Journal Article

DKFZ-2022-00121

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Toll-like receptor 1 locus re-examined in a genome-wide association study update on anti-Helicobacter pylori IgG titers.

Lam, S. Y. ; Mommersteeg, M. C. ; Yu, B. ; Broer, L. ; Spaander, M. C. W. ; Frost, F. ; Weiss, S. ; Völzke, H. ; Lerch, M. M. ; Schöttker, B.DKFZ* ; Zhang, Y.DKFZ* ; Stocker, H.DKFZ* ; Brenner, H.DKFZ* ; Levy, D. ; Hwang, S.-J. ; Wood, A. C. ; Rich, S. S. ; Rotter, J. I. ; Taylor, K. D. ; Tracy, R. P. ; Kabagambe, E. K. ; Leja, M. ; Klovins, J. ; Peculis, R. ; Rudzite, D. ; Nikitina-Zake, L. ; Skenders, G. ; Rovite, V. ; Uitterlinden, A. ; Kuipers, E. J. ; Fuhler, G. M. ; Homuth, G. ; Peppelenbosch, M. P.

2022
Saunders Philadelphia, Pa. [u.a.]

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Please use a persistent id in citations: doi:10.1053/j.gastro.2022.01.011

Abstract: A genome-wide significant association between anti-Helicobacter pylori (H. pylori) IgG titers and Toll-like receptor (TLR1/6/10) locus on 4p14 was demonstrated for individuals of European ancestry, but not uniformly replicated. We re-investigate this association in an updated genome-wide association study (GWAS) meta-analysis for low gastric cancer incidence populations, address potential causes of cohort heterogeneity and explore functional implications of genetic variation at the TLR1/6/10 locus.The dichotomous GWAS (25% individuals exhibiting highest anti-H. pylori IgG titers versus remaining 75%) included a discovery and replication sample of respectively n=15,685 and n=9,676, all of European ancestry. Longitudinal analysis of serological data was performed on H. pylori-eradicated subjects (n=132) and patients under surveillance for premalignant gastric lesions (n=107). TLR1/6/10 surface expression, TLR1 messenger RNA (mRNA) and cytokine levels were measured in leukocyte subsets of healthy subjects (n=26) genotyped for TLR1/6/10 variants.The association of the TLR1/6/10 locus with anti-H. pylori IgG titers (rs12233670; β=-0.267 SE±0.034; P=4.42x10-15) presented with high heterogeneity and failed replication. Anti-H. pylori IgG titers declined within 2-4 years following eradication treatment (P=0.004), and decreased over time in patients with premalignant gastric lesions (P<0.001). Variation at the TLR1/6/10 locus affected TLR1-mediated cytokine production and TLR1-surface expression on monocytes (P=0.016) and neutrophils (P=0.030), but not mRNA levels.The association between anti-H. pylori IgG titers and TLR1/6/10 locus was not replicated across cohorts, possibly due to dependency of anti-H. pylori IgG titers on therapy, clearance and antibody decay. H. pylori-mediated immune cell activation is partly mediated via TLR1 signaling, which in turn is affected by genetic variation.

Keyword(s): Polymorphism ; Single Nucleotide ; bacteria ; immunity ; serology

Note: 2022 May;162(6):1705-1715

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Contributing Institute(s):

1. C070 Klinische Epidemiologie und Alternf. (C070)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2022

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 30 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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