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000178524 0247_ $$2doi$$a10.1053/j.gastro.2022.01.011
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000178524 041__ $$aEnglish
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000178524 1001_ $$aLam, Suk Yee$$b0
000178524 245__ $$aToll-like receptor 1 locus re-examined in a genome-wide association study update on anti-Helicobacter pylori IgG titers.
000178524 260__ $$aPhiladelphia, Pa. [u.a.]$$bSaunders$$c2022
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000178524 500__ $$a2022 May;162(6):1705-1715
000178524 520__ $$aA genome-wide significant association between anti-Helicobacter pylori (H. pylori) IgG titers and Toll-like receptor (TLR1/6/10) locus on 4p14 was demonstrated for individuals of European ancestry, but not uniformly replicated. We re-investigate this association in an updated genome-wide association study (GWAS) meta-analysis for low gastric cancer incidence populations, address potential causes of cohort heterogeneity and explore functional implications of genetic variation at the TLR1/6/10 locus.The dichotomous GWAS (25% individuals exhibiting highest anti-H. pylori IgG titers versus remaining 75%) included a discovery and replication sample of respectively n=15,685 and n=9,676, all of European ancestry. Longitudinal analysis of serological data was performed on H. pylori-eradicated subjects (n=132) and patients under surveillance for premalignant gastric lesions (n=107). TLR1/6/10 surface expression, TLR1 messenger RNA (mRNA) and cytokine levels were measured in leukocyte subsets of healthy subjects (n=26) genotyped for TLR1/6/10 variants.The association of the TLR1/6/10 locus with anti-H. pylori IgG titers (rs12233670; β=-0.267 SE±0.034; P=4.42x10-15) presented with high heterogeneity and failed replication. Anti-H. pylori IgG titers declined within 2-4 years following eradication treatment (P=0.004), and decreased over time in patients with premalignant gastric lesions (P<0.001). Variation at the TLR1/6/10 locus affected TLR1-mediated cytokine production and TLR1-surface expression on monocytes (P=0.016) and neutrophils (P=0.030), but not mRNA levels.The association between anti-H. pylori IgG titers and TLR1/6/10 locus was not replicated across cohorts, possibly due to dependency of anti-H. pylori IgG titers on therapy, clearance and antibody decay. H. pylori-mediated immune cell activation is partly mediated via TLR1 signaling, which in turn is affected by genetic variation.
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000178524 650_7 $$2Other$$aPolymorphism
000178524 650_7 $$2Other$$aSingle Nucleotide
000178524 650_7 $$2Other$$abacteria
000178524 650_7 $$2Other$$aimmunity
000178524 650_7 $$2Other$$aserology
000178524 7001_ $$aMommersteeg, Michiel C$$b1
000178524 7001_ $$aYu, Bingting$$b2
000178524 7001_ $$aBroer, Linda$$b3
000178524 7001_ $$aSpaander, Manon C W$$b4
000178524 7001_ $$aFrost, Fabian$$b5
000178524 7001_ $$aWeiss, Stefan$$b6
000178524 7001_ $$aVölzke, Henry$$b7
000178524 7001_ $$aLerch, Markus M$$b8
000178524 7001_ $$0P:(DE-He78)c67a12496b8aac150c0eef888d808d46$$aSchöttker, Ben$$b9$$udkfz
000178524 7001_ $$0P:(DE-He78)d19149dd97b17ce55e70abd2f9e64d3d$$aZhang, Yan$$b10
000178524 7001_ $$0P:(DE-He78)104fae0755c89365b7ae32238b3f1f52$$aStocker, Hannah$$b11$$udkfz
000178524 7001_ $$0P:(DE-He78)90d5535ff896e70eed81f4a4f6f22ae2$$aBrenner, Hermann$$b12$$udkfz
000178524 7001_ $$aLevy, Daniel$$b13
000178524 7001_ $$aHwang, Shih-Jen$$b14
000178524 7001_ $$aWood, Alexis C$$b15
000178524 7001_ $$aRich, Stephen S$$b16
000178524 7001_ $$aRotter, Jerome I$$b17
000178524 7001_ $$aTaylor, Kent D$$b18
000178524 7001_ $$aTracy, Russell P$$b19
000178524 7001_ $$aKabagambe, Edmond K$$b20
000178524 7001_ $$aLeja, Marcis$$b21
000178524 7001_ $$aKlovins, Janis$$b22
000178524 7001_ $$aPeculis, Raitis$$b23
000178524 7001_ $$aRudzite, Dace$$b24
000178524 7001_ $$aNikitina-Zake, Liene$$b25
000178524 7001_ $$aSkenders, Girts$$b26
000178524 7001_ $$aRovite, Vita$$b27
000178524 7001_ $$aUitterlinden, André$$b28
000178524 7001_ $$aKuipers, Ernst J$$b29
000178524 7001_ $$aFuhler, Gwenny M$$b30
000178524 7001_ $$aHomuth, Georg$$b31
000178524 7001_ $$aPeppelenbosch, Maikel P$$b32
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