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@ARTICLE{Lam:178524,
      author       = {S. Y. Lam and M. C. Mommersteeg and B. Yu and L. Broer and
                      M. C. W. Spaander and F. Frost and S. Weiss and H. Völzke
                      and M. M. Lerch and B. Schöttker$^*$ and Y. Zhang$^*$ and
                      H. Stocker$^*$ and H. Brenner$^*$ and D. Levy and S.-J.
                      Hwang and A. C. Wood and S. S. Rich and J. I. Rotter and K.
                      D. Taylor and R. P. Tracy and E. K. Kabagambe and M. Leja
                      and J. Klovins and R. Peculis and D. Rudzite and L.
                      Nikitina-Zake and G. Skenders and V. Rovite and A.
                      Uitterlinden and E. J. Kuipers and G. M. Fuhler and G.
                      Homuth and M. P. Peppelenbosch},
      title        = {{T}oll-like receptor 1 locus re-examined in a genome-wide
                      association study update on anti-{H}elicobacter pylori
                      {I}g{G} titers.},
      journal      = {Gastroenterology},
      volume       = {162},
      number       = {6},
      issn         = {0016-5085},
      address      = {Philadelphia, Pa. [u.a.]},
      publisher    = {Saunders},
      reportid     = {DKFZ-2022-00121},
      pages        = {1705-1715},
      year         = {2022},
      note         = {2022 May;162(6):1705-1715},
      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.},
      keywords     = {Polymorphism (Other) / Single Nucleotide (Other) / bacteria
                      (Other) / immunity (Other) / serology (Other)},
      cin          = {C070},
      ddc          = {610},
      cid          = {I:(DE-He78)C070-20160331},
      pnm          = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
      pid          = {G:(DE-HGF)POF4-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35031300},
      doi          = {10.1053/j.gastro.2022.01.011},
      url          = {https://inrepo02.dkfz.de/record/178524},
}