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Original article
Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection
  1. Janett Fischer1,
  2. Alexander N R Weber2,
  3. Stephan Böhm1,
  4. Sabine Dickhöfer2,
  5. Souhayla El Maadidi1,2,
  6. Danilo Deichsel1,
  7. Viola Knop3,
  8. Hartwig Klinker4,
  9. Bernd Möller5,
  10. Jens Rasenack6,
  11. Lisa Wang7,
  12. Manu Sharma7,
  13. Holger Hinrichsen8,
  14. Ulrich Spengler9,
  15. Peter Buggisch10,
  16. Christoph Sarrazin3,
  17. Michael Pawlita11,
  18. Tim Waterboer11,
  19. Manfred Wiese1,
  20. Elsbeth Probst-Müller12,
  21. Raffaele Malinverni13,
  22. Pierre-Yves Bochud14,
  23. Clair Gardiner15,
  24. Cliona O'Farrelly15,
  25. Thomas Berg1
  1. 1 Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany
  2. 2 Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany
  3. 3 Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany
  4. 4 Department of Internal Medicine II, University of Würzburg, Würzburg, Germany
  5. 5 Department of Medical Practice, Charlottenstraße 81, Berlin, Germany
  6. 6 Medical Department, Albert-Ludwigs University Freiburg, Freiburg, Germany
  7. 7 Division of Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany
  8. 8 Department of Gastroenterology, Gastroenterologische Schwerpunkt-Praxis, Kiel, Germany
  9. 9 Department of Internal Medicine I, University of Bonn, Bonn, Germany
  10. 10 Liver Unit, IFI Institute for Interdisciplinary Medicine, Asklepios Klinik St. Georg Hamburg, Hamburg, Germany
  11. 11 Department of Genome Modifications and Carcinogenesis (F020), Research Program Infection and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
  12. 12 University Hospital, Zürich, Switzerland
  13. 13 Pourtalès Hospital, Neuchâtel, Switzerland
  14. 14 Infectious Diseases Service, University Hospital and University of Lausanne, Lausanne, Switzerland
  15. 15 School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
  1. Correspondence to Dr Janett Fischer, Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany, Liebigstraße 21, Leipzig 04103, Germany; janett.fischer{at}medizin.uni-leipzig.de

Abstract

Objective As pathogen sensors, Toll-like receptors (TLR) play a role in the first defence line during HCV infection. However, the impact of the DNA sensor TLR9 on the natural course of HCV infection is unknown. To address this, TLR9 promoter polymorphisms (single nucleotide polymorphisms (SNPs)) rs187084 and rs5743836 were investigated for their effect on disease progression.

Design Therefore, the TLR9 SNPs and the interferon lambda 4 (IFNL4) rs12979860 were genotyped in chronically HCV type 1 infected (n=333), in patients who spontaneously cleared the infection (n=161), in the Swiss HCV cohort (n=1057) and the well-characterised German (n=305) and Irish (n=198) ‘anti-D’ cohorts. Functional analyses were done with promoter reporter constructs of human TLR9 in B cells and assessing TLR9 mRNA levels in whole blood of healthy volunteers.

Results The TLR9 rs187084 C allele was associated with spontaneous virus clearance in women of the study cohort (OR=2.15 (95% CI 1.18 to 3.90) p=0.012), of the Swiss HCV cohort (OR=2.06 (95% CI 1.02 to 4.18) p=0.044) and in both ‘anti-D’ cohorts (German: OR=2.01 (95% CI 1.14 to 3.55) p=0.016; Irish: OR=1.93 (95% CI 1.10 to 3.68) p=0.047). Multivariate analysis in the combined study and Swiss HCV cohorts supported the results (OR=1.99 (95% CI 1.30 to 3.05) p=0.002). Functional analyses revealed higher transcriptional activities for both TLR9 variants and an association of the C allele of rs5743836 with allele-specific TLR9 mRNA regulation by oestrogens in women.

Conclusions TLR9 promoter SNPs are associated with the natural course of HCV infection and show higher transcriptional activities. Our results imply the DNA sensor TLR9 in natural immunity against the RNA virus, HCV.

  • HEPATITIS C
  • CELLULAR IMMUNITY
  • GENETIC POLYMORPHISMS
  • IMMUNOLOGY
  • MOLECULAR GENETICS

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