Helicobacter pylori (HP) infection is the greatest risk factor for gastric cancer (GC). Increasing evidence has clarified that tumor immune microenvironment (TIME) is closely related to the prognosis and therapeutic efficacy of HP-positive (HP+) GC patients. In this study, we aimed to construct a novel immune-related signature for predicting the prognosis and immunotherapy efficacy of HP+ GC patients. A total of 153 HP+ GC from three different cohorts were included in this study. An Immune-Related prognostic Signature for HP+ GC patients (IRSHG) was established using Univariate Cox regression, the LASSO algorithm, and Multivariate Cox regression. Univariate and Multivariate analyses proved IRSHG was an independent prognostic predictor for HP+ GC patients, and an IRSHG-integrated nomogram was established to quantitatively assessthe prognostic risk. The low-IRSHG group exhibited higher copy number load and distinct mutation profiles compared with the high-IRSHG group. In addition, the difference of hallmark pathways and immune cells infiltration between the two groups was investigated. Notably, tumor immune dysfunction and exclusion (TIDE) analysis indicated that the low-IRSHG group had a higher sensitivity to anti-PD-1 immunotherapy, which was validated by an external pabolizumab treatment cohort. Moreover, 98 chemotherapeutic drugs and corresponding potential biomarkers were identified for two groups, and several drugs with potential ability to reverse IRSHG score were identified using CMap analysis. Collectively, IRSHG may serve as a promising biomarker for survival outcome as well as immunotherapy efficacy. Furthermore, it can also help to prioritize potential therapeutics for HP+ GC patients, providing new insight for the personalized treatment of HP-infected GC.

Context. Existing literature demonstrated that thyroid-stimulating hormone (TSH) and free thyroid hormone (fT4) were associated with the C-reactive protein (CRP), an inflammatory risk factor of cardiovascular diseases (CVD), but the causal relationship between them remained unclear. Methods. Based on the latest genome-wide association study summary data, bidirectional two-sample Mendelian randomization (MR) was employed to detect the causal relationship and effect direction between TSH, fT4, and CRP. Furthermore, in view of obesity being an important risk factor of CVD, obesity trait waist-hip ratio (WHR) and body mass index (BMI) were treated as the research objects in MR analyses for exploring the causal effects of TSH and fT4 on them, respectively. Results. Genetically increased CRP was associated with increased TSH ( , ) and with increased fT4 ( , ), respectively, but there was no evidence that TSH or fT4 could affect CRP. In further analyses, genetically increased TSH was associated with decreased WHR ( , ). Genetically increased WHR was associated with decreased fT4 ( , ). Genetically increased BMI was associated with increased TSH ( , ) and with decreased fT4 ( , ). Causal associations of WHR and BMI with thyroid signaling were not supported by weighted median analysis in sensitivity analyses. Conclusion. TSH and fT4 were increased due to the higher genetically predicted CRP. WHR was decreased due to the higher genetically predicted TSH. These findings will provide reference for the prevention and treatment of inflammation and metabolic syndrome.