Causal associations between gastroesophageal reflux disease and lung cancer risk: A Mendelian randomization study.

Observational epidemiological studies suggest that lung cancer risk may be raised by gastroesophageal reflux disease (GERD); however, the causal relationship between them remains unknown. Our study performed the two-sample Mendelian randomization (MR) approach to examine the causal relationship between GERD and lung cancer. Instrument variables were found to be independent single nucleotide polymorphisms (SNPs) that were highly linked with GERD (n = 129,080). Summary data from genome-wide association studies (GWAS) data were used to determine outcomes for lung cancer (n = 11,348), squamous cell lung cancer (LUSC), and lung adenocarcinoma (LUAD). In this study, three MR statistical techniques (inverse variance weighted (IVW), MR-Egger, and weighted median) were used to examine the potential causative relationship between GERD and the risk of lung cancer. Cochran's Q test, MR-Egger intercept test, leave-one-out analysis, and the funnel plot were all used in sensitivity analyses. The main IVW method revealed that GERD substantially increased the risk of lung cancer [odds ratio (OR) = 1.37; 95% CI 1.16-1.63, p = 0. 0003], which was also supported by weighted median and MR-Egger analyses. Using IVW estimate, similar causal relationships were also observed between GERD and LUSC (OR = 1.56; 95% CI 1.26-1.93, p = 5.35 × 10-5 ) and LUAD (OR = 1.45; 95% CI 1.09-1.93, p = 0.01). Although potential heterogeneity was observed in some studies, random effect IVW was not violated by the heterogeneity, indicating that the causal effect was robust. GERD was positively associated with the risk of lung cancer, for LUSC and LUAD. This study shed light on a new direction for prevent strategy of lung cancer and therapeutic perspectives in patients with GERD.

Li L ，Ren Q ，Zheng Q ，Bai Y ，He S ，Zhang Y ，Ma H ... -  《Cancer Medicine》

No genetic causal association between human papillomavirus and lung cancer risk: a bidirectional two-sample Mendelian randomization analysis.

Several observational or retrospective studies have previously been conducted to explore the possible association between lung cancer and human papillomavirus (HPV) infection. However, there may be inconsistencies in the data and conclusions due to differences in study design and HPV testing methods. There are currently no studies that provide conclusive evidence to support the involvement of HPV in the occurrence and development of lung cancer. Therefore, the relationship between HPV and lung cancer remains controversial and uncertain. This study aimed to explore whether HPV infection is causally related to lung cancer risk by systematically performing a two-way Two-Sample Mendelian Randomization (TSMR) analysis. In the International Lung Cancer Consortium (ILCCO) genome-wide association study dataset, we included 11,348 lung cancer (LUCA) cases, including 3275 squamous cell carcinoma (LUSC) cases, 3442 adenocarcinoma (LUAD) cases, and 15,861 cases of control. Using genetic variants associated with the HPV E7 protein as instrumental variables, we summarized statistics associated with HPV infection in the MRC IEU OpenGWAS database, which included the HPV-16 E7 protein and the HPV-18 E7 protein. Two-sample Mendelian randomization (MR) results are expressed as odds ratios (OR) and 95% confidence intervals (CI). Based on a comprehensive analysis of genome-wide association study (GWAS) data from public databases, we mainly used inverse-variance weighted (IVW) to estimate causal relationships, while using MR-Egger, weighted median, simple mode, and weighted mode, and other four methods as supplements. Two-sample MR Analysis revealed no causal relationship between exposure factors (HPV-16 E7 protein and HPV-18 E7 protein) and outcome factors (lung cancer (LUCA) and its subtypes squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD)) in forward MR Analysis using the IVW approach.HPV-16 E7 protein and LUCA and its subtypes LUSC and LUAD by IVW method results: [OR] = 1.002; 95% [CI]: 0.961 - 1.045; p = 0.920; [OR] = 1.023; 95% [CI]: 0.966 - 1.084; p = 0.438; [OR] = 0.994; 95% [CI]: 0.927 - 1.066; p = 0.872); HPV-18 E7 protein and LUCA and its subtypes LUSC and LUAD by IVW method results: [OR] = 0.965; 95% [CI]: 0.914 - 1.019; p = 0.197; [OR] = 0.933; 95% [CI]: 0.834 - 1.043; p = 0.222; [OR] = 1.028; 95% [CI]: 0.945 - 1.118; p = 0.524. It was observed through reverse MR that LUCA and its subtypes LUSC and LUAD were used as exposure factors, and HPV infection (HPV-16 E7 protein and HPV-18 E7 protein) was used as the outcome factors, the results of the IVW method are also invalid.LUCA and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.036; 95% [CI]: 0.761 - 1.411; p = 0.82; [OR] = 1.318; 95% [CI]: 0.949 - 1.830; p = 0.099; LUSC and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.123; 95% [CI]0.847 - 1.489; p = 0.421; [OR] = 0.931; 95% [CI]: 0.660 - 1.313; p = 0.682; LUAD and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.182; 95% [CI] 0.983 - 1.421; p = 0.075; [OR] = 1.017; 95% [CI]: 0.817 - 1.267; p = 0.877.Our results indicate that there is no causal relationship between genetically predicted HPV infection and LUCA and its subtypes LUSC and LUAD. In addition, in the reverse MR analysis, we did not observe a significant causal relationship between LUCA and its subtypes LUSC and LUAD on HPV infection. Our findings do not support a genetic association between HPV infection and lung cancer.

Chen Y ，Xu Z ，Zhang Z ，Wang X ，Dong M ... -  《Trials》

The Causal Relationship Between Gastroesophageal Reflux Disease and Chronic Obstructive Pulmonary Disease: A Bidirectional Two-Sample Mendelian Randomization Study.

Liu B ，Chen M ，You J ，Zheng S ，Huang M ... -  《International Journal of Chronic Obstructive Pulmonary Disease》

Genetic evidence causally linking gastroesophageal reflux disease to cholecystitis: a two-sample mendelian randomization study.

Gastroesophageal reflux disease (GERD) and cholecystitis share overlapping symptoms, including belching, acid reflux, and heartburn. Despite this, the causal relationship between these two conditions remains unclear. This study aimed to investigate the causal link between GERD and cholecystitis using a Mendelian randomization (MR) approach. A two-sample MR analysis was conducted using the inverse variance weighted (IVW), weighted median, weighted mode, and MR-Egger method to assess the causal effects of GERD on the cholecystitis risk. Genome-wide association studies (GWASs) on GERD (N cases = 129080; N controls = 473524) and cholecystitis (N cases = 1930; N controls =359264) were obtained from the IEU Open GWAS project. Various techniques were employed to assess pleiotropy and heterogeneity. Seventy-seven single nucleotide polymorphisms from GERD GWASs were selected as instrumental variables (IVs). The primary IVW method revealed a significant association between GERD and an increased risk of cholecystitis (odds ratio = 1.004; 95% confidence interval = 1.003-1.005, p = 2.68 × 10- 9). The absence of heterogeneity and pleiotropy in the data supports the reliability of the results. GERD was positively associated with the risk of cholecystitis. This study provides insights into potential avenues for the development of prevention strategies and treatment options for cholecystitis in patients with GERD. These findings contribute to our understanding of the complex interplay between GERD and cholecystitis.

Wang C ，Wang J ，Fang M ，Fei B ... -  《BMC GASTROENTEROLOGY》

Unraveling the causality between gastroesophageal reflux disease and increased cancer risk: evidence from the UK Biobank and GWAS consortia.

Gastroesophageal reflux disease (GERD) is a common condition characterized by the reflux of stomach contents into the esophagus. Despite its widespread prevalence worldwide, the causal link between GERD and various cancer risks has not been fully established, and past medical research has often underestimated or overlooked this relationship. This study performed Mendelian randomization (MR) to investigate the causal relationship between GERD and 19 different cancers. We leveraged data from 129,080 GERD patients and 473,524 controls, along with cancer-related data, obtained from the UK Biobank and various Genome-Wide Association Studies (GWAS) consortia. Single nucleotide polymorphisms (SNPs) associated with GERD were used as instrumental variables, utilizing methods such as inverse variance weighting, weighted median, and MR-Egger to address potential pleiotropy and confounding factors. GERD was significantly associated with higher risks of nine types of cancer. Even after adjusting for all known risk factors-including smoking, alcohol consumption, major depression, and body mass index (BMI)-these associations remained significant, with higher risks for most cancers. For example, the adjusted risk for overall lung cancer was (OR, 1.23; 95% CI: 1.14-1.33), for lung adenocarcinoma was (OR, 1.18; 95% CI: 1.03-1.36), for lung squamous cell carcinoma was (OR, 1.35; 95% CI: 1.19-1.53), and for oral cavity and pharyngeal cancer was (OR, 1.73; 95% CI: 1.22-2.44). Especially noteworthy, the risk for esophageal cancer increased to (OR, 2.57; 95% CI: 1.23-5.37). Mediation analyses further highlighted GERD as a significant mediator in the relationships between BMI, smoking, major depression, and cancer risks. This study identifies a significant causal relationship between GERD and increased cancer risk, highlighting its role in cancer development and underscoring the necessity of incorporating GERD management into cancer prevention strategies.

Wu G ，Liu Y ，Ning D ，Zhao M ，Li X ，Chang L ，Hu Q ，Li Y ，Cheng L ，Huang Y ... -  《BMC Medicine》