Association of Human FOS Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study

Huber, René; Kirsten, Holger; Näkki, Annu; Pohlers, Dirk; Thude, Hansjörg; Eidner, Thorsten; Heinig, Matthias; Brand, Korbinian; Ahnert, Peter; Kinne, Raimund W.

doi:10.3390/ijms20061382

Open AccessArticle

Association of Human FOS Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study

by

René Huber

^1,2,†

,

Holger Kirsten

^{3,4,5,6,*,†}

,

Annu Näkki

^7,8,

Dirk Pohlers

^1,‡,

Hansjörg Thude

^9,§,

Thorsten Eidner

¹⁰,

Matthias Heinig

¹¹,

Korbinian Brand

²,

Peter Ahnert

^3,4

and

Raimund W. Kinne

¹

Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkrankenhaus ‘Rudolf Elle’, 07607 Eisenberg, Germany

²

Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany

³

Institute of Medical Informatics, Statistics, and Epidemiology, Universität Leipzig, 04107 Leipzig, Germany

⁴

LIFE–Leipzig Research Center for Civilization Diseases, Universität Leipzig, 04103 Leipzig, Germany

⁵

Translational Centre for Regenerative Medicine (TRM), Universität Leipzig, 04103 Leipzig, Germany

⁶

Fraunhofer Institute for Cell Therapy and Immunology IZI, 04103 Leipzig, Germany

⁷

Institute for Molecular Medicine Finland FIMM, University of Helsinki, 00014 Helsinki, Finland

⁸

Public Health Genomics Unit, National Institute for Health and Welfare, 00271 Helsinki, Finland

⁹

Institute of Transfusion Medicine, Jena University Hospital, 07747 Jena, Germany

¹⁰

Department of Internal Medicine III, Division of Rheumatology & Osteology, Jena University Hospital, 07747 Jena, Germany

¹¹

Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany

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^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

^‡

Present Address: Center for Diagnostic, Klinikum Chemnitz, 09116 Chemnitz, Germany.

^§

Present Address: Department of Hepatobiliary and Transplant Surgery, Transplantation Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Int. J. Mol. Sci. 2019, 20(6), 1382; https://doi.org/10.3390/ijms20061382

Submission received: 31 January 2019 / Revised: 13 March 2019 / Accepted: 15 March 2019 / Published: 19 March 2019

(This article belongs to the Special Issue Osteoarthritis and Cartilage Regeneration: Focus on Pathophysiology and Molecular Mechanisms)

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Abstract

Our aim was to analyse (i) the presence of single nucleotide polymorphisms (SNPs) in the JUN and FOS core promoters in patients with rheumatoid arthritis (RA), knee-osteoarthritis (OA), and normal controls (NC); (ii) their functional influence on JUN/FOS transcription levels; and (iii) their associations with the occurrence of RA or knee-OA. JUN and FOS promoter SNPs were identified in an initial screening population using the Non-Isotopic RNase Cleavage Assay (NIRCA); their functional influence was analysed using reporter gene assays. Genotyping was done in RA (n = 298), knee-OA (n = 277), and NC (n = 484) samples. For replication, significant associations were validated in a Finnish cohort (OA: n = 72, NC: n = 548). Initially, two SNPs were detected in the JUN promoter and two additional SNPs in the FOS promoter in perfect linkage disequilibrium (LD). JUN promoter SNP rs4647009 caused significant downregulation of reporter gene expression, whereas reporter gene expression was significantly upregulated in the presence of the FOS promoter SNPs. The homozygous genotype of FOS promoter SNPs showed an association with the susceptibility for knee-OA (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.2–3.7, p = 0.0086). This association was successfully replicated in the Finnish Health 2000 study cohort (allelic OR 1.72, 95% CI 1.2–2.5, p = 0.006). FOS Promoter variants may represent relevant susceptibility markers for knee-OA.

Keywords: AP-1; JUN; FOS; promoter; knee osteoarthritis

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MDPI and ACS Style

Huber, R.; Kirsten, H.; Näkki, A.; Pohlers, D.; Thude, H.; Eidner, T.; Heinig, M.; Brand, K.; Ahnert, P.; Kinne, R.W. Association of Human FOS Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study. Int. J. Mol. Sci. 2019, 20, 1382. https://doi.org/10.3390/ijms20061382

AMA Style

Huber R, Kirsten H, Näkki A, Pohlers D, Thude H, Eidner T, Heinig M, Brand K, Ahnert P, Kinne RW. Association of Human FOS Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study. International Journal of Molecular Sciences. 2019; 20(6):1382. https://doi.org/10.3390/ijms20061382

Chicago/Turabian Style

Huber, René, Holger Kirsten, Annu Näkki, Dirk Pohlers, Hansjörg Thude, Thorsten Eidner, Matthias Heinig, Korbinian Brand, Peter Ahnert, and Raimund W. Kinne. 2019. "Association of Human FOS Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study" International Journal of Molecular Sciences 20, no. 6: 1382. https://doi.org/10.3390/ijms20061382

APA Style

Huber, R., Kirsten, H., Näkki, A., Pohlers, D., Thude, H., Eidner, T., Heinig, M., Brand, K., Ahnert, P., & Kinne, R. W. (2019). Association of Human FOS Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study. International Journal of Molecular Sciences, 20(6), 1382. https://doi.org/10.3390/ijms20061382

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Association of Human FOS Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study

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