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Genetic Variants Associated with Mineral Metabolism Traits in Chronic Kidney Disease.

BACKGROUND AND OBJECTIVES
Chronic kidney disease (CKD) causes multiple interrelated disturbances in mineral metabolism. Genetic studies in the general population have identified common genetic variants associated with circulating phosphate, calcium, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23). In this study we aimed to discover genetic variants associated with circulating mineral markers in Chronic Kidney Disease.


DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS
We conducted candidate SNP analysis in 3,027 participants in the multi-ethnic Chronic Renal Insufficiency Cohort (CRIC) to determine the associations between SNPs and circulating levels of mineral markers.


RESULTS
SNPs adjacent to or within genes encoding the regulator of G protein coupled signaling 14 (RGS14) and the calcium sensing receptor (CASR), were associated with levels of mineral metabolites. The strongest associations (p<0.001) were at rs4074995 (RGS14) for phosphate (0.09 mg/dl lower per minor allele) and FGF23 (8.6 % lower), and at rs1801725 (CASR) for calcium (0.12 mg/dl higher). In addition, the prevalence of hyperparathyroidism differed by rs4074995 (RGS14) genotype (chi square p<0.0001). Differential inheritance by race was noted for the minor allele of RGS14. Expression quantitative loci (eQTL) analysis showed that rs4074995 was associated with lower RGS14 gene expression in glomeruli (p=1.03 x 10 -11) and tubules (p=4.0 x 10 -4).


CONCLUSIONS
We evaluated genetic variants associated with mineral metabolism markers in a CKD population. Participants with CKD and the minor allele of rs4074995 (RGS14) had lower phosphorus, lower plasma FGF23 and lower prevalence of hyperparathyroidism. The minor allele of RGS14 was also associated with lower gene expression in the kidney. Further studies are needed to elucidate the impact of rs4074995 on the pathogenesis of disordered mineral metabolism in CKD.