Endocrine Abstracts

Kidney stone disease (KSD) is a recurrent condition with limited prophylactic therapies. This study aimed to use Mendelian randomisation (MR) and colocalization analyses to identify novel drug targets for KSD. Utilising UK Biobank genome-wide association study data for MR, we identified forty-nine 1Mbp regions where genetic loci increase risk of KSD via effects on albumin-adjusted serum calcium or phosphate concentrations. Multi-trait statistical colocalization analyses identified full colocalization of KSD, serum calcium and phosphate concentrations in three regions (posterior probability>0.99) harbouring likely causal variants associated with DGKD (rs838717-G), SLC34A1 (rs10051765-C), and CYP24A1 (rs6127099-A). DGKD encodes diacylglycerol kinase delta, implicated in the calcium-sensing receptor (CaSR) signalling pathway; rs838717 (G) associates with higher serum calcium and lower phosphate concentrations, consistent with impaired CaSR-signal transduction. SLC34A1 encodes the renal sodium-phosphate transport protein 2A (NPT2a). Biallelic loss-of-function mutations in NPT2a cause idiopathic infantile hypercalcaemia (IIH) type 2 via increased renal phosphate excretion. IIH type 2 can be successfully treated with oral phosphate supplementation; rs10051765 (C) is associated with higher serum calcium and lower phosphate concentrations, consistent with renal phosphate leak. CYP24A1 encodes 24-hydroxylase which inactivates 1,25 hydroxyvitamin-D. Biallelic loss-of-function mutations in 24-hydroxylase cause IIH type 1; rs6127099 (A) is associated with higher serum calcium and phosphate concentrations, consistent with increased vitamin-D activation. Using drug target MR we demonstrated the potential utility of reducing serum calcium concentrations via genes implicated in CaSR-signalling (CASR OR=0.67, 95%CI=0.48-0.93, P=0.02) or vitamin-D activation (CYP24A1 OR=0.04, 95%CI=0.02-0.10, P=1.49x10-14) to prevent KSD. There were insufficient genetic instruments to confirm whether elevation of serum phosphate concentrations via SLC34A1 may reduce risk of KSD. These findings indicate that positive allosteric modulators of the CaSR or alteration of vitamin-D metabolism may represent novel therapeutic approaches to prevent KSD.