Freedman B I, Yu H, Spray B J, Rich S S, Rothschild C B, Bowden D W
Department of Internal Medicine/Section on Nephrology, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina, USA.
Kidney Int. 1997 Mar;51(3):819-25. doi: 10.1038/ki.1997.115.
Hypertension, diabetes mellitus and chronic glomerular diseases reportedly cause in excess of 80% of the incident cases of end-stage renal disease (ESRD) in the U.S. The factors that initiate progressive renal failure in patients with these disorders remain unknown. Several investigators have reported enhanced synthesis and activity of cytokines in the kidneys of patients with renal failure. The ensuing inflammation and fibrosis have been postulated to contribute to the development of progressive renal failure. There is also abundant evidence supporting the contribution of genetic factors in ESRD susceptibility based upon the strong familial clustering of ESRD, particularly in African Americans. Therefore, genetic linkage analysis may be useful to evaluate the role of candidate genes in several cytokine cascades that could contribute to the pathogenesis of chronic renal failure. We tested for genetic linkage between eight cytokine candidate genes and chronic renal failure in a collection of African American sibling pairs concordant for ESRD. Epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF) beta 1, TGF-beta 2 and TGF-beta 3, and tumor necrosis factor (TNF)-alpha and TNF-beta candidate genes were selected for analysis due to their putative roles in diabetic renal disease and chronic glomerulonephritis. The interleukin-1 receptor antagonist gene (IL1RN) was also genotyped due to its reported association with diabetic nephropathy. Non-parametric (genetic model independent) affected sib pair linkage analysis was used to evaluate evidence for linkage. In order to genotype TGF-beta 3, we identified four closely linked, previously unidentified, highly polymorphic microsatellite loci near the TGF-beta 3 gene. Linkage of ESRD and transforming growth factor beta 2 polymorphisms on human chromosome 1 approached significance for non-diabetic nephropathy (predominantly chronic glomerular disease, hypertensive nephrosclerosis and unknown etiology) (P = 0.08), but showed no linkage to diabetic nephropathy. The other candidate loci did not demonstrate linkage to ESRD in the total population or in the subgroups with diabetic or non-diabetic etiologies of ESRD. The IL1RN gene did not show significant evidence for linkage to ESRD; however, we did confirm an association between allele 2 of IL1RN and ESRD (as reported in diabetic nephropathy). Overall, these results suggest that these growth factor loci do not make major contributions to the pathogenesis of ESRD in African Americans.
据报道，在美国，超过80%的终末期肾病（ESRD）新发病例由高血压、糖尿病和慢性肾小球疾病引起。这些疾病患者引发进行性肾衰竭的因素仍不清楚。几位研究人员报告称，肾衰竭患者肾脏中细胞因子的合成和活性增强。由此产生的炎症和纤维化被认为与进行性肾衰竭的发展有关。基于ESRD的强烈家族聚集性，尤其是在非裔美国人中，也有大量证据支持遗传因素在ESRD易感性中的作用。因此，基因连锁分析可能有助于评估候选基因在几个可能导致慢性肾衰竭发病机制的细胞因子级联反应中的作用。我们在一组ESRD一致的非裔美国同胞对中测试了八个细胞因子候选基因与慢性肾衰竭之间的基因连锁。由于表皮生长因子（EGF）、血小板衍生生长因子（PDGF）、转化生长因子（TGF）β1、TGF-β2和TGF-β3以及肿瘤坏死因子（TNF）-α和TNF-β候选基因在糖尿病肾病和慢性肾小球肾炎中可能发挥的作用，因此选择它们进行分析。白细胞介素-1受体拮抗剂基因（IL1RN）也因其与糖尿病肾病的报道关联而进行基因分型。使用非参数（独立于遗传模型）受累同胞对连锁分析来评估连锁证据。为了对TGF-β3进行基因分型，我们在TGF-β3基因附近鉴定了四个紧密连锁、先前未鉴定的高度多态性微卫星位点。人类染色体1上ESRD与转化生长因子β2多态性的连锁对于非糖尿病肾病（主要是慢性肾小球疾病、高血压性肾硬化和病因不明）接近显著水平（P = 0.08），但与糖尿病肾病无连锁关系。其他候选位点在总人群或ESRD糖尿病或非糖尿病病因亚组中均未显示与ESRD的连锁关系。IL-1RN基因未显示与ESRD连锁的显著证据；然而，我们确实证实了IL1RN的2等位基因与ESRD之间的关联（如糖尿病肾病中所报道）。总体而言，这些结果表明这些生长因子位点对非裔美国人ESRD的发病机制没有重大贡献。
