Causal association between helicobacter pylori and lymphoma.

Epidemiology and etiology of diffuse large B-cell lymphoma

Anthropometric indicators may explain the high incidence of follicular lymphoma in Europeans: Results from a bidirectional two-sample two-step Mendelian randomisation

Recently, the relationship between cathepsins and a variety of diseases has gained increasing attention, especially various solid tumors and hematologic malignancies. However, there is no consensus on the causality between cathepsins and malignant lymphomas. The cathepsin genome-wide association studies (GWAS) dataset for this study was derived from THE INTERVAL STUDY and was freely downloaded via the OPENGWAS website. GWAS summary statistics for lymphomas were obtained from the FinnGen database. Single nucleotide polymorphisms satisfying the genome-wide association significance (P < 5 × 10−6) and linkage disequilibrium parameters (r2 = 0.001 and clumping distance = 10,000 kb) were screened for the subsequent 2-sample Mendelian randomization (MR) analysis. Sensitivity analyses were utilized to assess the stability and robustness of the MR conclusions. Genetically predicted Cathepsin S (CTSS) level was positively associated with the increased risk of diffuse large B cell lymphoma (DLBCL). Patients with elevated levels of CTSS are more susceptible to DLBCL, which corresponds to a 20.6% increased hazard (odds ratio inverse variance weighted [ORIVW] = 1.206, 95% confidence interval [CI] 1.054–1.380, P = .006). The causal role of the remaining cathepsins in DLBCL and other types of lymphoma was not established. No reverse causality between DLBCL and CTSS was observed after the backward MR analysis (ORIVW = 1.076, 95% CI 0.984–1.177, P = .109). The multivariate MR results supported that CTSS was causally responsible for DLBCL (ORIVW = 1.204, 95% CI 1.042–1.392, P = .012, ORMR-Egger = 1.200, 95% CI 1.038–1.387, P = .014). This study demonstrated a causal effect of CTSS on DLBCL based on the MR algorithm. Follow-up studies are needed to elucidate the underlying mechanisms between them and explore promising new therapeutic options for DLBCL patients.

The precise causal relationship between alterations in the gut microbiota, microbiota-derived metabolites, and the development of diffuse large B-cell lymphoma (DLBCL) remains unclear. To investigate the potential causal relationships between gut microbiota, microbiota-derived metabolites, and DLBCL. Genetic data on gut microbiota were obtained from the MiBioGen consortium, while data on microbiota-derived metabolites were sourced from the TwinsUK and KORA studies.Statistics for DLBCL were retrieved from FinnGen. Mendelian randomization (MR) analysis was performed, with inverse-variance weighting (IVW) used as the primary analytical method. Sensitivity analyses included Cochran's Q test, the MR-Egger intercept test, and MR-PRESSO. Reverse MR analysis was conducted to assess potential bidirectional causal relationships between gut microbiota and DLBCL. Bayesian weighted MR (BWMR) was applied for additional validation to enhance the robustness of the findings. Among 196 gut microbial taxa analyzed, Bilophila (odds ratio (OR) = 1.777, 95% confidence interval (95% CI): 1.053-3.000, p = 0.031) was associated with an increased risk of DLBCL. In contrast, Alistipes (OR = 0.521, 95% CI: 0.311-0.873, p = 0.013) and Ruminococcaceae UCG011 (OR = 0.749, 95% CI: 0.574-0.978, p = 0.034) were associated with a reduced risk. Reverse MR analysis demonstrated a positive association between DLBCL risk and the abundance of Anaerofilum (OR = 1.087, 95% CI: 1.008-1.173, p = 0.031). Negative associations were observed between DLBCL risk and the abundance of Deltaproteobacteria (OR = 0.959, 95% CI: 0.922-0.997, p = 0.037), Desulfovibrionales (OR = 0.959, 95% CI: 0.922-0.998, p = 0.041), Oxalobacteraceae (OR = 0.914, 95% CI: 0.843-0.992, p = 0.031), and Oxalobacter (OR = 0.909, 95% CI: 0.837-0.988, p = 0.024). Analysis of microbiota-derived metabolites identified a causal association between indolepropionate (OR = 0.296, 95% CI: 0.131-0.669, p = 0.003) and reduced DLBCL risk, whereas 7-alpha-hydroxy-3-oxo-4-cholestenoate (7-HOCA) (OR = 9.561, 95% CI: 1.426-64.088, p = 0.020) was associated with an increased risk. No evidence of directional pleiotropy or heterogeneity was detected. This MR study provides evidence that specific gut microbial taxa and microbiota-derived metabolites may causally influence the risk of DLBCL.

Higher Body Mass Index Is Associated with an Increased Risk of Diffuse Large B-Cell Lymphoma

PD-L1 Gene Alterations Identify a Unique Subset of Diffuse Large B Cell Lymphoma That Harbors a T Cell Inflamed Phenotype

BackgroundThe results of observational studies indicate a potential link between Helicobacter pylori infection and Sjogren’s syndrome (SS), but the causal relationship between them remains unknown. This study applied Mendelian randomization (MR) to evaluate this relationship.MethodGenome-wide association study (GWAS) summary statistics on H. pylori infection [sample size=8735 (EBI, https://gwas.mrcieu.ac.uk/)] and SS [sample size=368,028 (cases=2495, controls=365533) (FinnGen, https://r9.finngen.fi/)] were analyzed. We used bidirectional MR to evaluate the association between H. pylori infection and SS and identify causation. The major MR analysis method was inverse-variance weighted (IVW) MR, supplemented by MR‒Egger and weighted median approaches. In addition, the stability and reliability of the results were tested using the retention method, heterogeneity test, and horizontal gene pleiotropy test.ResultsEvidence of the impact of H. pylori infection on SS risk was found in the IVW results [odds ratio (OR)=1.6705; 95% confidence interval (CI)=1.0966 to 2.5446; P=0.0168]. Evidence of the impact of SS on H. pylori infection risk was also found (OR=1.0158; 95% CI=1.0033 to 1.0285; P=0.0128).ConclusionThe results of MR analysis support a causal association between H. pylori infection and SS and indicate that SS can lead to a greater risk of H. pylori infection. Our research will support the development of novel approaches for continued H. pylori and SS-related research and therapy that consider the genetic relationship between H. pylori infection and SS.

BackgroundVenous thromboembolism (VTE) is still one of the most severe health issues, increasing mortality and lengthening hospital stays. Different abundances of gut microbiota have been clinically linked to VTE and coagulopathy. However, whether gut microbiota affected VTE formation remained uncertain.MethodsThe causative links between VTE and 211 gut microbiota at phylum, class, order, family and genus level were separately investigated using two-sample Mendelian Randomization (MR) analysis. Firstly, single nucleotide polymorphisms (SNPs) locus-wide significantly (P < 1.0 × 10− 5) related with gut microbiome abundance were extracted from large genome-wide analysis (GWAS) meta-analysis summary data. Instrumental variables (IVs) without pleiotropy were selected using the PhenoScanner and MR PRESSO test. Then, the MR analysis was implemented using the inverse variance weighted (IVW) method. Moreover, weighted median method, MR Egger method, simple median method and MR PRESSO were conducted to validate the causal associations. The reliability of the results was also assessed utilizing various sensitivity analyses, reverse MR analysis and multivariate Mendelian Randomization analysis (MVMR).ResultsWe found the phylum Firmicutes was robustly protective against VTE with MR analysis. Moreover, five taxa of Actinobacteria phylum (Bifidobacteriales order, Actinomycetales order, Bifidobacteriaceae family, Actinomycetaceae family, Slackia genus) and two taxa of Firmicutes phylum (Bacillales order, Lachnospiraceae UCG-010 genus) were suggestively protective for VTE. While three taxa of Firmicutes phylum (Bacilli class, Lactobacillales order and Lactococcus genus) might suggestively increase the risk of VTE. Sensitivity analyses indicated no significant horizontal pleiotropy, heterogeneity, or reverse causal associations. Furthermore, MVMR analysis unveiled independently positive causal association of Firmicutes phylum and Lachnospiraceae UCG-010 genus with risk of VTE.ConclusionTwo taxa of gut microbes (Firmicutes phylum and Lachnospiraceae UCG-010 genus) were independently protective against VTE, which suggests a potential avenue for developing new cost-effective strategies with minor side effects for VTE prevention and treatment.

Helicobacter pylori eradication therapy is effective in the treatment of early-stage H pylori–positive gastric diffuse large B-cell lymphomas

Prior observational research has indicated a potential link between pediatric asthma and united airways disease (UAD). However, these findings could be subject to confounding factors and reverse causation. Therefore, our study utilizes Mendelian randomization (MR) method to further investigate the causal relationship between pediatric asthma and UAD. We conducted a comprehensive two-sample Mendelian randomization (MR) analysis to investigate the association between pediatric asthma and seven groups of UAD, including chronic sinusitis, chronic rhinitis, nasopharyngitis and pharyngitis, chronic diseases of tonsils and adenoids, chronic laryngitis and laryngotracheitis, chronic bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD). The present study employed a range of methods for two-sample MR analysis, including inverse variance weighted (IVW), MR-Egger regression, Simple mode, weighted median, and weighted models. The conclusion of the MR analysis primarily relies on the IVW results, while other analytical methods are utilized as supplementary evidence to ensure result robustness in this MR analysis. And sensitivity analyses were conducted, including heterogeneity test, horizontal pleiotropy test, MR-PRESSO test, and leave-one-out analysis to validate the results. The results of the MR analysis indicate significant causal effects of pediatric asthma on chronic rhinitis, nasopharyngitis and pharyngitis (IVW: OR = 1.15, 95%CI: 1.05-1.26, p-value = 0.003), chronic diseases of tonsils and adenoids (IVW: OR = 1.07, 95%CI: 1.00-1.15, p-value = 0.038), chronic bronchitis (IVW: OR = 1.51, 95%CI: 1.42-1.62, p-value <0.001), bronchiectasis (IVW: OR = 1.51, 95%CI: (1.30-1.75), p-value <0.001), and COPD (IVW: OR = 1.43, 95%CI: 1.34-1.51, p-value <0.001). However, no significant causal association was observed between pediatric asthma and chronic sinusitis (IVW: OR = 1.00, 95%CI: 1.00-1.00, p-value = 0.085), chronic laryngitis and laryngotracheitis (IVW: OR = 1.05, 95%CI: 0.90-1.21, p-value = 0.558). Our findings support a potential causal relationship between pediatric asthma and UAD, suggesting that pediatric asthma may be a potential risk factor for various UAD.

Background: The association of socioeconomic status and individual behavior (SES/IB) with human health is receiving increasing attention. However, the causal effects between SES/IB and lymphomas remain unclear. Methods: A two-sample Mendelian randomization (MR) study was used to assess the causal effects of 25 SES/IB traits (dietary habits, physical activity, smoking/drinking behaviors, sleeping behaviors, leisure sedentary behaviors, risky behaviors, and reproductive behaviors) on six distinct types of lymphomas, including Hodgkin lymphoma (HL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mature T/NK-cell lymphomas, marginal zone B-cell lymphoma (MZL), and mantle cell lymphoma (MCL). The inverse variance weighted (IVW) method was the primary approach used for the MR analysis. A series of sensitivity analyses were also conducted to ensure the robustness of the findings. Results: Two-sample MR revealed six SES/IB traits causally associated with lymphomas, including relative fat intake, drive time, television watching time, computer use time, vigorous physical activity, and number of children ever born. After false discovery rate (FDR) correction, the causal associations between longer television watching time and DLBCL (OR: 4.048, 95% CI: 1.688 to 9.708, P fdr=0.009), and the number of children ever born with both FL (OR: 0.008, 95% CI: 1.412E-04 to 0.484, P fdr=0.021) and DLBCL (OR: 0.001, 95% CI:1.587E-05 to 0.081, P fdr=0.002) were identified. Conclusions: These findings suggest that certain lifestyle and behavioral factors have a measurable impact on specific lymphoma types.

The relationship between peripheral immune cells and immunoglobulin A nephropathy (IgAN) is widely known; however, causal evidence of this link is lacking. Here, we aimed to determine the causal effect of peripheral immune cells, specifically total white blood cells, lymphocytes, monocytes, basophils, eosinophils, and neutrophils, as well as lymphocyte subset traits, on the IgAN risk using a Mendelian randomization (MR) analysis. The inverse-variance weighted (IVW) method was used for the primary analysis. We applied three complementary methods, including the weighted median, MR-Egger regression, and MR-PRESSO, to detect and correct for the effect of horizontal pleiotropy. Additionally, we performed a multivariable MR (MVMR) analysis, adjusting for the effects of C-reactive protein (CRP) levels. The roles of specific lymphocyte subtypes and their significance have garnered interest. Bidirectional two-sample MR analysis was performed to test the potential causal relationships between immune traits, including median fluorescence intensities (MFIs) and the relative cell count (AC), and IgAN. The IVW-MR analysis suggested a potential causal relationship between lymphocyte counts and IgAN in Europe (OR per 1-SD increase: 1.43, 95% CI: 1.08-1.88, P = 0.0123). The risk effect of lymphocytes remained even after adjusting for CRP levels using the MVMR method (OR per 1-SD increase: 1.44, 95% CI: 1.05-1.96, P = 0.0210). The other sensitivity analyses showed a consistent trend. The largest GWAS published to date was used for peripheral blood immunophenotyping to explore the potential causal relationship between peripheral immune cell subsets and IgAN. Six AC-IgAN and 14 MFI-IgAN pairs that reached statistical significance (P < 0.05) were detected. Notably, CD3, expressed in eight subsets of T cells, consistently showed a positive correlation with IgAN. The bidirectional MR analysis did not reveal any evidence of reverse causality. According to the sensitivity analysis, horizontal pleiotropy was unlikely to distort the causal estimates. Genetically determined high lymphocyte counts were associated with IgAN, supporting that high lymphocyte counts is causal risk factor for IgAN.

Diffuse large B-cell lymphoma (DLBC) is the most common subtype of non-Hodgkin lymphoma, characterized by its aggressive nature and poor prognosis in advanced stages. Despite advances in treatment, the molecular mechanisms driving DLBC progression remain incompletely understood, necessitating the identification of novel biomarkers for diagnosis and prognosis. In this study, we analyzed two publicly available datasets (GSE32018 and GSE56315) from the Gene Expression Omnibus database (GEO) to identify overlapping differentially expressed genes (DEGs). Later on, a comprehensive in silico and in vitro methodology was adopted to decipher the role of identify DEGs in DLBC. DEGs analysis of GSE32018 and GSE56315 datasets identified five overlapping gene: SP3, CSNK1A1, STYX, SIRT5, and MGEA5. Expression validation using the GEPIA2 database confirmed the upregulation of SP3, CSNK1A1, STYX, and SIRT5, and the downregulation of MGEA5 in DLBC tissues compared to normal controls. Furthermore, mutational analysis revealed that CSNK1A1 was the only gene among these DEGs to exhibit mutations, with a 2.7% mutation frequency in DLBC patients. Methylation analysis highlighted a negative correlation between DEGs methylation levels and mRNA expression, while survival analysis identified high STYX expression as significantly associated with poorer overall survival in DLBC patients. Functional assays demonstrated that STYX knockdown in U2932 cells led to reduced cell proliferation, colony formation, and enhanced wound healing, indicating STYX’s pivotal role in DLBC cell survival and migration. Additionally, gene enrichment analysis revealed the involvement of these DEGs in key biological processes, including intracellular trafficking and myeloid progenitor cell differentiation. These findings emphasize the potential of SP3, CSNK1A1, STYX, SIRT5, and MGEA5 as biomarkers and therapeutic targets in DLBC, particularly highlighting STYX as a promising prognostic marker and potential target for therapeutic intervention.

Non-small cell lung cancer (NSCLC) represents a major global health burden with complex genetic etiology. While observational studies have identified numerous potential risk factors, establishing causal relationships remains challenging due to confounding and reverse causation. We conducted a comprehensive Mendelian randomization (MR) analysis to investigate causal relationships between circulating biomarkers, lung tissue gene expression levels, and NSCLC risk. The analysis employed three complementary MR methods: inverse variance weighted (IVW), MR Egger, and weighted median approaches. Genetic instruments were selected from 10 to 26 single nucleotide polymorphisms (SNPs) significantly associated with exposure variables. We validated key findings through quantitative real-time PCR (qRT-PCR) analysis in A549 and H1299 NSCLC cell lines. We examined multiple biomarkers including inflammatory mediators, immune-related proteins, and particularly focused on the HLA region within the major histocompatibility complex. Among circulating biomarkers, thymic stromal lymphopoietin demonstrated a statistically significant positive association with increased NSCLC risk (OR: 1.240, 95% CI: 1.073–1.433, p = 0.003). Gene expression analysis identified 18 genes with significant causal associations (FDR < 0.05), revealing a complex pattern of protective and risk-associated effects. qRT-PCR validation in A549 and H1299 cell lines confirmed differential expression patterns, with protective genes (HLA-DQB2, GMPPA) showing lower expression and risk-associated genes (VDR, P4HTM) showing higher expression in cancer cells compared to normal bronchial epithelial cells. Notable protective genes included HLA-DQB2 (OR: 0.917), HLA-DRB9 (OR: 0.875), and GMPPA (OR: 0.697), while risk-associated genes included VDR (OR: 1.825), P4HTM (OR: 1.520), and multiple HLA variants. Regional association analysis of the HLA-DQB2 locus revealed extremely high significance levels (p-values > 10^-135) within the MHC region on chromosome 6. This MR analysis provides robust genetic evidence for causal relationships between immune system regulation, inflammatory pathways, and NSCLC development, with experimental validation supporting the functional relevance of identified genetic associations.

BackgroundAlthough observational studies have suggested an association between male infertility and prostate cancer (PCa) risk, the causal relationship has not been established.MethodsWe conducted a bidirectional two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary data to investigate the causal relationship between male infertility and PCa. The primary analysis was performed using the inverse variance weighted (IVW) method, supplemented by three additional MR approaches. We systematically evaluated the heterogeneity and pleiotropy of the instrumental variables and employed linkage disequilibrium score regression (LDSC) to assess the genetic correlation between the two conditions. Furthermore, we incorporated factors such as obesity and prostatitis into a multivariable Mendelian randomization framework. Additionally, within the bidirectional MR framework, we explored the causal association between the expression of the PCa biomarker prostate-specific antigen (PSA) and male infertility. Finally, we employed a summary data-based Mendelian randomization (SMR) analysis to identify genes potentially involved in the pathogenesis of PCa. We then performed a preliminary analysis of the differential expression of these significant candidate genes between normal and cancerous tissues using publicly available databases.ResultsBased on the fundamental principles of MR, six instrumental variables for male infertility were selected for analysis with PCa. All four analytical methods (primarily the IVW method, OR = 1.0044, 95% CI = 0.9824–1.0269, P = 0.697) consistently indicated the absence of a causal association. Reverse MR analysis suggested no significant causal relationship (IVW, OR = 0.9769, 95% CI = 0.85–1.1123, P = 0.724). Sensitivity analyses, including heterogeneity tests (Cochran’s Q), pleiotropy assessment (MR-Egger intercept), and leave-one-out validation, confirmed the robustness of these findings. Furthermore, LDSC indicated no significant genetic correlation between male infertility and PCa (Rg = − 0.1102, P = 0.494). After excluding the influence of other exposure factors, multivariable Mendelian randomization results suggested an independent causal effect of prostatitis on PCa risk (IVW, OR = 1.093, 95% CI = 1.0206–1.1707, P = 0.011). No significant causal association was demonstrated between PSA and male infertility (IVW, OR = 0.981, 95% CI = 0.8055–1.1942, P = 0.847).ConclusionOur findings provide no evidence for a causal relationship between male infertility and PCa in either direction.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40001-025-03461-y.