Genetic Variants Associated with Circulating Parathyroid Hormone

Abstract

Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 3 10 253 ), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 3 10 217 ), rs219779 adjacent to CLDN14 (P=3.5 3 10 216 ), rs4443100 near RTDR1 (P=8.7 3 10 29 ), and rs73186030 near CASR (P=4.8 3 10 28). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.

Genetic variants disrupt human RGS14 binding to NHERF1 and regulation of NPT2A-mediated phosphate transport

“…We determined the effects of identified human genetic variants within the PDZ motif of RGS14 on NHERF1 binding, and found that one (Asp 563 Asn) disrupted the RGS14:NHERF1 complex and blocked RGS14 actions. RGS14 is implicated by numerous GWAS studies to be involved in various forms of chronic kidney diseases (14)(15)(16)(17)(18)(19). Relevant to that, we identified here at least one human genetic variant that blocks RGS14 actions on PTH-sensitive phosphate uptake.…”

“…The RGS14 PDZ ligand is present throughout the primate order and in sheep. RGS14 has been implicated by numerous GWAS studies in various forms of chronic human kidney diseases (14)(15)(16)(17)(18)(19). Relevant to that, we identify here one human genetic variant (D563N) that disrupts RGS14 binding to NHERF1 and its capacity to inhibit PTH-sensitive phosphate uptake.…”

“…HA-NHERF1 was generated as described (46). [Nle 8,18 ,Tyr 34 ]PTH(1-34) was from Bachem, Torrance, CA (H9110).…”

“…However, human/primate RGS14 differ from the rodent protein in that they also contain a C-terminal Class I PDZ-recognition sequence. Numerous genomewide association studies have implicated RGS14 in kidney diseases (14)(15)(16)(17)(18)(19), including disordered phosphate metabolism. The RGS14 gene on human chromosome 5 is adjacent to SLC34A1 that encodes the NPT2A sodiumphosphate cotransporter.…”

The Calcium-Sensing Receptor Gene Polymorphism rs1801725 and Calcium-Related Phenotypes in Hemodialysis Patients

“…GWAS concerning serum PTH concentrations in European ancestry showed that among genes showing the most influential association with serum PTH levels are rs6127099 upstream of CYP24A1 that encodes the catabolic enzyme for 1, 25-dihydroxyvitamin D and 25-dihydroxyvitamin D, and rs73186030 near CASR [16]. Other CASR SNPs, rs7652589 [6] and rs1801725 [7], were individually involved in serum PTH levels in HD patients.…”