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Genetic variants associated with circulating parathyroid hormone

Robinson-Cohen, Cassianne
; 
Lutsey, Pamela L.
; 
Kleber, Marcus E.
; 
Nielson, Carrie M.
; 
Mitchell, Braxton D.
; 
Bis, Joshua C.
; 
Eny, Karen M.
; 
Portas, Laura
; 
Eriksson, Joel
; 
Lorentzon, Mattias
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Author
Robinson-Cohen, Cassianne
Lutsey, Pamela L.
Kleber, Marcus E.
Nielson, Carrie M.
Mitchell, Braxton D.
Bis, Joshua C.
Eny, Karen M.
Portas, Laura
Eriksson, Joel
Lorentzon, Mattias
Koller, Daniel L.
Milaneschi, Yuri
Teumer, Alexander
Pilz, Stefan
Nethander, Maria
Selvin, Elizabeth
Tang, Weihong
Weng, Lu-Chen
Wong, Hoi Suen
Lai, Dongbing
Peacock, Munro
Hannemann, Anke
Völker, Uwe
Homuth, Georg
Nauk, Matthias
Murgia, Federico
Pattee, Jack W.
Orwoll, Eric
Zmuda, Joseph M.
Riancho, Jose Antonio
Wolf, Myles
Williams, Frances
Penninx, Brenda
Econs, Michael J.
Ryan, Kathleen A.
Ohlsson, Claes
Paterson, Andrew D.
Psaty, Bruce M.
Siscovick, David S.
Rotter, Jerome I.
Pirastu, Mario
Streeten, Elizabeth
März, Winfried
Fox, Caroline
Coresh, Josef
Wallaschofski, Henri
Pankow, James S.
de Boer, Ian H,
Kestenbaum, Bryan
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.
Keywords
parathyroid hormone, mineral metabolism, human genetics, genome-wide association study
Date
2017
Type
Journal article
Journal
Journal of the American Society of Nephrology
Book
Volume
28
Issue
5
Page Range
1553-1565
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Centre for Education and Innovation
Collections
Mary MacKillop Institute for Health Research
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URI
https://hdl.handle.net/20.500.14802/24282
Relation URI
DOI
10.1681/ASN.2016010069
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Open Access Status
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File Access
Controlled
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