Mendelian Randomization Research Articles

Candida albicans and colorectal cancer: A paradoxical role revealed through metabolite profiling and prognostic modeling

BACKGROUND Emerging evidence implicates Candida albicans (C. albicans ) in human oncogenesis. Notably, studies have supported its involvement in regulating outcomes in colorectal cancer (CRC). This study investigated the paradoxical role of C. albicans in CRC, aiming to determine whether it promotes or suppresses tumor development, with a focus on the mechanistic basis linked to its metabolic profile. AIM To investigate the dual role of C. albicans in the development and progression of CRC through metabolite profiling and to establish a prognostic model that integrates the microbial and metabolic interactions in CRC, providing insights into potential therapeutic strategies and clinical outcomes. METHODS A prognostic model integrating C. albicans with CRC was developed, incorporating enrichment analysis, immune infiltration profiling, survival analysis, Mendelian randomization, single-cell sequencing, and spatial transcriptomics. The effects of the C. albicans metabolite mixture on CRC cells were subsequently validated in vitro . The primary metabolite composition was characterized using liquid chromatography-mass spectrometry. RESULTS A prognostic model based on five specific mRNA markers, EHD4 , LIME1 , GADD45B , TIMP1 , and FDFT1 , was established. The C. albicans metabolite mixture significantly reduced CRC cell viability. Post-treatment analysis revealed a significant decrease in gene expression in HT29 cells, while the expression levels of TIMP1 , EHD4 , and GADD45B were significantly elevated in HCT116 cells. Conversely, LIME1 expression and that of other CRC cell lines showed reductions. In normal colonic epithelial cells (NCM460), GADD45B , TIMP1 , and FDFT1 expression levels were significantly increased, while LIME1 and EHD4 levels were markedly reduced. Following metabolite treatment, the invasive and migratory capabilities of NCM460, HT29, and HCT116 cells were reduced. Quantitative analysis of extracellular ATP post-treatment showed a significant elevation (P < 0.01). The C. albicans metabolite mixture had no effect on reactive oxygen species accumulation in CRC cells but led to a reduction in mitochondrial membrane potential, increased intracellular lipid peroxidation, and induced apoptosis. Metabolomic profiling revealed significant alterations, with 516 metabolites upregulated and 531 downregulated. CONCLUSION This study introduced a novel prognostic model for CRC risk assessment. The findings suggested that the C. albicans metabolite mixture exerted an inhibitory effect on CRC initiation.

Abstract 6209: Different types of diabetes and pancreatic ductal adenocarcinoma risk: A Mendelian randomization and pathway/gene-set analysis

Abstract Objective: The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not fully understood. We investigated associations of genetic susceptibility to type 2 diabetes (T2D), its eight mechanistic clusters and type 1 diabetes (T1D) using Mendelian randomization (MR) and maturity-onset diabetes of the young (MODY) pathway/gene-set analysis with PDAC risk. Method: Using summary-level genome-wide association statistics for T2D (242, 283 cases, 1, 569, 734 controls), T1D (18, 942 cases, 501, 638 controls), and PDAC (10, 244 cases and 360, 535 controls) in individuals of European ancestry, we conducted two-sample MR to examine associations of genetic susceptibility to T2D and T1D with PDAC risk, using single nucleotide polymorphisms (SNP) significantly associated with T2D, eight mechanistic TD2 clusters (i.e., β-cell dysfunction with a positive or negative association with proinsulin, residual glycaemic, body fat, metabolic syndrome, obesity, lipodystrophy, and liver and lipid metabolism), and T1D identified from published genome-wide association studies (P<5×10-8) as instrumental variables. We also assessed associations of genetic susceptibility to PDAC risk with T2D and T1D using reverse MR. We used MR-RAPS method as the primary analysis approach complemented with sensitivity analyses using MR-IVW, weighted-median, MR-Egger, MR-PRESSO and MR-PIVW. We applied the Summary-based Adaptive Rank Truncated Product (sARTP) method to evaluate the associations for PDAC and the MODY gene set, which consists of 26 genes identified from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results: Genetic susceptibility to T2D (MR-RAPS: OR=1.10; 95% CI 1.05-1.14), particularly the obesity (OR=1.28; 95% CI 1.15-1.42) and lipodystrophy (OR=1.25; 95% CI 1.04-1.50) clusters, was associated with PDAC risk. T1D showed no association with PDAC risk (OR=1.01; 95% CI 0.99-1.02). Reverse MR found no evidence that genetic susceptibility to PDAC risk was associated with T2D or T1D (P>0.05). Sensitivity analyses using other MR methods supported these findings, with no evidence of pleiotropic effects (MR-Egger intercept P>0.05). The MODY gene-set was significantly associated with PDAC risk (P=2.5×10-6), with HNF1A, HNF1B, FOXA3, HNF4A, and HNF4G as the top five contributing genes. Conclusion: Our findings support a role of T2D, particularly the obesity and lipodystrophy clusters, in PDAC risk. Additionally, the genomic susceptibility regions of MODY were significantly associated with PDAC. Citation Format: Ting Zhang, Xing Hua, Chirayu Mohindroo, Xiaoyu Wang, PanScan and PanC4 Consortium, Brian M. Wolpin, Harvey A. Risch, Laufey T. Amundadottir, Alison P. Klein, Kai Yu, Haoyu Zhang, Rachael Z. Stolzenberg-Solomon. Different types of diabetes and pancreatic ductal adenocarcinoma risk: A Mendelian randomization and pathway/gene-set analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6209.

Associations between dietary intake and sarcopenia: a Mendelian randomization study.

Background: sarcopenia, typified by the progressive diminution of skeletal muscle mass and functionality, represents a substantial public health challenge, particularly among the geriatric population. Dietary intake, as a modifiable determinant, has elicited considerable interest due to its prospective role in preventing and alleviating sarcopenia. Methods: this investigation employed Mendelian randomization (MR) analysis, a robust statistical method, to investigate the causal associations between dietary consumption and sarcopenia-associated phenotypes, including appendicular lean mass (ALM), hand grip strength, and walking pace. Genetic variants extracted from the extensive UK Biobank cohort served as instrumental variables for a comprehensive set of 26 dietary elements. Results: our MR analysis unveiled that the ingestion of oily fish and cheese was significantly correlated with augmented ALM, diminished risk of low hand grip strength, and enhanced walking pace. In addition, cooked vegetables, fresh fruit, dried fruit, cereal, and raw vegetables were protective of one or both of the sarcopenia-associated phenotypes. These findings were robust to potential confounding influences owing to the sophisticated MR design. Conclusions: our results underscore that specific dietary constituents play a pivotal protective role against sarcopenia, underscoring the necessity for tailored nutritional strategies to bolster muscle health in the elderly. Further investigations are requisite to corroborate these findings across heterogeneous populations and to unravel the underlying biological mechanisms.

Abstract 2266: Evaluations of more than 1500 blood metabolite biomarkers with risk of eight common cancers and their subtypes using genetic instruments

Abstract Background: Many epidemiologic studies have measured blood metabolites and evaluated their associations with risk of cancers. However, conventional epidemiologic studies may suffer from various biases, limiting their ability for causal inferences. We performed a large Mendelian randomization (MR) study to systematically evaluate blood metabolite biomarkers in relation to cancer risk, including large numbers of associations not previously investigated in either convention epidemiologic or MR studies. Methods: We systematically searched the literature and obtained data from 29 genome-wide association studies (GWAS) to identify blood metabolite-associated genetic loci (mQTLs) among 324, 771 individuals of European ancestry. After systematically evaluating all metabolites and mQTLs evaluated in these studies, we selected 1630 metabolite biomarkers for MR analyses using summary statistic data generated from GWAS conducted among 2, 068, 121 individuals of European ancestry for eight common cancers (breast, colorectal, endometrial, kidney, lung, ovarian, pancreatic, and prostate) and 19 subtypes of breast, kidney, lung, and ovarian cancers. The inverse variance weighted (IVW) method was used as the primary approach for MR analyses. Other methods, including MR-Egger, and MR-PRESSO, were used to evaluate possible pleiotropic effects and robustness of study findings. Statistical significance was judged using Bonferroni and FDR corrected P-value to reduce type 1 errors. Results: We identified 106 biomarker-cancer associations under the significant threshold after Bonferroni correction. Among these, 68 were associated with an increased risk of cancer, while 38 were associated with a decreased risk of cancer. Under an FDR-corrected P < 0.05 but not reaching the Bonferroni-adjusted significant threshold, we identified 119 additional associations, including 65 metabolite biomarkers as potential risk factors and 54 as potential protective factors. Conclusion: Our MR analysis uncovered large numbers of novel associations and provided strong evidence for causal inferences of blood metabolite biomarkers with cancer risk. Citation Format: Zheng Guo, Guochong Jia, Fangcheng Yuan, Lili Liu, Shuai Xu, Jirong Long, Wei Zheng. Evaluations of more than 1500 blood metabolite biomarkers with risk of eight common cancers and their subtypes using genetic instruments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2266.

Association of the gut microbiome with diabetic nephropathy and the mediated effect of metabolites: friend or enemy?

The effects of gut microbiome and its metabolites on diabetic nephropathy (DN) have been inadequately elucidated. The aim of this study is to assess the causal effect of gut microbiome on DN and the mediated effect of metabolites by a two-step Mendelian randomization (MR). Datasets of gut microbiome, metabolites, and DN were acquired in genome-wide association studies and screened for single nucleotide polymorphisms according to the underlying assumptions of MR. Subsequently, inverse variance weighted was used as the primary method for MR analysis to assess the causal effect of gut microbiome on DN and the mediated effect of metabolites. Finally, MR-Egger intercept, Cochran's Q test, and leave-one-out sensitivity analysis were used to assess the horizontal pleiotropy, heterogeneity, and robustness of the results, respectively. The MR analysis demonstrated that Parabacteroides merdae increased the genetic susceptibility to DN by reducing acetylcarnitine (C2) to propionylcarnitine (C3) ratio (mediated proportion 8.95%, mediated effect 0.024) and alpha-ketobutyrate to 3-methyl-2-oxovalerate ratio (mediated proportion 19.90%, mediated effect 0.053). MR Egger showed that these results lack horizontal pleiotropy (p ≥ 0.05). Cochran's Q and sensitivity analysis suggested these results had no heterogeneity (p ≥ 0.05) and were robust. Our findings revealed the pathway by which Parabacteroides merdae increased the genetic susceptibility to DN by regulating acetylcarnitine (C2) to propionylcarnitine (C3) ratio and alpha-ketobutyrate to 3-methyl-2-oxovalerate ratio. It provides new genetic insights for understanding the pathogenesis of DN and related drug research.

Investigating the causal association between coffee and migraine using Mendelian randomization analysis

ABSTRACT Background: Migraine is a chronic neurological disorder influenced by various risk factors, including inadequate medication, anxiety, sleep disorders, depression, and stress-inducing events. Coffee is well-known for its diverse bioactive properties and may help relieve acute migraine symptoms; however, stopping long-term coffee consumption can unexpectedly trigger migraines. While some migraine sufferers view caffeine as a potential trigger, research suggests it may also have preventive effects. The complex physiological and pharmacological mechanisms behind coffee and its active components are not fully understood. Objective: This study aims to clarify the relationship between coffee consumption and its components and the risk of developing migraines. Methods: We conducted a Mendelian randomization (MR) analysis, using genetic variants as proxies for exposure to reduce confounding factors and biases. Results: Our results show a significant inverse relationship between coffee intake and migraine risk, consistent with previous epidemiological studies that indicate coffee may protect against headache disorders. The MR analysis also found that 7-methylxanthine is linked to a lower risk of migraines, while caffeic acid sulfate is associated with a higher risk. Sensitivity analyses showed no heterogeneity in SNP selection for all components, except for trigonelline, and both MR-Egger and MR-PRESSO tests did not indicate horizontal pleiotropy or outliers. Our research highlights the significant impact of coffee and its components on migraine risk, providing valuable dietary recommendations. The protective effect of coffee may be closely related to adenosine receptor antagonism, which warrants further investigation to better understand the underlying mechanisms.

Abstract 2268: Prospective and genetic analyses implicate lower immunosurveillance in the aetiology of prostate cancer

Abstract Tumor promoting inflammation and the ability to evade immune destruction are two of the hallmarks of cancer, but there is limited prospective evidence for the role of specific inflammation and immune-related pathways and protein markers in the development of prostate cancer. This study used data on the circulating levels of 368 inflammation and immune-related proteins (Olink Explore Inflammation I panel) from a nested case-control design within the European Prospective Investigation into Cancer and Nutrition (EPIC), including 1, 434 men who developed prostate cancer and 1, 434 matched controls - 488 of the cases also had clinically aggressive disease. Conditional logistic regression was used to estimate protein associations with cancer risk in EPIC, per standard deviation and the effective number of tests (ENT) was used to control for multiple testing. We additionally performed a fixed-effect meta-analysis combining associations for these proteins estimated in EPIC with those in 21, 481 men from UK Biobank (UKBB), of whom 1, 147 developed prostate cancer. Logistic regression was used to estimate exome protein score association with cancer risk in UKBB and replication analyses were performed in the Multiethnic Cohort (MEC). Mendelian randomisation and colocalisation analyses using data on 79, 148 overall prostate cancer cases from the PRACTICAL consortium were also conducted to aid triangulation. In EPIC, no inflammatory proteins were associated with prostate cancer risk overall or with more clinically aggressive subtypes after correction for multiple testing. In the EPIC+UKBB meta-analyses, FLT3LG and CNTNAP2 were significantly associated with overall prostate cancer risk (RRMeta: 0.88, 95% CI: 0.84-0.92 and RRMeta: 1.10, 95% CI: 1.05-1.16, respectively), and in the analyses stratified by time to diagnosis, IL15 was associated with risk of prostate cancer diagnosed more than seven years after blood draw (RRMeta: 0.86, 95% CI: 0.81-0.93), along with five other proteins (FLT3LG, BCL2L11, PGF, CKAP4, and TNFRSF11A). Exome protein scores in UKBB identified PARP1 as associated with an increased risk of prostate cancer (OR: 1.05, 95% CI: 1.02-1.07), which replicated in MEC (OR: 1.04, 95% CI: 1.01-1.08). MR and colocalisation analyses also identified SPINT2 (OR: 2.11, 95% CI: 1.70-2.63) and NME3 (OR: 1.25, 95% CI: 1.11-1.41) as being associated with an increased risk of prostate cancer overall. Our findings suggest higher levels of proteins involved in immunosurveillance pathways, including the recruitment and activation of natural killer and T cells, may be linked to a lower risk of developing prostate cancer, while PARP1 inhibition may be relevant for prostate cancer prevention. Citation Format: Mahboubeh Parsaeian, Wing Ching Chan, Joshua Atkins, Keren Papier, Trishna Desai, Zhe Huang, David Conti, David Bogumil, Jiayi Shen, Malcolm Sim, Konstantinos Tsilidis, James Yarmolinsky, Sabina Rinaldi, Rudolf Kaaks, Verena Katzke, Matthias Schulze, Catarina Schiborn, Saverio Caini, Lorenzo Milani, Raul Zamora-Ros, Marcela Guevara, Maria-Jose Sánchez, María-Dolores Chirlaque, Pilar Amiano, The PRACTICAL Consortium, Timothy Elliott, Ian Mills, Elio Riboli, Loïc Le Marchand, Christopher Haiman, Tim Key, Karl Smith-Byrne, Ruth Travis. Prospective and genetic analyses implicate lower immunosurveillance in the aetiology of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2268.

Exploring the role of gut microbiota in intervertebral disc degeneration: insights from bidirectional Mendelian randomization analysis.

Although previous studies have indicated a potential association between the gut microbiota and intervertebral disc degeneration (IVDD), the precise nature of this relationship remains unclear. The objective of this study is to further explore the potential causal relationship between gut microbiota and IVDD using a bidirectional Mendelian randomization approach, with the aim of identifying potential microbial characteristics associated with IVDD. Using the data from genome-wide association studies (GWAS) involving 412 gut microbiota species and 227,388 controls and 29,508 cases of IVDD. Inverse variance weighted (IVW) was used as the primary Mendelian randomization (MR) analysis, complemented by weighted median, MR-Egger regression, weighted mode and simple mode methods. Extensive sensitivity analyses were performed to confirm the robustness of the results and to assess heterogeneity and horizontal pleiotropy. This study revealed a positive genetic predisposition between 6 types of gut microbiota and IVDD through the IVW method, indicating that increased levels of these microbiota may lead to a higher risk of IVDD. Conversely, 6 types of gut microbiota were found to have negative effects on IVDD, suggesting that increased levels of these microbiota may have a protective effect against IVDD. Reverse MR analysis results revealed such possibilities as 1 positive and 5 negative causal relationships between IVDD and gut microbiota. The results of Cochran's Q test, MR-Egger regression, and MR-PRESSO analysis from the bidirectional Mendelian randomization all yielded p-values greater than 0.05, indicating that there is no significant heterogeneity or pleiotropy in the genetic effect analysis between gut microbiota and IVDD. We used a bidirectional Mendelian randomization approach to identify various gut microbiota associated with IVDD. Our findings lay the foundation for further exploration of the pathogenesis and treatment strategies of gut microbiota and IVDD, and provide new possibilities for research on biomarkers of IVDD-related metabolic microbiota.

Abstract 6184: A literature-based data scanning and prioritization study to guide future systematic literature reviews for WCRF International CUP Global Programme

Abstract Background: In 2018, the World Cancer Research Fund (WCRF)/American Institute for Cancer Research published the Third Expert Report (TER) synthesizing the evidence on diet, adiposity, physical activity and risk of 19 cancers and 10 updated evidence-based cancer prevention recommendations. As part WCRF International’s Global Cancer Update Programme, we aimed to develop a prioritization support tool to identify what systematic literature reviews (SLR) of the epidemiological evidence published after the TER would help strengthen the TER’s conclusions and deepen our understanding on emerging topics. Methods: We developed a literature scanning and prioritization strategy in six actions. From January 2019 (after TER publication) to February 2024, we searched PubMed for: 1) meta- and pooled analyses, 2) randomized controlled trials (RCTs) and protocols, 3) Mendelian randomization (MR) studies, and 4) prospective cohort studies (≥100, 000 participants) on diet, adiposity, physical activity, sedentary behavior and cancer risk. In action 5, we utilized the fail-safe number and conditional power statistics to estimate the number of additional studies needed to change the existing TER meta-analytic findings. Finally, action 6 integrated data from actions 1-5, to construct an exposure-based prioritization ranking across all cancer sites. A prioritization score (PS) was derived by assessing the number of new studies, the concordance of association measures (direction and statistical significance) against the TER, and the volume of new associations not covered in the TER. Results: We reviewed 366 meta-analyses, 121 pooled analyses, 19 RCTs, 368 MR studies and 359 cohort studies covering 151 exposures and 28 cancers, comparing them to 1371 TER meta-analyses. TER meta-analyses most likely to change from not statistically significant to significant when adding new studies included folate and colorectal cancer, waist circumference and lung cancer in never smokers, poultry and breast cancer, total fat and ovarian cancer, tea and ovarian cancer, and red meat and kidney cancer, but most associations observed in the TER are unlikely to change with additional similar research. The median PS score across exposures was 6 (range -11 to 163). Top ranked exposures with new literature evidence included anthropometric measurements (PSheight 40 to PSBMI 163), physical activity (PS 100), sedentary behavior (PS 64), alcohol (PS 52), tea (PS 36), milk and dairy products (PS 29), micronutrients (PSretinol 27 to PSiron 38), vitamins (PSB12 22 to PSvitD 91), soy (PS 24), isoflavones (PS 23), and soft drinks (PS 22). Across exposures, the top cancers were colorectal, breast, lung, liver, and endometrium. Conclusions: The outputs from the prioritization support tool can help target SLRs that would most usefully contribute to evidence-based cancer prevention recommendations. Citation Format: Georgios Markozannes, Ahmad Jayedi, Sofia Cividini, Sayada Zartasha Kazmi, Margarita Cariolou, Rita Vieira, Sonia Kiss, Katia Balducci, Dagfinn Aune, Marc Gunter, Amanda Cross, Doris Chan, Konstantinos Tsilidis. A literature-based data scanning and prioritization study to guide future systematic literature reviews for WCRF International CUP Global Programme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6184.

Causal effects of vitamin D on leukemia risk: insights from two-sample Mendelian randomization analysis.

Background: vitamin D plays a crucial role in immune regulation, anti-inflammatory processes, and tumor suppression, but its relationship with leukemia risk remains unclear. This study aims to evaluate the causal relationship between vitamin D levels and the risk of different types of leukemia through a two-sample Mendelian randomization (MR) analysis. Methods: data from large-scale genome-wide association studies (GWAS) were used, and genetic variants associated with vitamin D were selected as instrumental variables. The relationship between vitamin D levels and the risk of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML) was examined. The inverse variance weighted (IVW) method was applied as the primary analytical approach. Heterogeneity was assessed through Cochran's Q test, pleiotropy was evaluated using the MR-Egger intercept, and sensitivity analyses were performed to ensure the robustness of the results. Results: MR analysis showed a significant inverse association between serum 25-hydroxyvitamin D levels and the risk of CML (OR = 0.44, 95 % CI: 0.25-0.78, p = 0.005), suggesting a potential protective effect of vitamin D against CML. No significant causal relationships were found between vitamin D levels and the risks of AML, ALL, or CLL. Sensitivity analyses supported the robustness of these findings, with no evidence of heterogeneity or pleiotropy. Conclusion: the findings indicate that higher vitamin D levels may reduce the risk of CML, while the effects on other types of leukemia require further investigation. The potential role of vitamin D in leukemia prevention warrants more mechanistic studies and clinical validation.

A Multi-omics approach to identify and validate shared genetic architecture in rheumatoid arthritis, multiple sclerosis, and type 1 diabetes: integrating GWAS, GEO, MSigDB, and scRNA-seq data

The notable comorbidity among autoimmune diseases underscores their shared genetic underpinnings, particularly evident in rheumatoid arthritis (RA), type 1 diabetes (T1D), and multiple sclerosis (MS). However, the exact components and mechanisms of this shared genetic structure remain poorly understood. Here we show that ROMO1 is a key shared genetic component among RA, MS, and T1D. Using differential gene expression (DGE) and LASSO regression analyses of bulk RNA-seq data from whole blood tissues, we identified ROMO1 as a potential shared genetic factor. A multi-sample analysis with external Gene Expression Omnibus (GEO) data revealed ROMO1’s consistent association with immune cell patterns across tissues in all three diseases. Single-gene Gene Set Enrichment Analysis (GSEA) suggested ROMO1’s involvement in the reactive oxygen species (ROS) pathway, which was further substantiated by conjoint analysis with 256 ROS pathway-related genes(ROSGs) from Molecular Signatures Database (MSigDB). Single-gene Receiver Operating Characteristic (ROC) analysis highlighted ROMO1’s potential as a disease biomarker. Single-cell RNA sequencing (scRNA-seq) analysis showed significantly altered ROMO1 expression in monocytes and other immune cells compared to healthy control (HC). Immune infiltration analysis revealed ROMO1’s significant association with monocytes across all three diseases. Furthermore, two-sample Mendelian randomization (MR) analysis using genome-wide association studies (GWAS) data demonstrated that ROMO1 could regulate epitopes on monocytes, potentially lowering autoimmune disease risk. Our findings clarify the importance of ROMO1 in the shared genetic architecture of RA, MS, and T1D, and its underlying mechanism in disease development.

Deciphering causal interactions between autoimmune and thyroid diseases: a Mendelian randomization analysis

Deciphering causal interactions between autoimmune and thyroid diseases: a Mendelian randomization analysis

Genetic insights into neuroblastoma: the role of immune cell features.

Genetic insights into neuroblastoma: the role of immune cell features.

A Mendelian randomization analysis of cardiac MRI measurements as surrogate outcomes for heart failure and atrial fibrillation

BackgroundDrug development and disease prevention of heart failure (HF) and atrial fibrillation (AF) are impeded by a lack of robust early-stage surrogates. We determined to what extent cardiac magnetic resonance (CMR) measurements act as surrogates for the development of HF or AF.MethodsGenetic data were sourced on the association with 21 atrial and ventricular CMR measurements. Mendelian randomization was used to determine CMR associations with AF, HF, non-ischaemic cardiomyopathy (NICM), and dilated cardiomyopathy (DCM), noting that the definition of NICM includes DCM as a subset. Additionally, for the CMR surrogates of AF and HF, we explored their association with non-cardiac traits potentially influenced by cardiac disease liability.ResultsIn total we find that 7 CMR measures (biventricular ejection fraction (EF) and end-systolic volume (ESV), as well as LV systolic volume (SV), end-diastolic volume (EDV), and mass to volume ratio (MVR)) associate with the development of HF, 5 with the development of NICM (biventricular EDV and ESV, LV-EF), 7 with DCM (biventricular EF, ESV, EDV, and LV end-diastolic mass (EDM), and 3 associate with AF (LV-ESV, RV-EF, RV-ESV). Higher EF of both ventricles associate with lower risk of HF and DCM, with biventricular ESV associating with all four cardiac outcomes. Higher values of biventricular EDV associate with lower risk of HF, and DCM. Exploring the associations of these CMR cardiac disease surrogates with non-cardiac traits confirms a strong link with diastolic blood pressure, as well as more specific associations with lung function (LV-ESV), HbA1c (LV-EDM), and type 2 diabetes (LV-SV).ConclusionsThe current paper identifies key CMR measurements that may act as surrogate endpoints for the development of HF (including NICM and DCM) or AF.

COVID-19 Predisposition Inherently Increases Cardiovascular Risk Before SARS-CoV-2 Infection.

As COVID-19 transitions to an endemic stage, its long-term impacts on health, particularly cardiovascular disease (CVD), remain significant. While prior studies have focused on cardiovascular complications following SARS-CoV-2 infection, the question of inherent cardiovascular risk associated with genetic predisposition to COVID-19 has been less explored. This study investigates whether individuals genetically predisposed to COVID-19 may also be at higher risk for CVD, independent of actual infection. Using Mendelian randomization (MR) analysis with data from pre-pandemic, SARS-CoV-2-naive populations, this study assessed the impact of genetic susceptibility to COVID-19 on various CVD outcomes across 18 distinct cohorts. This approach allowed us to simulate COVID-19 predisposition without infection, providing insights into cardiovascular risks associated solely with genetic susceptibility. These findings reveal a significant association between genetic predisposition to COVID-19 and elevated risks for several CVD outcomes, particularly hypertensive heart disease. Notably, individuals with a genetic profile linked to severe COVID-19 (hospitalization-prone) showed a marked increase in risk for hypertensive heart disease. These findings suggest a shared genetic architecture that predisposes individuals to both COVID-19 and cardiovascular risks, irrespective of viral exposure. COVID-19 susceptibility, thus, may act as a "natural stress test," revealing latent cardiovascular vulnerabilities. This connection implies that individuals predisposed to severe COVID-19 may have inherently higher cardiovascular risks, even without SARS-CoV-2 infection. This study highlights the value of COVID-19 susceptibility as a novel marker for assessing CVD risk, enabling timely preventive strategies and mitigating future CVD burden in the post-COVID-19 era. Moreover, this study highlights disease predisposition as a "black box" until clinical onset. While COVID-19 demands an external viral trigger for acute onset, cardiovascular disease unfolds much more slowly, requiring prolonged exposure to detrimental lifestyle and genetic factors. Together, their intersection illustrates how acute environmental triggers and chronic disease processes can converge to influence overall health outcomes.

Plasma protein levels and hepatocellular carcinoma: a Mendelian randomization study with drug screening implications

BackgroundHepatocellular carcinoma (HCC) remains a significant cause of cancer-related mortality, highlighting the need for novel therapeutic strategies. Identifying key proteins and potential therapeutic agents is critical for improving treatment outcomes.MethodsWe employed Mendelian randomization to identify proteins associated with HCC risk and utilized drug enrichment and molecular docking analyses to discover potential therapeutic agents. The efficacy of identified drugs was evaluated in vitro using immune-tumor co-culture systems and in vivo in a murine HCC model. Single-cell expression profiling and clinical sample analyses were conducted to explore expression patterns.ResultsOur analyses identified 16 proteins linked to HCC pathogenesis. Among the therapeutic agents tested, Belinostat significantly enhanced T cell-mediated cytotoxicity against HCC cells and effectively reduced tumor growth in vivo. Single-cell analysis revealed significant modulation of immune cells within the tumor microenvironment, suggesting potential mechanisms for the observed therapeutic effects.ConclusionThis study highlights the potential of Belinostat as a promising therapeutic agent for HCC. By modulating immune responses and tumor growth, Belinostat offers a novel approach to HCC treatment, warranting further clinical investigation to validate its efficacy and therapeutic potential.

Evaluating the impact of gut microbiota, circulating cytokines and plasma metabolites on febrile seizure risk in Mendelian randomization study

Febrile seizures (FS) is the most common type of convulsion in infants and preschool children. This study aimed to investigate the associations between gut microbiota abundance, plasma metabolites, circulating cytokines, and FS. Summary statistics of 211 gut microbiota traits, 1,400 plasma metabolite traits, 91 circulating cytokine traits, and FS were obtained from publicly available genome-wide association studies. Two-sample Mendelian randomization (MR) analysis and causality was inferred using Inverse variance-weighted (IVW), Weighted median, MR-Egger, simple mode-based estimate and weighted mode-based estimate 5 methods. Several sensitivity analyses were also used to ensure the robustness of the results. Furthermore, mediation analysis was used to determine the pathway from gut microbiota to FS mediated by plasma metabolites and circulating cytokines. MR revealed the associations of 1 gut microbiota (phylum Verrucomicrobia), 4 circulating cytokines and 50 plasma metabolites on FS. Based on the known pathogenic metabolites, we observed that the tryptophan, androgen, and sphingolipids pathways are associated with FS. Mediation analysis revealed 1 strongly documented plasma metabolite (Ascorbic acid 2-sulfate) as a mediator linking “gut microbiota to plasma metabolite to FS”. Sensitivity analysis was represented no heterogeneity or pleiotropy in this study.Our study provides some causal evidence concerning the effects of the gut microbiota, circulating cytokines, and plasma metabolites on FS, which needs to be verified in randomized controlled trials. These biomarkers provide new insights into the underlying mechanisms of FS and contribute to its prevention, diagnosis, and treatment.

The causal effect of multiple lifestyles and myopia: a Mendelian randomization study

Previous studies have demonstrated that lifestyle was associated with myopia. This study used Mendelian randomization (MR) analysis to examine the causal relationships between the time of computer use, the time outdoors in summer and the time outdoors in winter and myopia. Subsequently, univariate MR (UVMR) analyses were carried out respectively on the three exposure factors and myopia, and the results were mainly based on the inverse-variance-weighted method. In addition, sensitivity analyses were also conducted, including heterogeneity tests, horizontal pleiotropy and leave-one-out methods, to evaluate the stability of the MR results. Multivariate MR (MVMR) analysis was also carried out. The UVMR analysis showed that two of the exposure factors had causal relationships with myopia: the time of computer use was a risk factor, and the time spent outdoors in summer was a protective factor. However, the time spent outdoors in winter had no direct impact on myopia. Furthermore, further mediation analysis showed that the frequency of solarium/sunlamp use was a mediating factor between the time outdoors in winter-myopia, and the mediating effect accounted for 36.93%. In conclusion, when multiple factors occurred simultaneously, the time of computer use in summer and the time of outdoor activities had a potential impact on myopia, and the time outdoors in winter affected myopia through the frequency of solarium/sunlamp use.

Exploring the genetic link between gastroesophageal reflux disease and pancreatic cancer: insights from Mendelian randomization

BackgroundGastroesophageal reflux disease (GERD) is increasingly recognized for its associations with extragastric diseases, yet its potential role in pancreatic cancer (PC) etiology remains underexplored. This study investigates the genetic causal relationship between GERD and PC using Mendelian randomization (MR), a method designed to reduce confounding factors.MethodsA two-sample MR analysis was conducted using genome-wide association studies (GWAS) data. The inverse variance weighted (IVW) method was applied, with additional sensitivity analyses performed to evaluate pleiotropy and heterogeneity.ResultsThe IVW analysis demonstrated a significant genetic association between the genetic signature predisposing to GERD and an increased risk of PC (OR: 1.36, 95% CI: 1.04–1.80, P = 0.03). There was no evidence of pleiotropy (P = 0.71) or heterogeneity (P = 0.94).ConclusionsOur study provides robust genetic evidence supporting that the genetic predisposition to GERD is associated with an increased risk of PC. These findings emphasize the necessity of integrating GERD into PC risk assessments and encourage further research to elucidate the underlying biological mechanisms. This insight holds potential to inform strategies for early detection, prevention, and personalized management of PC in GERD patients.

Identifying causal brain structures, genes and proteins for osteoarthritis: A large-scale genetic correlation study based on brain imaging-derived phenotypes, transcriptomes, and proteomes.

Recent epidemiological studies have linked the central nervous system (CNS) to osteoarthritis (OA), suggesting that targeting the CNS could offer new therapeutic strategies. This study aimed to validate the correlation between brain structures and OA risk, and to identify key causal genes by integrating brain transcriptomic and proteomic data with OA genome-wide association studies (GWAS). We analyzed OA summary statistics from 826,690 participants. Using linkage disequilibrium score regression (LDSC) and Mendelian randomization (MR), we explored the genetic relationships between brain structures and OA. A transcriptome-wide association study (TWAS) was conducted with 5,138 brain transcriptomes. Additionally, a proteome-wide association study (PWAS) combined GWAS data with 152 human brain proteomes. Single-cell RNA-Seq eQTL data helped identify causal genes in brain cells linked to OA. LDSC and MR indicated brain structures, such as the putamen and amygdala, are strongly associated with OA. Seven genes were linked to knee OA and four to hip OA (FDR < 0.05). Proteins associated with knee, hip, and thumb OA were also identified. scRNA analysis revealed CPNE1 in excitatory neurons and EMILIN2 in oligodendrocyte progenitor cells as causally linked to knee OA. This study enhances our understanding of the brain-joint axis in OA genetics, potentially informing new treatment strategies and therapeutic targets.