Hans Jürgen Hoffmann

Genetically determined high activities of the TNF-alpha, IL23/IL17, and NFkB pathways were associated with increased risk of ankylosing spondylitis

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Jacob Sode, Department of Rheumatology, Skåne University Hospital, Lund, Sweden.
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  • Steffen Bank, Focused Research Unit for Molecular Diagnostic and Clinical Research, Hospital of Southern Jutland, Aabenraa, Denmark. stb@mb.au.dk.
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  • Ulla Vogel, The National Research Centre for the Working Environment, Copenhagen Denmark.
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  • Paal Skytt Andersen, University of Copenhagen
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  • Signe Bek Sørensen, b Institute of Regional Health Research , University of Southern Denmark , Odense , Denmark., Focused Research Unit for Molecular Diagnostic and Clinical Research, IRS-Center Soenderjylland, Laboratory Center, Hospital of Southern Jutland, Aabenraa, Denmark., University of Southern Denmark
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  • Anders Bo Bojesen, Focused Research Unit for Molecular Diagnostic and Clinical Research, IRS-Center Soenderjylland, Laboratory Center, Hospital of Southern Jutland, Aabenraa, Denmark.
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  • Malene Rohr Andersen, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.
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  • Ivan Brandslund, Department of Biochemistry, Center Hospital Lillebaelt, Vejle, Denmark.
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  • Ram Benny Dessau, Department of Clinical Microbiology , Slagelse Hospital, Slagelse Denmark
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  • Hans Jürgen Hoffmann
  • Bente Glintborg, The DANBIO registry and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Rigshospitalet, Glostrup, Denmark.
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  • Merete Lund Hetland, g Department of Clinical Medicine, Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark.
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  • Henning Locht, Department of Rheumatology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Denmark.
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  • Niels Henrik Heegaard, Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen, Denmark., Department of Clinical Biochemistry, Rigshospitalet Glostrup, Copenhagen, Denmark; OPEN, Odense Patient Data Explorative Network, Odense University, Hospital/Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
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  • Vibeke Andersen, b Institute of Regional Health Research , University of Southern Denmark , Odense , Denmark., Focused Research Unit for Molecular Diagnostic and Clinical Research, IRS-Center Soenderjylland, Laboratory Center, Hospital of Southern Jutland, Aabenraa, Denmark., University of Southern Denmark, OPEN Odense Patient data Explorative Network, Odense University Hospital and University of Southern Denmark

BACKGROUND: Ankylosing spondylitis (AS) results from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the heritability of AS.

METHODS: Using a candidate gene approach in this case-control study, 51 mainly functional single nucleotide polymorphisms (SNPs) in genes regulating inflammation were assessed in 709 patients with AS and 795 controls. Data on the patients with AS were obtained from the DANBIO registry where patients from all of Denmark are monitored in routine care during treatment with conventional and biologic disease modifying anti-rheumatic drugs (bDMARDs). The results were analyzed using logistic regression (adjusted for age and sex).

RESULTS: Nine polymorphisms were associated with risk of AS (p < 0.05). The polymorphisms were in genes regulating a: the TNF-α pathway (TNF -308 G > A (rs1800629), and - 238 G > A (rs361525); TNFRSF1A -609 G > T (rs4149570), and PTPN22 1858 G > A (rs2476601)), b: the IL23/IL17 pathway (IL23R G > A (rs11209026), and IL18-137 G > C (rs187238)), or c: the NFkB pathway (TLR1 743 T > C (rs4833095), TLR4 T > C (rs1554973), and LY96-1625 C > G (rs11465996)). After Bonferroni correction the homozygous variant genotype of TLR1 743 T > C (rs4833095) (odds ratios (OR): 2.59, 95% confidence interval (CI): 1.48-4.51, p = 0.04), and TNFRSF1A -609 G > T (rs4149570) (OR: 1.79, 95% CI: 1.31-2.41, p = 0.01) were associated with increased risk of AS and the combined homozygous and heterozygous variant genotypes of TNF -308 G > A (rs1800629) (OR: 0.56, 95% CI: 0.44-0.72, p = 0.0002) were associated with reduced risk of AS.

CONCLUSION: We replicated associations between AS and the polymorphisms in TNF (rs1800629), TNFRSF1A (rs4149570), and IL23R (rs11209026). Furthermore, we identified novel risk loci in TNF (rs361525), IL18 (rs187238), TLR1 (rs4833095), TLR4 (rs1554973), and LY96 (rs11465996) that need validation in independent cohorts. The results suggest that genetically determined high activity of the TNF-α, IL23/IL17, and NFkB pathways increase risk of AS.

Original languageEnglish
Article number165
JournalBMC Medical Genetics
Volume19
Issue1
Number of pages16
ISSN1471-2350
DOIs
Publication statusPublished - 12 Sep 2018

    Research areas

  • Ankylosing spondylitis, CYTOKINE PROFILES, Case-control study, GENE POLYMORPHISMS, INFLAMMATORY-BOWEL-DISEASE, KAPPA-B, PROMOTER, RECEPTOR, SNP, SUSCEPTIBILITY, Single nucleotide polymorphism, TREATMENT RESPONSE, TUMOR-NECROSIS-FACTOR, VARIANTS

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