ECE1 gene variant shows tendency toward chronic kidney disease advancement among autosomal polycystic kidney disease patients

Abstract

Background/Purpose

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by numerous epithelium-lined cysts in the kidney and is the leading genetic cause of end-stage renal disease worldwide. Endothelin-1 is a potent vasoactive peptide implicated in the regulation of basal vascular tone. Endothelin (ET)-converting enzyme 1 (ECE1) is well known for its critical role in the process of ET.

Methods

We investigated ECE1 gene variants to unravel ECE1 modifier effects associated with renal disease progression in ADPKD. Three ECE1 functional polymorphisms [rs213046 (−839 A>C), rs213045 (−338 G>T), and rs1076669 (Thr338Ile)] were genotyped using a fluorescence resonance energy transfer-based KASPar method in 106 ADPKD patients and 112 healthy participants. A Chi-square test was used to determine the relationship between ADPKD and ECE1 variants, and multivariate logistic regression analysis was performed to assess the effect of ECE1 variants on chronic kidney disease (CKD) progression. Mantel-Haenszel stratified analysis was performed to assess relationships between different CKD stages, hypertension, and their interaction.

Results

All loci are polymorphic and followed a Hardy-Weinberg equilibrium. Distribution of ECE1 genotypes in controls and ADPKD groups was not statistically significant, and linkage disequilibrium was not strong between pairs of single-nucleotide polymorphisms. The rs213046 variant genotypes were overrepresented in advanced CKD stages (p = 0.031).

Conclusion

Significant confounding effects of hypertension on CKD progression in ADPKD were observed. These results suggested that the ECE1 gene variant is a modifier of CKD advancement among ADPKD patients.

背景

自體顯性多囊性腎病 (ADPKD) 的特點，是腎臟呈現相當多由上皮構成的囊腫，在全球是導致末期腎病 (ESRD) 的主要遺傳性原因。Endothelin-1 (ET-1) 是一種具有高度血管活性的胜肽，被認為與基礎血管張力的調節有關。眾所周知，endothelin (ET) 轉化酵素 1 (ECE1) 則在 ET 代謝上佔有重要的角色。

方法

在本研究中，我們調查了在 ADPKD 患者間，ECE1 基因變體與 CKD 病情發展的可能關聯。我們採用以 FRET 為基礎的 KASPar 方法，對 106 位 ADPKD 患者及 112 位健康人士，作出 3 種 ECE1 功能性多態性 [rs213046 (-839 A>C)、rs213045 (-338 G>T) 及 rs1076669 (Thr338Ile)] 的基因型辨識。對於 ADPKD 與 ECE1 基因變體的關聯，我們採取卡方檢驗；ECE1 基因變體與 CKD 病情發展的關聯，以多變項邏輯迴歸進行分析；CKD 分期與高血壓的關聯及兩者的交互作用，則採用 Mantel-Haenszel 分層分析。

結果

所有基因座 (loci) 均呈現多態性，且遵循 Hardy-Weinberg 平衡。ADPKD 患者與對照組間的 ECE1 基因型分佈並無明顯差別。單核苷酸多態性鹼基對 (SNP pairs) 之間，並未呈現出明顯的連鎖不平衡 (LD)。在晚期 CKD 患者間，rs213046 變體基因型呈現過度的表達 (p = 0.031)。

結論

我們觀察到，在 ADPKD 患者間，高血壓是 CKD 病情發展的一個明顯的干擾因素。以上結果意味著，在 ADPKD 患者間，ECE1 基因變體可影響 CKD 的病情發展。