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=4.2310-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of theminor allele at this SNP associatedwith 7%higher serum PTHconcentration. The other SNPs associatedwith serum PTH concentration included rs4074995 within RGS14 (P=6.6 3 10-17), rs219779 adjacent to CLDN14 (P=3.5310-16), rs4443100 nearRTDR1 (P=8.7310-9), and rs73186030 nearCASR(P=4.8310-8). 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.
Bibliographical noteFunding Information:
The Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA Single Nucleotide Polymorphism Health Association Resource (SHARe) project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, UL1-TR-000040, and DK063491. Support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071258, R01HL071259, by the National Center for Research Resources, Grant UL1RR033176, and the National Center for Advancing Translational Sciences, Grant UL1TR000124. Industry contributors have had no role in the DCCT/EDIC study but have provided free or discounted supplies or equipment to support participants’ adherence to the study: Abbott Diabetes Care (Alameda, CA), Animas (Westchester, PA), Bayer Diabetes Care (North America Headquarters, Tarrytown, NY), Becton Dickinson (Franklin Lakes, NJ), Eli Lilly (Indianapolis, IN), Extend Nutrition (St. Louis, MO), Insulet Corporation (Bedford, MA), Lifescan (Milpitas, CA), Medtronic Diabetes (Minneapolis, MN), Nipro Home Diagnostics (Ft. Lauderdale, FL), Nova Diabetes Care (Billerica, MA), Omron (Shelton, CT), Perrigo Diabetes Care (Allegan, MI), Roche Diabetes Care (Indianapolis, IN), and Sanofi-Aventis (Bridgewater, NJ). The DCCT/EDIC has been supported by cooperative agreement grants (1982–1993, 2012–2017), and contracts (1982–2012) with the Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) (current grant numbers U01 DK094176 and U01 DK094157), and through support by the National Eye Institute, the National Institute of Neurologic Disorders and Stroke, the General Clinical Research Centers Program (1993– 2007), and Clinical Translational Science Center Program (2006– present), Bethesda, MD. Trial Registration: clinicaltrials.gov NCT00360815 and NCT00360893. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694, National Human Genome Research Institute Grant U01HG004402, and National Institutes of Health (NIH) contract HHSN268200625226C. PTH measurements were supported by R01HL103706. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. For the Gothenburg Osteoporosis and Obesity Determinants Study, financial support was received from the Swedish Research Council, the Swedish Foundation for Strategic Research, the Avtal om Läkarutbildning och Forskning (ALF-LUA) research grant in Gothenburg, the Lundberg Foundation, the Torsten and Ragnar Söderberg’s Foundation, the Västra Götaland Foundation, the Göteborg Medical Society, the Novo Nordisk foundation, and the European Commission grant HEALTH-F2-2008-201865-GEFOS. The work within the Indiana Sisters cohort was supported by NIH Grant R01AG041517. Genotyping services were provided by Center for Inherited Disease Research, which is fully funded through a federal contract from the NIH to the Johns Hopkins University (contract HHSN268200782096C). This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. The Osteoporotic Fractures in Men Study is supported by NIH funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences, and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. C.M.N.’s work is supported by NIAMS: K01AR062655. For the Netherlands Study of Depression and Anxiety, funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10-000-1002), the Center for Medical Systems Biology (CSMB, NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University’s Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, and the NIH (R01D0042157-01A, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network of the Foundation for the NIH. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by The Netherlands Organisation for Scientific Research. Funding for the Amish studies was provided by R01 AR46838 and P30 DK072488.The Study of Health in Pomerania is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg–West Pomerania. The University of Greifswald is a member of the ‘Center of Knowledge Interchange’ program of the Siemens Aktiengesellschaft and the Caché Campus program of the InterSystems GmbH. E.S. was supported by NIH/NIDDK grant K24DK106414. For the Ludwigshafen Risk and Cardiovascular Health study, the genotyping was funded by the Seventh Framework Program AtheroRemo (grant agreement number 201668) of the European Union and the analyses were supported by the Seventh Framework Program RiskyCAD (grant agreement number 305739). The TwinsUK study was funded by the Wellcome Trust, European Community’s Seventh Frame-work Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research–funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ National Health Service Foundation Trust in partnership with King’s College London. Single nucleotide polymorphism genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/Center for Inherited Disease Research. The Cardiovascular Health Study (CHS) research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and NHLBI grants U01HL080295, R01HL087652, R01HL085251, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01AG023629 from the NIA. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. Infrastructure for the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium is supported in part by the NHLBI grant R01HL105756.
B.K. reports receiving consulting fees and grant support from Amgen Inc. (Thousand Oaks, CA). I.H.d.B. reports receiving research support from Abbvie (Chicago, IL), MedTronic (Minneapolis, MN), and Abbott (Chicago, IL), and consulting fees from Amgen Inc., Bayer (Leverkusen, Germany), and Janssen (Beerse, Belgium). B.M.P. serves on the Data and Safety Monitoring Board of a clinical trial of a device funded by the manufacturer (Zoll LifeCor Corp.; Pittsburgh, PA) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson (New Brunswick, NJ).