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J Am Soc Nephrol. 2017 May;28(5):1553-1565. doi: 10.1681/ASN.2016010069. Epub 2016 Dec 7.

Genetic Variants Associated with Circulating Parathyroid Hormone.

Author information

1
Division of Nephrology, Department of Medicine, Kidney Research Institute, cassyrc@uw.edu.
2
Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington.
3
Divisions of Epidemiology and Community Health and.
4
Vth Department of Medicine, Mannheim Medical Faculty, Heidelberg University, Mannheim, Germany.
5
Department of Public Health and Preventive Medicine, Oregon Health & Science University, Portland, Oregon.
6
Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
7
Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland.
8
Cardiovascular Health Research Unit, Department of Medicine, and.
9
Program in Genetics & Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
10
Institute of Population Genetics, National Research Council of Italy, Rome, Italy.
11
Department of Internal Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, and.
12
Departments of Medical and Molecular Genetics and.
13
Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, Vrije Universiteit Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
14
Institutes for Community Medicine, Department Study of Health in Pomerania - Klinisch-Epidemiologische Forschung (SHIP-KEF), and.
15
Department of Epidemiology and Biostatistics, EMGO Institute for Health and Care Research, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
16
Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine, and.
17
Bioinformatics Core Facility, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
18
Department of Epidemiology, Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
19
Medicine, Indiana University, Indianapolis, Indiana.
20
Clinical Chemistry and Laboratory Medicine, and.
21
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
22
Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
23
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
24
Department of Medicine, University of Cantabria, and Hospital Universitario Marques de Valdecilla, Insituto de Investigacion Sanitaria, Santander, Spain.
25
Division of Nephrology and Hypertension, Department of Medicine and.
26
Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
27
Department of Twin Research and Genetic Epidemiology, Division of Genetics & Molecular Medicine, King's College, London, United Kingdom.
28
Departments of Health Services and.
29
Group Health Research Institute, Group Health Cooperative, Seattle, Washington.
30
The New York Academy of Medicine, New York, New York.
31
Medicine, University of Washington, Seattle, Washington.
32
Department of Pediatrics and Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles, Medical Center, Institute for Translational Genomics and Population Sciences, Torrance, California.
33
Synlab Academy, Synlab Services GmbH, Mannheim, Germany; and.
34
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
35
Department of Genetics and Pharmacogenomics, Merck Research, Whitehouse Station, New Jersey.
36
Division of Nephrology, Department of Medicine, Kidney Research Institute.

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:

genome-wide association study; human genetics; mineral metabolism; parathyroid hormone

PMID:
27927781
PMCID:
PMC5407713
DOI:
10.1681/ASN.2016010069
[Indexed for MEDLINE]
Free PMC Article

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