RT Journal Article
SR Electronic
T1 Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1829
OP 1837
DO 10.1136/gutjnl-2015-310239
VO 66
IS 10
A1 Fischer, Janett
A1 Weber, Alexander N R
A1 Böhm, Stephan
A1 Dickhöfer, Sabine
A1 El Maadidi, Souhayla
A1 Deichsel, Danilo
A1 Knop, Viola
A1 Klinker, Hartwig
A1 Möller, Bernd
A1 Rasenack, Jens
A1 Wang, Lisa
A1 Sharma, Manu
A1 Hinrichsen, Holger
A1 Spengler, Ulrich
A1 Buggisch, Peter
A1 Sarrazin, Christoph
A1 Pawlita, Michael
A1 Waterboer, Tim
A1 Wiese, Manfred
A1 Probst-Müller, Elsbeth
A1 Malinverni, Raffaele
A1 Bochud, Pierre-Yves
A1 Gardiner, Clair
A1 O'Farrelly, Cliona
A1 Berg, Thomas
YR 2017
UL http://gut.bmj.com/content/66/10/1829.abstract
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.