Toll-like receptor 1 locus re-examined in a genome-wide association study update on anti-Helicobacter pylori IgG titers

Authors: LAM, SUK - Erasmus Medical Center; MOMMERSTEEG, MICHIEL - Erasmus Medical Center; YU, BINGTING - Erasmus Medical Center; BROER, LINDA - Erasmus Medical Center; SPAANDER, MANON - Erasmus Medical Center; FROST, FABIAN - University Of Greifswald; WEISS, STEFAN - University Of Greifswald; VÖLZKE, HENRY - University Of Greifswald; LERCH, MARKUS - University Of Greifswald; SCHÖTTKER, BEN - German Cancer Research Center (DKFZ)- Germany; ZHANG, YAN - German Cancer Research Center (DKFZ)- Germany; STOCKER, HANNAH - German Cancer Research Center (DKFZ)- Germany; BRENNER, HERMANN - German Cancer Research Center (DKFZ)- Germany; LEVY, DANIEL - Framingham Heart Study; HWANG, SHIH - Framingham Heart Study; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); RICH, STEPHEN - University Of Virginia; ROTTER, JEROME - Harbor-Ucla Medical Center; TAYLOR, KENT - Harbor-Ucla Medical Center; TRACY, RUSSELL - University Of Vermont; KABAGAMBE, EDMOND - Ochsner Health; LEJA, MARCIS - University Of Latvia; KLOVINS, JANIS - Latvian Biomedical Research And Study Centre; PECULIS, RAITIS - Latvian Biomedical Research And Study Centre; RUDZITE, DACE - University Of Latvia; NIKITINA-ZAKE, LIENE - Riga Stradinš University; SKENDERS, GIRTS - University Of Latvia; ROVITE, VITA - Latvian Biomedical Research And Study Centre; UITTERLINDEN, ANDRE - Erasmus Medical Center; KUIPERS, ERNST - Erasmus Medical Center; FUHLER, GWENNY - Erasmus Medical Center; HOMUTH, GEORG - University Of Greifswald; PEPPELENBOSCH, MAIKEL - Erasmus Medical Center

Submitted to: Gastroenterology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/7/2022
Publication Date: 1/11/2022
Citation: Lam, S.Y., Mommersteeg, M.C., Yu, B., Broer, L., Spaander, M.C., Frost, F., Weiss, S., Volzke, H., Lerch, M.M., Schöttker, B., Zhang, Y., Stocker, H., Brenner, H., 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. Toll-like receptor 1 locus re-examined in a genome-wide association study update on anti-Helicobacter pylori IgG titers. Gastroenterology. https://doi.org/10.1053/j.gastro.2022.01.011.
DOI: https://doi.org/10.1053/j.gastro.2022.01.011

Interpretive Summary: Individuals with overweight/obesity are more likely to have stomach ulcers, but which people with excess adiposity will develop these, and why, is not well understood. It is likely that some people are genetically predisposed to risk, but only one gene (TLR1) has previously been associated with an increased likelihood of having a stomach ulcer. To better understand how to predict who is at most risk, we screened the entire genome for associations with past stomach ulcers in data from a large, nationally-representative sample of US adults. We did not replicate past findings that the TLR1 gene was associated with risk of stomach ulcers, however further investigations did show that the TLR1 gene was more active in those with stomach ulcers and lead to more inflammation in these individuals. Further studies are needed to test whether these findings based on analyses in people from the general population also generalize to adults with overweight/obesity.

Technical 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; Beta=-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.