Oral Presentation ESA-SRB-NZSE-CaSR 2026 in conjunction with ENSA

  From association to mechanism: rs838717 in regulation of DGKD and CaSR signalling in kidney stone disease (141926)

Catherine E Lovegrove 1 2 , Michelle Goldsworthy 2 , Michael V Holmes 3 , Dominic Furniss 2 , Rajesh V Thakker 2 , Sarah A Howles 2
  1. University of Glasgow, Glasgow, SCOTLAND, United Kingdom
  2. University of Oxford, Oxford, United Kingdom
  3. University of Bristol, Bristol, United Kingdom

Background:

Gain of function mutations in the calcium-sensing receptor (CaSR) result in autosomal dominant hypocalcaemia, featuring hypercalciuria, which can be associated with nephrocalcinosis and nephrolithiasis. We previously identified a non-coding, intronic variant, rs838717-G, of DGKD, encoding diacylglycerol kinase δ (DGKδ), implicated in CaSR signalling, as a candidate causal variant associated with nephrolithiasis, higher serum calcium, and lower serum phosphate concentrations. However, the molecular mechanisms linking rs838717 to nephrolithiasis susceptibility remain unknown.

 

Aim:

To define the regulatory mechanisms by which rs838717 influences gene expression and effector gene(s) mediating its association with nephrolithiasis .

 

Methods:

We analysed chromatin accessibility, co-accessibility, gene activity, and RNA expression across renal cell types using integrated single-cell multiomic datasets (snRNA-seq, snATAC-seq). We performed chromatin conformational capture (Capture-C) in renal cells (RPTEC, HK2, and HEK293) to identify physical interactions between the rs838717 locus and candidate gene promoters.

 

Results:

We identified correlations between regulatory activity at rs838717 and expression of five genes (INPP5D, NGEF, DGKD, UGT1A6, and USP40; Pearson r2>0.77, P<0.05). DGKD, NGEF, UGT1A6, and USP40 showed enriched activity and expression in proximal tubule cells.

 

Capture-C analyses confirmed reproducible chromatin interactions between the rs838717 region and the promoters of two genes (DGKD, USP40) across all cell lines, indicating that rs838717 influences their transcription (Marginal posterior probability of contact≥0.01). These findings provide a mechanistic link between rs838717 and altered CaSR signalling with the established role of DGKδ in CaSR signal transduction. USP40, ~181 kb downstream of rs838717, encodes a deubiquitinating enzyme and has been associated with circulating calcium, phosphate, and urate concentrations.

 

Conclusions:

Our  study, which integrates chromatin interaction data with known gene functions, advances rs838717 from a candidate causal variant to a mechanistically-characterised nephrolithiasis locus that alters CaSR signalling and potentially ubiquitination. Additionally, our findings provide a framework for resolving causal genes and mechanisms at complex disease loci.

  1. Lovegrove CE, et al. Genetic variants predisposing to an increased risk of kidney stone disease. J Clin Invest. 2025;135(15):e186915.