title: Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection.
abstract: 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,TLR9promoter polymorphisms (single nucleotide polymorphisms (SNPs)) rs187084 and rs5743836 were investigated for their effect on disease progression.
  
  
  
  Therefore, theTLR9SNPs and theinterferon 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 humanTLR9in B cells and assessingTLR9mRNA levels in whole blood of healthy volunteers.
  
  
  
  TheTLR9rs187084 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 bothTLR9variants and an association of the C allele of rs5743836 with allele-specificTLR9mRNA regulation by oestrogens in women.
  
  
  
  TLR9promoter 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.
authors.affiliation: Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany.
authors.forename: Janett
authors.initials: J
authors.lastname: Fischer
authors.affiliation: Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
authors.forename: Alexander N R
authors.initials: ANR
authors.lastname: Weber
authors.affiliation: Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Böhm
authors.affiliation: Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Dickhöfer
authors.affiliation: Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany.|Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
authors.forename: Souhayla
authors.initials: S
authors.lastname: El Maadidi
authors.affiliation: Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany.
authors.forename: Danilo
authors.initials: D
authors.lastname: Deichsel
authors.affiliation: Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany.
authors.forename: Viola
authors.initials: V
authors.lastname: Knop
authors.affiliation: Department of Internal Medicine II, University of Würzburg, Würzburg, Germany.
authors.forename: Hartwig
authors.initials: H
authors.lastname: Klinker
authors.affiliation: Department of Medical Practice, Charlottenstraße 81, Berlin, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Möller
authors.affiliation: Medical Department, Albert-Ludwigs University Freiburg, Freiburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Rasenack
authors.affiliation: Division of Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany.
authors.forename: Manu
authors.initials: M
authors.lastname: Sharma
authors.affiliation: Department of Gastroenterology, Gastroenterologische Schwerpunkt-Praxis, Kiel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Hinrichsen
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
authors.affiliation: Liver Unit, IFI Institute for Interdisciplinary Medicine, Asklepios Klinik St. Georg Hamburg, Hamburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Buggisch
authors.affiliation: Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Sarrazin
authors.affiliation: Department of Genome Modifications and Carcinogenesis (F020), Research Program Infection and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Pawlita
authors.affiliation: Department of Genome Modifications and Carcinogenesis (F020), Research Program Infection and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Waterboer
authors.affiliation: Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Wiese
authors.affiliation: University Hospital, Zürich, Switzerland.
authors.forename: Elsbeth
authors.initials: E
authors.lastname: Probst-Müller
authors.affiliation: Pourtalès Hospital, Neuchâtel, Switzerland.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Malinverni
authors.affiliation: Infectious Diseases Service, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Bochud
authors.affiliation: School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
authors.forename: Clair
authors.initials: C
authors.lastname: Gardiner
authors.affiliation: School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
authors.forename: Cliona
authors.initials: C
authors.lastname: O'Farrelly
authors.affiliation: Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005858:Germany; D006239:Haplotypes; D019698:Hepatitis C, Chronic / Q000235:genetics*; D006801:Humans; D007378:Interleukins / Q000235:genetics*; D007494:Ireland; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000097:blood*; D012075:Remission, Spontaneous; D012189:Retrospective Studies; D012737:Sex Factors; D013557:Switzerland; D051217:Toll-Like Receptor 9 / Q000235:genetics*; D014158:Transcription, Genetic; D000095022:Interferon Lambda
chemical_list: D007378:Interleukins; D012333:RNA, Messenger; D051217:Toll-Like Receptor 9; C579163:IFNL4 protein, human; D000095022:Interferon Lambda; C495371:TLR9 protein, human
keywords: CELLULAR IMMUNITY; GENETIC POLYMORPHISMS; HEPATITIS C; IMMUNOLOGY; MOLECULAR GENETICS