DPEP1 Recall by Genotype Study
Research type
Research Study
Full title
DPEP1 Recall by Genotype Study
IRAS ID
297655
Contact name
Ben Challis
Contact email
Sponsor organisation
AstraZeneca
Duration of Study in the UK
1 years, 0 months, 1 days
Research summary
The aim of this RbG study is to recruit individuals with suspected loss-of-function (LoF) mutations in the DPEP1 gene encoding renal Dipeptidase 1 (DPEP1). Blood and urine collected from consenting participants with suspected LoF DPEP1 mutations will be used to measure selected biomarkers to assess the impact of the mutations on DPEP1 activity. Although qualified assays will be used for biochemical evaluations, the study is deemed exploratory.
DPEP1 is the principal enzyme involved in the conversion of the vasoactive and pro-inflammatory lipid mediator leukotriene D4 (LTD4) generated by the 5-lipoxygenase (5-LO) pathway to the relatively inert metabolite leukotriene E4 (LTE4) (Kozak and Tate 1982). It is expressed on microvillar membranes in the brush border of the proximal tubules of kidneys but can also be cleaved from the surface and released into the urine. Due to renal DPEP1 activity, LTE4 can readily be detected in urine from healthy volunteers whilst levels of LTD4 are normally below the level of detection.
In addition to its role in leukotriene metabolism, DPEP1 has also been identified as a dipeptidase responsible for the breakdown of cysteinyl/cystinyl-lysine and as a β-lactamase capable of metabolising β-lactam antibiotics (Campbell et al 1984).
It has been reported that renal DPEP1 expression is lower in patients with chronic kidney disease (CKD) (Berthier et al 2012;Grayson et al 2018;Levin et al 2020) and that DPEP1 activity in the urine is reduced in patients with renal impairment (Fukumura et al 1999; Stokman et al 2019). These observations suggest that the level of the biologically active leukotriene LTD4 and its precursor LTC4 could be elevated in kidneys and urine in CKD patients. This is partly supported by a study that identified an individual believed to carry a LoF mutation in DPEP1 (Mayetepak et al 2005). LTE4 was undetectable in urine obtained from this individual whilst levels of both LTD4 and LTC4 were significantly elevated compared to a range of healthy volunteers. Levels of the DPEP1 dipeptide substrate cystinyl-glycine were also elevated in both urine and plasma, further supporting the hypothesis that the individual carried a LoF mutation in DPEP1. Confirmation of this hypothesis was, however, not possible since consent was not provided to perform any genetic analysis.
A decrease in DPEP1 activity in patients with CKD may have pathological consequences since activity of the 5-LO pathway has been associated with renal dysfunction in both preclinical and clinical studies (Montford et al 2019; Gausch et al, 1999). An increase in 5-LO activity in conjunction with decreased metabolism of LTD4 by DPEP1 may accentuate the potential contribution of leukotrienes to disease progression since LTD4 is significantly more active than the relatively inert LTE4. The primary objective of the present study is to test the link between DPEP1 and LTD4/LTE4 balance by using a genetic approach.REC name
Yorkshire & The Humber - Bradford Leeds Research Ethics Committee
REC reference
21/YH/0195
Date of REC Opinion
2 Sep 2021
REC opinion
Further Information Favourable Opinion