原发性 IgA 肾病在 TGF-β1 高分泌者中更为严重。

Primary IgA nephropathy is more severe in TGF-beta1 high secretor patients.

机构信息

Department of Biomedical and Surgical Sciences, Division of Nephrology, University of Verona, Verona, Italy.

出版信息

J Nephrol. 2009 Nov-Dec;22(6):747-59.

PMID:19967654

Abstract

BACKGROUND

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and is characterized by extremely variable clinical and morphological features and outcome. TGF-beta1 has a key role in fibrogenesis and the progression of renal damage. Its production is under genetic control.

METHODS

We recruited 105 Italian biopsy-proven IgAN patients for genotyping for the TGF-beta1 C-509T, T869C (COD 10) and G915C (COD 25) polymorphisms; 200 healthy blood donors were used as normal controls. Glomerular and interstitial mRNA levels of TGF-beta1 were assessed by real-time PCR in 34 patients to seek relationships with clinical, renal histopathological features and outcome.

RESULTS

The genotype distributions in the IgAN population were not statistically different from the controls. The COD 10 TT genotype was associated with more severe histological damage as assessed by Lee's classification (CC 50%, CT 39.6% and TT 17.2% were graded as mild; CC 35.7%, CT 43.7% and TT 44.8% as moderate, and CC 14.3%, CT 16.7% and TT 37.9% as severe [p=0.0049]) and with severe interstitial infiltrates (CC 10.4%, CT 35.2% and TT 54.2% [p=0.03]). A higher interstitial immunodeposition was observed for TGF-beta1, collagen IV and alpha-SMA in patients with the COD 10 T allele (p=0.045, p=0.049, p=0.032, respectively). The T allele was associated with significantly higher TGF-beta1 mRNA levels in the interstitium (TT+CT vs. CC: 0.52 +/- 0.16 vs. 0.18 +/- 0.10 copies/mL, respectively; p=0.000). The T allele was also associated with higher mRNA levels in glomeruli, though the difference was not statistically significant. Finally, the T allele was significantly associated with a worse prognosis, the end points being reached by 40% of TT+CT and 32% of CC patients (p=0.009).

CONCLUSIONS

In primary IgA nephropathy, the T allele of the TGF-beta1 COD 10 C/T polymorphism seems to be associated with more severe histological lesions, higher renal TGF-beta1 mRNA levels and a worse prognosis. This polymorphism seems to be functionally relevant and to have a prognostic impact.

摘要

背景

IgA 肾病（IgAN）是全球最常见的原发性肾小球肾炎，其临床和形态学表现及预后具有极强的可变性。TGF-β1 在纤维化和肾脏损害进展中具有关键作用。其产生受遗传控制。

方法

我们招募了 105 名意大利经活检证实的 IgAN 患者进行 TGF-β1 C-509T、T869C（COD10）和 G915C（COD25）多态性的基因分型；200 名健康献血者作为正常对照。通过实时 PCR 检测 34 例患者的肾小球和间质 TGF-β1mRNA 水平，以寻找与临床、肾脏组织病理学特征和预后的关系。

结果

IgAN 人群的基因型分布与对照组无统计学差异。Lee 分级评估的组织学损伤越严重，COD10 TT 基因型的比例越高（CC 为 50%，CT 为 39.6%，TT 为 17.2%为轻度；CC 为 35.7%，CT 为 43.7%，TT 为 44.8%为中度，CC 为 14.3%，CT 为 16.7%，TT 为 37.9%为重度[P=0.0049]），间质浸润也越严重（CC 为 10.4%，CT 为 35.2%，TT 为 54.2%[P=0.03]）。T 等位基因与 TGF-β1、胶原 IV 和 α-SMA 的间质免疫沉积较高有关（P=0.045，P=0.049，P=0.032，分别）。T 等位基因与间质 TGF-β1mRNA 水平显著升高相关（TT+CT 与 CC：0.52+/-0.16 与 0.18+/-0.10 拷贝/mL，P=0.000）。T 等位基因也与肾小球中更高的 mRNA 水平相关，尽管差异无统计学意义。最后，T 等位基因与预后不良显著相关，TT+CT 和 CC 患者的终点分别达到 40%和 32%（P=0.009）。