Genetic Variants Associated With Mineral Metabolism Traits in Chronic Kidney Disease

Marciana L Laster; Bryce Rowan; Hua-Chang Chen; Tae-Hwi Schwantes-An; Xin Sheng; Peter A Friedman; T Alp Ikizler; Janet S Sinshiemer; Joachim H Ix; Katalin Susztak; Ian H de Boer; Bryan Kestenbaum; Adriana Hung; Sharon M Moe; Farzana Perwad; Cassianne Robinson-Cohen

doi:10.1210/clinem/dgac318

Genetic Variants Associated With Mineral Metabolism Traits in Chronic Kidney Disease

J Clin Endocrinol Metab. 2022 Aug 18;107(9):e3866-e3876. doi: 10.1210/clinem/dgac318.

Authors

Marciana L Laster¹, Bryce Rowan², Hua-Chang Chen², Tae-Hwi Schwantes-An³, Xin Sheng⁴, Peter A Friedman⁵, T Alp Ikizler^{6

7}, Janet S Sinshiemer^{8

9}, Joachim H Ix¹⁰, Katalin Susztak⁴, Ian H de Boer¹¹, Bryan Kestenbaum¹², Adriana Hung⁶, Sharon M Moe^{13

14}, Farzana Perwad¹⁵, Cassianne Robinson-Cohen^{6

7}

Affiliations

¹ Department of Pediatrics, University of California, Los Angeles, Los Angeles, California 90095-1752, USA.
² Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
³ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
⁴ Department of Medicine and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
⁵ Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
⁶ Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁷ Vanderbilt O'Brien Center for Kidney Disease, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
⁸ Department of Human Genetics and Computational Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1752, USA.
⁹ Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, California 90095-1752, USA.
¹⁰ Department of Medicine, University of California, San Diego, San Diego, California 92161, USA.
¹¹ Department of Medicine, University of Washington, Seattle, Washington 98195-6420, USA.
¹² Kidney Research Institute, University of Washington, Seattle, Washington 98195-6420, USA.
¹³ Clinical Translational Sciences Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
¹⁴ Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
¹⁵ Department of Pediatrics, University of California, San Francisco, San Francisco, California 94143, USA.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Biomarkers
Calcium*
Fibroblast Growth Factors / genetics
Humans
Minerals / metabolism
Parathyroid Hormone
Phosphates
Receptors, Calcium-Sensing
Renal Insufficiency, Chronic* / epidemiology
Renal Insufficiency, Chronic* / genetics

Substances

Biomarkers
Minerals
Parathyroid Hormone
Phosphates
Receptors, Calcium-Sensing
Fibroblast Growth Factors
Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding