍｌＴＮＦα刺激后,６小时即有ＭＣＰ１蛋白表达增强,于１２小时达高峰,不同浓度的ＴＮＦα（２５、５０、１００ｎｇ／ｍｌ）刺激ＨＵＧＥＣ６小时后,与正常对照组相比差异显著（Ｐ＜００１）。（２）ＴＮＦα刺激ＨＵＧＥＣ后的条件培养基对ＭＣ有明显趋化作用,并被抗ＭＣＰ１抗体抑制。结论ＨＵＧＥＣ在ＴＮＦα诱导下,其ＭＣＰ１的表达增强,其条件培养基对ＭＣ有趋化作用,从而可能招引单核细胞迁入内皮下间隙。     

小儿激素敏感性肾病综合征辅助性T细胞亚群研究

目的进一步探讨微小病变型肾病综合征（ＭＣＮＳ）的发病有否ＴＨ１／ＴＨ２反应失衡。方法通过逆转录－聚合酶链反应（ＲＴ－ＰＣＲ）和双抗体夹心ＥＬＩＳＡ法，检测１１例激素敏感型肾病综合征患儿外周血单个核细胞（ＰＢＭＣ）淋巴因子基因表达和蛋白产生。结果与正常对照组相比，ＮＳ患儿ＩＬ－１０、ＩＬ－４基因表达和蛋白产生明显增高、ＩＬ－２、ＩＬ－６降低，干扰素（ＩＦＮ）－γ和ＩＬ－５无明显差异。结论激素敏感性ＮＳ患儿ＴＨ１类和ＴＨ２类淋巴因子产生有重叠，不能用单一的ＴＨ１或ＴＨ２亚群过度活化解释，其淋巴因子产生异常可能是某些ＴＨ细胞克隆活化异常所致     

IgA肾病患者尿白介素6检测的意义

我们用尿白介素６（ＩＬ－６）依赖细胞株７ＴＤ１细胞，测定了２１例原发性ＩｇＡ肾病患者尿和血清ＩＬ－６活性水平，并分析了ＩＬ－６活性水平与ＩｇＡＮ临床及病理改变的联系。结果：ＩｇＡＮ患者尿及血清ＩＬ－６与活性均增高，（活性增高者分别占４６．７％及２５％），尿ＩＬ－６与血清ＩＬ－６水平无平行关系，尿ＩＬ－６活性水平与ＩｇＡＮ严重蛋白尿的发生以及肾小球病变＊节段肾小球硬化、新月体、系膜扩张等）和小管一间     

Association of interleukin-1 receptor antagonist gene polymorphism with IgA nephropathy

It is evident that cytokines play an important role in the pathogenesis as well as disease progression of IgA nephropathy (IgAN). Several gene polymorphisms of the pertinent cytokines have an influence on the level of cytokine production. Interleukin-1 receptor antagonist (IL-1ra) gene polymorphism has been found to affect disease susceptibility and activity in several inflammatory diseases. In the present study, we analyzed polymorphism of the variable number tandem repeat (VNTR) of IL-1ra in patients diagnosed as having IgAN (n = 106) and normal controls (n = 74). The allele frequency of IL-1ra polymorphism in IgAN patients was not statistically different from that of the control group. There was no significant difference in the carriage rate of the two-repeat allele (IL1RN*2) between IgAN patients and the control group (8.5 vs. 6.8%). The carriage rate of IL1RN*2 was significantly higher in IgAN patients with severe proteinuria (>or=1.6 g/day) or increased serum creatinine level (>or=2.0 mg/dl; p < 0.05). Furthermore, the carriage rate of IL1RN*2 was significantly higher in patients with severe mesangial cell proliferation (p < 0.01). Our results suggest that IL-1ra polymorphisms are not associated with the development of IgAN in Japanese patients but the presence of IL1RN*2 may be associated with increased disease activity.     

Impact of interleukin-1 receptor antagonist and tumor necrosis factor-alpha gene polymorphism on IgA nephropathy

BACKGROUND: It is evident that cytokines play an important role in the pathogenesis as well as disease progression in IgA nephropathy (IgAN). The level of cytokine production is influenced by different genotypes that reflect gene polymorphism of the pertinent cytokine. Interleukin-1 receptor antagonist (IL-1ra) and tumor necrosis factor-alpha (TNF-alpha) gene polymorphism have been found to affect disease susceptibility and activity in several inflammatory diseases. However, the impact of these polymorphisms in IgAN patients has not previously been thoroughly studied. METHODS: We investigated 111 cases of biopsy-proven IgAN and 100 healthy, normal controls for their IL-1ra and TNF-alpha gene polymorphism. IL-1ra gene polymorphism was characterized as a variable number of tandem repeats of a 86 bp sequence within intron 2. Five alleles were identified and were designated as IL1RN*1, IL1RN*2, IL1RN*3, IL1RN*4, and IL1RN*5, corresponding to 4, 2, 5, 3, 6 repeats, respectively. A polymorphism in the promoter region of the TNF-alpha gene was also studied. This polymorphism involved a guanidine to adenosine transition at position -308 and was designated as TNF1 (-308G) and TNF2 (-308A). RESULTS: There were 54 male and 57 female patients with a mean age of 30.3 +/- 12.5 years and a disease duration of 66. 8 +/- 47.2 months. The mean duration of the follow-up period was 47. 3 +/- 32.6 months. In the patient group, the allele frequencies of IL1RN*1, IL1RN*2, IL1RN*3, IL1RN*4, and IL1RN*5 were 89.6%, 9.9%, 0%, 0.5%, and 0%, respectively, whereas the corresponding carriage rates were 100%, 19.8%, 0%, 0.9%, and 0%, respectively. An excessive carriage of IL2RN*2 was found in the patients when compared with normal controls (allele frequency, 9.9 vs. 2.5%, P < 0.0001). The allele frequencies of TNF1 and TNF2 were 94.1 and 5.9%, respectively, and the carriage rates were 99.1 and 10.8%, respectively, in the patients, which was not significantly different from those of normal controls. When the patients were stratified into mild and severe groups according to their initial presentation, none of the studied alleles correlated with the severity. However, patients with gross hematuria were associated with a higher carriage rate of TNF2 when compared with patients without gross hematuria (allele frequency, 15. 4 vs. 4.6%, P = 0.0552; carriage rate, 30.8% vs. 8.2%, P = 0.0272). Renal survival analysis revealed that the TNF2 carrier had a renal survival comparable with TNF2 (-) patients. However, the carriage of the IL1RN*2 allele was associated with a significantly poorer long-term outcome with a median survival time of 72 months, as compared with those without IL1RN*2 (134 months, P < 0.01). CONCLUSION: IL-1ra and TNF-alpha gene polymorphism may affect disease susceptibility as well as disease activity and long-term outcome in human IgAN. Treatment with an IL-1ra or IL-1 blocking agent may be relevant in those carrying the IL1RN*2 allele.     

白细胞介素1受体拮抗剂等位基因与紫癜性肾炎和IgA肾病的相关联系

目的 为了进一步阐明紫癜性肾炎(HSPN)及IgA肾病(IgAN)二者在发病机理上可能存在的联系。方法 用PCR方法对43例HSPN,97例IgAN患者和98名正常人IL-l受体拮抗剂(IL-lra)基因数目可变的串联重复(VNTR)多态性进行了分析。结果 HSPN患者白细胞介素l受体拮抗剂等位基因(IL IRN 2)的携带率明显高于正常人(P<0.02)和IgAN患者(P<0.05)。在IgAN患者中表现为反复发作性肉眼血尿者其IL IRN 2等位基因的携带率明显高于其它临床类型IgAN患者(P<0.o1),而与HSPN无显著性差异(P>0.05)。结论 HSPN患者IL-lra基因特定的遗传背景在其发病机理中可能起一定作用。IgAN患者中表现为反复发作性肉眼血尿者较其它临床类型IgAN患者与HSPN有更多的相似之处,而ILlRN 2等位基因高携带率可能是二者发病机理的共同点之一。     

Polymorphism in IgA nephropathy

Summary: IgA nephropathy (IgAN) is polyphormic in its clinical manifestation, course and prognosis. Patients with isolated IgA deposit in glomeruli tend to have a high incidence of macroscopic haematuria and carry a better prognosis. In contrast, patients with deposits of IgA and IgG and IgM have a higher incidence of nephrotic syndrome and hypertension. In parallel, patients with IgA and IgG and IgM tend to have more glomerulosclerosis and tubulointestitial lesions. Recently, the angiotensin converting enzyme (ACE) gene polymorphism and its association in disease risk provided interesting exploration leading us to speculate about a possible mechanism to explain the variation in the rate of progression of IgAN; although, the results are still controversial. The variability of plasma ACE concentration has been shown to be associated with an insertion/deletion polymorphism. The frequencies of ACE genotype in 177 Chinese patients with IgAN has been observed. We found that patients with IgAN showed a higher frequency of DD genotype than normal population. In contrast to the previous reports, we did not find any association between ACE genotype and the rate of progression of IgAN. As different genotypes of IL-1 receptor antagonist (IL-1 ra) are also responsible for the circulating levels of IL-1 ra, the polymorphism of IL-1 ra gene has been analyzed in 100 IgAN patients. There was no significant difference in the frequency of IL1RN*2 allele between normal subjects and IgAN. However, patients with recurrent macroscopic haematuria showed a higher carriage rate of IL1RN*2. Hereditable factors, in combination with a number of recognized environmental risk factors, are important determinants of the pathogenesis and natural history of IgAN. The notion that the gene polymorphism might be responsible for the clinical features and progression of IgAN is both intriguing and provocative. The lessons from previous multiple small size studies have produced conflicting results illustrating the need for observation of large numbers of cases in further studies to verify these observed associations.     

Interleukin 1 receptor antagonist and tumor necrosis factor-alpha gene polymorphism in patients with end-stage renal failure

End-stage-renal disease (ESRD) is a final result of various etiologies. Prognostic indicators leading to ESRD in chronic kidney diseases have been studied extensively, of which, genetic factors remain a subject of great concern. Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) are potent proinflammatory cytokines that are involved in several chronic kidney diseases. Studies on cytokine gene polymorphism have revealed important information about the role of genetic factors in disease susceptibility and severity. Gene polymorphism of interleukin-1 receptor antagonist (IL-1ra) and TNF-alpha were determined in 297 ESRD patients and in 145 normal healthy controls. IL-1ra gene polymorphism was characterized as a variable number of tandem repeats of a 86 bp sequence within intron 2. Five alleles were identified and were designated as IL1RN*1, IL1RN*2, IL1RN*3, IL1RN*4, and IL1RN*5, corresponding to 4,2,5,3, and 6 repeats, respectively. A polymorphism in the promoter region of the TNF-alpha gene was also studied. This polymorphism involved a guanidine to adenosine transition at position -308 and was designated as TNF1 (- 308 G) and TNF2 (-308 A). The genotypes and allele frequencies were compared between patients and control group. The distributions of genotypes of IL-1ra and TNF-alpha did not differ significantly between ESRD patients and normal controls. Analysis of allele frequencies revealed a trend toward an increase in IL1RN*2 frequency (7.5% versus 3.8 %, p=0.064) and noncarriage of TNF2 in the patient group (7.2% versus 11.0%, p=0.076) when compared with the control group. When both alleles were considered together, the patient group had a significantly higher frequency of carriage of IL1RN*2 in combination with noncarriage of TNF2 (p=0.0468). We conclude that carriage of IL-1RN*2 and noncarriage of TNF2 allele appear to be poor prognostic factors in patients suffering from various chronic renal diseases that eventually enter end-stage renal failure.     

Polymorphisms in interleukin-1 beta and Interleukin-1 receptor antagonist genes are associated with kidney failure in Korean patients with type 2 diabetes mellitus

BACKGROUND/AIM: Cytokines play an important role in the pathogenesis of kidney diseases. The aim of the study was to investigate the impact of interleukin (IL)-1 cluster genes on diabetic nephropathy in Korean patients with type 2 diabetes mellitus (DM). METHODS: We investigated -511 C/T polymorphism of IL-1 beta and tandem repeat polymorphism in intron 2 of IL-1 receptor antagonist in type 2 DM patients with end-stage kidney failure as compared with patients without nephropathy. RESULTS: The IL1B2 allele was found more frequently in patients with kidney failure than in controls (57.4 vs. 46.1%, p < 0.05). An excessive homozygous carriage of IL1B2 was found in patients with kidney failure when compared with controls (30.5 vs. 18.3%, p < 0.05). The allelic frequency of IL1RN*2 was also higher in cases than in controls without nephropathy (8.4 vs. 2.8 %, p < 0.05). The carriage rate of IL1RN*2 was significantly associated with an increased risk of kidney failure (15.8 vs. 5.6%; OR 3.19, 95% CI 1.24-8.17). The risk of kidney failure was highest in those carrying both IL1RN*2 and IL1B2 (OR 3.90, 95% CI 1.34-11.40). CONCLUSION: IL1B2 and IL1RN*2 genotypes of the IL-1 cluster genes are associated with diabetic nephropathy in Korean patients with type 2 DM.     

Association of IL-1β, IL-1ra, and TNF-α gene polymorphisms in childhood nephrotic syndrome

We investigated the association between IL-1, IL-1ra, and TNF- gene polymorphisms and childhood nephrotic syndrome (NS). We analyzed the genetic polymorphism of IL-1, IL-1ra, and TNF- genes in 152 patients with childhood NS and 292 healthy adult controls. The C to T exchange at position –511 of IL-1 and the G to A at –308 of the TNF- gene were genotyped. Five alleles of the IL-1ra gene were identified and designated as IL1RN*1, IL1RN*2, IL1RN*3, IL1RN*4, and IL1RN*5, according to the variable number of tandem repeats in intron 2. The allele frequencies of IL-11 (-511C), IL-12 (-511T), TNF1 (-308G), and TNF2 (-308A) were 53.0, 47.0, 92.1, and 7.9%, respectively, in the childhood NS group. This was not significantly different from normal controls. In the childhood NS group, the allele frequencies of IL1RN*1, IL1RN*2, IL1RN*3, IL1RN*4, and IL1RN*5 were 90.8, 7.6, 1.6, 0, and 0% [IL1RN*1 odds ratio (OR)=0.296, P=0.0001, IL1RN*2 OR=3.902, P=0.0002]. A high allele frequency of IL1RN*2 and a lower allele frequency of IL1RN*1 were found in childhood NS, although there was no association with IL-1 and TNF-. A high allele frequency of the IL1RN*2 allele may affect disease susceptibility in childhood NS.     

Polymorphism of the cytokine genes and IgA nephropathy

BACKGROUND: IgA nephropathy (IgAN) is a form of chronic glomerulonephritis of unknown etiology and pathogenesis. Cytokine gene polymorphisms regulate cytokine production and play a role in immune and inflammatory responses; these immunological responses thus are possibly involved in the etiology and pathogenesis of IgAN. METHODS: We studied by polymerase chain reaction (PCR) polymorphisms of important cytokine genes of inflammation interleukin-1 (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1Ra) in 167 patients with IgAN and 400 healthy blood donor controls. IgAN patients had been followed up for 6 to 17 (median 11) years from renal biopsy. RESULTS: Carriage of the IL-1beta allele 2 (IL1beta2) or IL-1Ra allele 2 (IL1RN*2) was associated with an increased risk of IgAN. These alleles were highly linked and the odds ratio (OR) of IgAN for carriage of both alleles was 1.8 (95% confidence interval 1.2 to 2.6; P = 0.002). Carriage of the TNF-alpha allele 2 (TNF2) was associated with a decreased risk of IgAN (OR 0.5, range 0.3 to 0.7; P = 0.001). The risk of IgAN was found to be highest in those carrying IL1beta2 and IL1RN*2 but not TNF2 as compared to those who did not carry both of these IL-1 cluster genes and were carriers of TNF2 (OR 5.0 (2.4-10.3); P < 0.001). None of the polymorphisms studied was associated with poor prognosis. CONCLUSION: Carriage of IL1beta2 and IL1RN*2 together with non-carriage of TNF2 is associated with increased susceptibility, but not with a prognosis of IgAN.     

Interleukin-1 receptor antagonist genotype is associated with coronary atherosclerosis in patients with type 2 diabetes

Recently, inflammation has received considerable attention in the pathogenesis of both type 2 diabetes and atherosclerosis. The interleukin-1 receptor antagonist (IL-1ra) is a major modulator of the interleukin-1 pro-inflammatory pathway. We studied the relationship between a variable number tandem repeat (VNTR) polymorphism in intron 2 of the IL-1ra gene (IL1RN) and coronary artery disease (CAD) in patients with and without type 2 diabetes, following 787 consecutive patients admitted for suspected CAD. According to the current criteria of the American Diabetes Association, 250 patients had type 2 diabetes. In this group of patients, allele 2 carriers (n = 108) had an increased prevalence of CAD compared with noncarriers (85.2 vs. 73.2%), a difference that remained significant in a multivariate logistic regression model (odds ratio 2.2, 95% CI 1.1-4.3, P = 0.02). No association of CAD with allele 2 carrier status was present among nondiabetic patients (n = 537). Enzyme-linked immunosorbent assays showed decreased baseline plasma levels of IL-1ra in patients with type 2 diabetes, which may in part explain the role of the IL1RN VNTR in these patients.     

No association of the -2518 MCP-1 A/G promoter polymorphism with incidence and clinical course of IgA nephropathy.

BACKGROUND: The clinical course of IgA nephropathy is highly variable, ranging from complete remission to progression with end-stage renal disease. Although the mechanisms involved in disease progression are not characterized in detail, loss of renal function is positively correlated with mononuclear cell infiltration. In general, chemokines play an important role in the directional recruitment of inflammatory cells. Recently, a polymorphism in the distal 5' regulatory region of the chemokine monocyte chemoattractant protein-1 (MCP-1), which affects gene expression, has been described (A/G at position -2518). The aim of our study was to evaluate a possible association of this polymorphism with disease progression in patients with IgA nephropathy, as well as susceptibility to this form of glomerulonephritis. METHODS: Blood samples from 207 patients with biopsy proven IgA nephropathy and 140 ethnically, age and sex-matched healthy controls were collected and genomic DNA was extracted. MCP-1 -2518 genotype was assessed by PCR, followed by restriction fragment length polymorphism analysis. Genotype distribution between the two groups was compared by chi(2) test. Cumulative renal survival was assessed by Kaplan-Meier plot and log-rank analysis. RESULTS: 111 (53.6%) patients had the MCP-1 -2518 wild-type A/A, 83 (40.1%) were heterozygous for the G allele and 13 (6.3%) patients showed homozygosity. The allelic distribution was not significantly different in the control group of 140 healthy blood donors (P = 0.71). Renal survival analysis of patients did not reveal statistically significant differences in cumulative survival (P = 0.32), median survival time and 5 year survival rate between the wild-type group and carriers of the G allele. Furthermore, the number of infiltrating CD68-positive monocytes/macrophages into the kidneys of patients with IgA nephropathy was not statistically different between the groups. CONCLUSION: Our data indicate that no association exists between the -2518 A/G polymorphism and susceptibility to IgA nephropathy or its clinical course.