Genetic Variants Associated With Mineral Metabolism Traits in Chronic Kidney Disease

Abstract

Context: 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).

Objective: In this study we aimed to discover genetic variants associated with circulating mineral markers in CKD.

Methods: We conducted candidate single-nucleotide variation (SNV) analysis in 3027 participants in the multiethnic Chronic Renal Insufficiency Cohort (CRIC) to determine the associations between SNVs and circulating levels of mineral markers.

Results: SNVs 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 < .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 < .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 × 10-11) and tubules (P = 4.0 × 10-4).

Conclusion: 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 effect of rs4074995 on the pathogenesis of disordered mineral metabolism in CKD.

Keywords: CKD-MBD; chronic kidney disease; genetics; mineral metabolism.

Figure 1.

Mineral marker associations with rs4074995 within RGS14. Comparison of the associations between RGS14 single-nucleotide polymorphisms between the general population, the Chronic Renal Insufficiency Cohort (CRIC) population, and the CRIC population stratified by White and Black race. Results of model 2 are presented. Phosphate and calcium are presented as mg/dL difference per additional minor allele. Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are presented as percentage difference per additional minor allele.

Figure 2.

The prevalence of abnormal mineral markers by rs4074995 (RGS14) genotype (28). The prevalence of hyperparathyroidism differs by rs4074995 (RGS14) genotype (chi-square P < .0001). The minor allele is A. The AA genotype had the lowest prevalence of hyperparathyroidism. The prevalence of hyperphosphatemia and fibroblast growth factor 23 (FGF23) excess were not significantly different between the genotypes: hyperphosphatemia (chi-square P = .08) and FGF23 excess (chi-square P = .8).

Figure 3.

Expression quantitative loci analysis of RGS14 in renal tissue. A, The minor allele (A) of rs4074995 is associated with decreased gene expression of RGS14 in glomeruli (P = 1.03 × 10^–11). B, The minor allele (A) of rs4074995 is associated with decreased gene expression of RGS14 in renal tubules (P = 3.99 × 10^–4).