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2017 ; 28
(5
): 1553-1565
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Genetic Variants Associated with Circulating Parathyroid Hormone
#MMPMID27927781
Robinson-Cohen C
; Lutsey PL
; Kleber ME
; Nielson CM
; Mitchell BD
; Bis JC
; Eny KM
; Portas L
; Eriksson J
; Lorentzon M
; Koller DL
; Milaneschi Y
; Teumer A
; Pilz S
; Nethander M
; Selvin E
; Tang W
; Weng LC
; Wong HS
; Lai D
; Peacock M
; Hannemann A
; Völker U
; Homuth G
; Nauk M
; Murgia F
; Pattee JW
; Orwoll E
; Zmuda JM
; Riancho JA
; Wolf M
; Williams F
; Penninx B
; Econs MJ
; Ryan KA
; Ohlsson C
; Paterson AD
; Psaty BM
; Siscovick DS
; Rotter JI
; Pirastu M
; Streeten E
; März W
; Fox C
; Coresh J
; Wallaschofski H
; Pankow JS
; de Boer IH
; Kestenbaum B
J Am Soc Nephrol
2017[May]; 28
(5
): 1553-1565
PMID27927781
show ga
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.
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