title: 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 andn=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 ofCYP24A1(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 withinRGS14(P=6.6 × 10-17), rs219779 adjacent toCLDN14(P=3.5 × 10-16), rs4443100 nearRTDR1(P=8.7 × 10-9), and rs73186030 nearCASR(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.
authors.affiliation: Division of Nephrology, Department of Medicine, Kidney Research Institute, cassyrc@uw.edu.|Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington.
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authors.affiliation: Department of Public Health and Preventive Medicine, Oregon Health & Science University, Portland, Oregon.
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authors.affiliation: Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland.|Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland.
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authors.affiliation: Bioinformatics Core Facility, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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authors.affiliation: Department of Epidemiology, Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
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authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Uwe
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authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
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authors.initials: JM
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authors.initials: JA
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authors.affiliation: Department of Twin Research and Genetic Epidemiology, Division of Genetics & Molecular Medicine, King's College, London, United Kingdom.
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authors.affiliation: Institutes for Community Medicine, Department Study of Health in Pomerania - Klinisch-Epidemiologische Forschung (SHIP-KEF), and.|Departments of Health Services and.|Group Health Research Institute, Group Health Cooperative, Seattle, Washington.
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authors.initials: BM
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authors.affiliation: Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington.|The New York Academy of Medicine, New York, New York.|Medicine, University of Washington, Seattle, Washington.
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authors.initials: DS
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authors.initials: JI
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authors.affiliation: Vth Department of Medicine, Mannheim Medical Faculty, Heidelberg University, Mannheim, Germany.|Synlab Academy, Synlab Services GmbH, Mannheim, Germany; and.|Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
authors.forename: Winfried
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authors.affiliation: Department of Genetics and Pharmacogenomics, Merck Research, Whitehouse Station, New Jersey.
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authors.affiliation: Divisions of Epidemiology and Community Health and.
authors.forename: James S
authors.initials: JS
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authors.affiliation: Division of Nephrology, Department of Medicine, Kidney Research Institute.|Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington.
authors.forename: Ian H
authors.initials: IH
authors.lastname: de Boer
authors.affiliation: Division of Nephrology, Department of Medicine, Kidney Research Institute.|Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington.
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mesh_terms: D000328:Adult; D000368:Aged; D005060:Europe; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D010281:Parathyroid Hormone / Q000097:blood* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D010281:Parathyroid Hormone
keywords: genome-wide association study; human genetics; mineral metabolism; parathyroid hormone