Associations between single nucleotide polymorphisms in the calcium sensing receptor and chronic kidney disease-mineral and bone disorder in cats

R.F Geddes,R.E Jepson,Y Forcada,J Elliott,H.M Syme

doi:10.1016/j.tvjl.2018.02.010

R.F Geddes, R.E Jepson + Show 3 more

Open Access

https://doi.org/10.1016/j.tvjl.2018.02.010

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Abstract

Feline chronic kidney disease (CKD) is associated with high variability in severity of CKD-mineral and bone disorder (CKD-MBD). The calcium sensing receptor (CaSR) regulates circulating parathyroid hormone (PTH) and calcium concentrations. Single nucleotide polymorphisms (SNPs) in the CaSR are associated with severity of secondary renal hyperparathyroidism and total calcium concentrations in human patients receiving haemodialysis. The objective of this study was to explore associations between polymorphisms in the feline CaSR (fCaSR) and biochemical changes observed in CKD-MBD.Client owned cats (≥9years) were retrospectively included. SNP discovery was performed in 20 cats with azotaemic CKD and normal or dysregulated calcium concentrations. Non-pedigree cats (n=192) (125 with azotaemic CKD and 66 healthy), Persians (n=40) and Burmese (n=25) were genotyped for all identified SNPs using KASP. Biochemical parameters from the date of CKD diagnosis or from first visit to the clinic (healthy cats) were used. Associations between genotype and ionized calcium, total calcium, phosphate, PTH and FGF-23 were performed for non-pedigree cats using logistic regression.Sequence alignment against the fCaSR sequence revealed eight novel exonic SNPs. KASP genotyping had high accuracy (99.6%) and a low failure rate (<6%) for all SNPs. Allele frequencies varied between breeds. In non-pedigree cats, one synonymous SNP CaSR:c.1269G>A was associated with logPTH concentration (adjusted for plasma creatinine concentration), with a recessive model having the best fit (G/G vs A/A-G/A, P=0.031).Genetic variation in the fCaSR is unlikely to explain the majority of the variability in presence and severity of CKD-MBD in cats.

Highlights

Decreased glomerular filtration rate in chronic kidney disease (CKD) leads to phosphate retention and disruption to calcium-phosphate homeostasis, which can lead to renal osteodystrophy
All three were in the intracellular tail of the fCaSR, in a nearby location to three non-synonymous Single nucleotide polymorphisms (SNPs) identified in humans: p.Ala986Ser, I p.Arg990Gly, p.Gln1011Glu (Heath et al, 1996)
The haplotype CR of these SNPs accounts for 49.1 % of variation in ionised serum S calcium concentrations (Scillitani et al, 2004) and a meta-analysis of 11 studies examining U p.Ala986Ser found a strong association between this SNP and total and ionised calcium AN concentrations but no association with parathyroid hormone (PTH) concentration (He et al, 2012)

Summary

Introduction

Decreased glomerular filtration rate in chronic kidney disease (CKD) leads to phosphate retention and disruption to calcium-phosphate homeostasis, which can lead to renal osteodystrophy. The term CKD-mineral and bone disorder (CKD-MBD) is used to describe these abnormalities in humans (Moe et al, 2006). The biochemical changes involved in CKD-MBD have been documented in azotaemic cats, including. T hyperphosphataemia, hypocalcaemia, hyperparathyroidism (Barber and Elliott, 1998) and IP elevations in the phosphatonin fibroblast growth factor 23 (FGF-23) (Geddes et al, 2013). For as yet undetermined reasons, S cats with similar degrees of CKD show marked individual variation in the presence and severity ANU of CKD-MBD (Barber and Elliott, 1998; Geddes et al, 2013).

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