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Gut. 2017 Oct;66(10):1829-1837. doi: 10.1136/gutjnl-2015-310239. Epub 2016 Apr 21.

Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection.

Author information

1
Department of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital, Leipzig, Germany.
2
Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
3
Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany.
4
Department of Internal Medicine II, University of Würzburg, Würzburg, Germany.
5
Department of Medical Practice, Charlottenstraße 81, Berlin, Germany.
6
Medical Department, Albert-Ludwigs University Freiburg, Freiburg, Germany.
7
Division of Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany.
8
Department of Gastroenterology, Gastroenterologische Schwerpunkt-Praxis, Kiel, Germany.
9
Department of Internal Medicine I, University of Bonn, Bonn, Germany.
10
Liver Unit, IFI Institute for Interdisciplinary Medicine, Asklepios Klinik St. Georg Hamburg, Hamburg, Germany.
11
Department of Genome Modifications and Carcinogenesis (F020), Research Program Infection and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
12
University Hospital, Zürich, Switzerland.
13
Pourtalès Hospital, Neuchâtel, Switzerland.
14
Infectious Diseases Service, University Hospital and University of Lausanne, Lausanne, Switzerland.
15
School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.

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.

KEYWORDS:

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

PMID:
27196570
DOI:
10.1136/gutjnl-2015-310239
[Indexed for MEDLINE]

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