功能性激肽释放酶-1 启动子多态性与急性肾损伤的关联：病例对照和纵向队列研究。

Association of functional kallikrein-1 promoter polymorphisms and acute kidney injury: a case-control and longitudinal cohort study.

机构信息

Department of Medicine, Division of Nephrology, Kidney and Dialysis Research Laboratory, St. Elizabeth's Medical Center, Boston, Mass., USA.

出版信息

Nephron Clin Pract. 2012;122(3-4):107-13. doi: 10.1159/000350733. Epub 2013 Apr 25.

DOI:10.1159/000350733

PMID:23635481

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3700581/

Abstract

BACKGROUND

Kallikrein-1 (KLK1) is a highly conserved serine protease that is expressed in the kidney and involved in blood pressure regulation. The activity of this enzyme is diminished in acute kidney injury (AKI).

METHODS

We first evaluated the potential role of functional multiallelic KLK1 promoter gene polymorphisms in a case-control study of 481 subjects (214 hospitalized patients with AKI of mixed causes and 267 healthy subjects). The complex, multiallelic G/C-rich repeat region of the proximal KLK1 promoter was determined by direct Sanger/capillary resequencing.

RESULTS

16 alleles were identified in a complex, polymorphic G/C-rich region of the KLK1 proximal promoter; 5 of these alleles (F, G, H, I, and K) were associated with development of AKI. Alleles I and G were classified as risk-alleles (unadjusted OR 1.86; 95% CI 1.23, 2.81; p = 0.003), whereas alleles F, H, and K were classified as protective-alleles (unadjusted OR 0.32; 95% CI 0.22, 0.46; p < 0.001) according to their directional association with development of AKI. After adjustment for sex, race, preexisting chronic kidney disease and APACHE II score, the KLK1 risk-allele (I or G) carrier state was associated with the composite of ≥2-fold increase in serum creatinine, oliguria, or dialysis requirement (adjusted OR 2.71; 95% CI 1.14, 6.44; p = 0.02). The KLK1 risk-allele carrier state was also marginally associated with the composite of ≥2-fold increase in serum creatinine, oliguria, dialysis requirement, or in-hospital death (adjusted OR 2.33; 95% CI 0.98, 5.52; p = 0.06).

CONCLUSIONS

KLK1 promoter polymorphisms are associated with development of AKI and adverse outcomes. Further studies are needed to validate these findings.

摘要

背景

激肽释放酶 1（KLK1）是一种高度保守的丝氨酸蛋白酶，在肾脏中表达，参与血压调节。这种酶的活性在急性肾损伤（AKI）中降低。

方法

我们首先在一项包含 481 名受试者的病例对照研究中评估了功能性多等位基因 KLK1 启动子基因多态性的潜在作用（214 名患有混合病因 AKI 的住院患者和 267 名健康受试者）。KLK1 启动子近端的复杂、多态性 G/C 丰富重复区通过直接 Sanger/毛细管测序确定。

结果

在 KLK1 近端启动子的复杂、多态性 G/C 丰富区鉴定出 16 个等位基因；其中 5 个等位基因（F、G、H、I 和 K）与 AKI 的发生有关。等位基因 I 和 G 被归类为风险等位基因（未调整的 OR 1.86；95%CI 1.23，2.81；p = 0.003），而等位基因 F、H 和 K 则被归类为保护等位基因（未调整的 OR 0.32；95%CI 0.22，0.46；p < 0.001），根据它们与 AKI 发生的定向关联。在调整性别、种族、预先存在的慢性肾脏疾病和 APACHE II 评分后，KLK1 风险等位基因（I 或 G）携带者状态与血清肌酐、少尿或透析需求增加 2 倍以上的复合结果相关（调整后的 OR 2.71；95%CI 1.14，6.44；p = 0.02）。KLK1 风险等位基因携带者状态也与血清肌酐、少尿、透析需求或住院死亡增加 2 倍以上的复合结果呈边缘相关（调整后的 OR 2.33；95%CI 0.98，5.52；p = 0.06）。