Dataset Information

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 × 10-53), 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 × 10-17), rs219779 adjacent to CLDN14 (P=3.5 × 10-16), rs4443100 near RTDR1 (P=8.7 × 10-9), and rs73186030 near CASR (P=4.8 × 10-8). 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.

SUBMITTER: Robinson-Cohen C

PROVIDER: S-EPMC5407713 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Genetic Variants Associated with Circulating Parathyroid Hormone.

Robinson-Cohen Cassianne C Lutsey Pamela L PL Kleber Marcus E ME Nielson Carrie M CM Mitchell Braxton D BD Bis Joshua C JC Eny Karen M KM Portas Laura L Eriksson Joel J Lorentzon Mattias M Koller Daniel L DL Milaneschi Yuri Y Teumer Alexander A Pilz Stefan S Nethander Maria M Selvin Elizabeth E Tang Weihong W Weng Lu-Chen LC Wong Hoi Suen HS Lai Dongbing D Peacock Munro M Hannemann Anke A Völker Uwe U Homuth Georg G Nauk Matthias M Murgia Federico F Pattee Jack W JW Orwoll Eric E Zmuda Joseph M JM Riancho Jose Antonio JA Wolf Myles M Williams Frances F Penninx Brenda B Econs Michael J MJ Ryan Kathleen A KA Ohlsson Claes C Paterson Andrew D AD Psaty Bruce M BM Siscovick David S DS Rotter Jerome I JI Pirastu Mario M Streeten Elizabeth E März Winfried W Fox Caroline C Coresh Josef J Wallaschofski Henri H Pankow James S JS de Boer Ian H IH Kestenbaum Bryan B

Journal of the American Society of Nephrology : JASN 20161207 5

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 (<i>n</i>=22,653 an ...[more]

PMID: 27927781

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Project description:Disorders related to parathyroid hormone (PTH) resistance and PTH signaling pathway impairment are historically classified under the term of pseudohypoparathyroidism (PHP). The disease was first described and named by Fuller Albright and colleagues in 1942. Albright hereditary osteodystrophy (AHO) is described as an associated clinical entity with PHP, characterized by brachydactyly, subcutaneous ossifications, round face, short stature and a stocky build. The classification of PHP is further divided into PHP-Ia, pseudo-PHP (pPHP), PHP-Ib, PHP-Ic and PHP-II according to the presence or absence of AHO, together with an in vivo response to exogenous PTH and the measurement of Gs? protein activity in peripheral erythrocyte membranes in vitro. However, PHP classification fails to differentiate all patients with different clinical and molecular findings for PHP subtypes and classification become more complicated with more recent molecular characterization and new forms having been identified. So far, new classifications have been established by the EuroPHP network to cover all disorders of the PTH receptor and its signaling pathway. Inactivating PTH/PTH-related protein signaling disorder (iPPSD) is the new name proposed for a group of these disorders and which can be further divided into subtypes - iPPSD1 to iPPSD6. These are termed, starting from PTH receptor inactivation mutation (Eiken and Blomstrand dysplasia) as iPPSD1, inactivating Gs? mutations (PHP-Ia, PHP-Ic and pPHP) as iPPSD2, loss of methylation of GNAS DMRs (PHP-Ib) as iPPSD3, PRKAR1A mutations (acrodysostosis type 1) as iPPSD4, PDE4D mutations (acrodysostosis type 2) as iPPSD5 and PDE3A mutations (autosomal dominant hypertension with brachydactyly) as iPPSD6. iPPSDx is reserved for unknown molecular defects and iPPSDn+1 for new molecular defects which are yet to be described. With these new classifications, the aim is to clarify the borders of each different subtype of disease and make the classification according to molecular pathology. The iPPSD group is designed to be expandable and new classifications will readily fit into it as necessary.

Dataset Information

Genetic Variants Associated with Circulating Parathyroid Hormone.

Publications

Genetic Variants Associated with Circulating Parathyroid Hormone.

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