PT  - JOURNAL ARTICLE
AU  - Fischer, Janett
AU  - Weber, Alexander N R
AU  - Böhm, Stephan
AU  - Dickhöfer, Sabine
AU  - El Maadidi, Souhayla
AU  - Deichsel, Danilo
AU  - Knop, Viola
AU  - Klinker, Hartwig
AU  - Möller, Bernd
AU  - Rasenack, Jens
AU  - Wang, Lisa
AU  - Sharma, Manu
AU  - Hinrichsen, Holger
AU  - Spengler, Ulrich
AU  - Buggisch, Peter
AU  - Sarrazin, Christoph
AU  - Pawlita, Michael
AU  - Waterboer, Tim
AU  - Wiese, Manfred
AU  - Probst-Müller, Elsbeth
AU  - Malinverni, Raffaele
AU  - Bochud, Pierre-Yves
AU  - Gardiner, Clair
AU  - O'Farrelly, Cliona
AU  - Berg, Thomas
TI  - Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection
AID  - 10.1136/gutjnl-2015-310239
DP  - 2017 Oct 01
TA  - Gut
PG  - 1829--1837
VI  - 66
IP  - 10
4099  - http://gut.bmj.com/content/66/10/1829.short
4100  - http://gut.bmj.com/content/66/10/1829.full
SO  - Gut2017 Oct 01; 66
AB  - 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.