Causal Association Research Articles

The causal association between circulating metabolites and Alzheimer's disease: a systematic review and meta-analysis of Mendelian randomization studies.

Some Mendelian randomization (MR) studies have found that there may be a genetic causal relationship between circulating metabolites and Alzheimer 's disease (AD), but the strength of evidence and the direction of association are not always consistent. In this study, a systematic review and meta-analysis of all the literature using MR methods to study the causal relationship between metabolites and AD was conducted to enhance the robustness and correlation of predicting genetic causality. We conducted a comprehensive review of Mendelian randomization (MR) studies which are within the timeframe of all years to 20 December 2023. Circulating metabolites were considered as the exposure factor, and AD served as the outcome. Two researchers, each with relevant professional backgrounds, independently evaluated study quality and extracted data from the selected studies. Meta-analysis was carried out using R Studio version 4.3.1. In total, 30 studies were included, with 13 selected for meta-analysis. The meta-analysis results revealed that genetically predicted high levels of some metabolites may be associated with a reduced risk of AD. (HDL-C: OR = 0.90, 95% CI 0.83-0.97, p = 0.004; Testosterone: OR = 0.93, 95% CI 0.90-0.97, p = 0.001; Male hormones exclude testosterone: OR = 0.85, 95% CI 0.75-0.96, p = 0.007; Glutamine: OR = 0.85, 95% CI 0.81-0.89, p < 0.001) Meanwhile, genetically predicted high LDL-C levels are associated with an increased risk of AD. (LDL-C: OR = 1.52, 95% CI 1.15-2.00, p = 0.003). There is not enough evidence to prove that there is a genetic causal relationship between diabetes and AD. (OR = 1.02, 95% CI 1.00-1.03, p = 0.12).

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.

Clinical features and outcomes of Human Herpesvirus-6 DNAemia in critically ill patients: a retrospective multicenter analysis.

Human Herpesvirus-6 (HHV-6) DNAemia is not rare in intensive care unit (ICU) patients. However, evidence for a causal association of HHV-6 DNAemia with organ disease and with mortality is limited in this setting. In ICU patients with HHV-6 DNAemia, we sought to 1) assess the prevalence of HHV-6 disease, 2) identify risk factors for HHV-6 disease and 3) investigate its association with mortality. Retrospective multicenter case-matched study in three ICUs from January 2011 to January 2022 of patients with HHV-6 viral load in the whole blood (genome equivalent copies/106 cells) detected during the ICU stay. One hundred and sixty-eight patients were included. Seventeen (10%) were classified as HHV-6 disease (i.e., HHV-6 DNAemia with attributable end-organ disease) and 151 (90%) as HHV-6 reactivation (i.e., HHV-6 DNAemia without any attributable end-organ disease). Immunodepression was significantly more frequent in HHV-6 disease patients (100% vs. 48%, p < 0.001). Eleven (65%) HHV-6 disease patients received hematopoietic stem cell transplantation (HSCT). End-organ diseases were encephalitis (n = 10) and pneumonia (n = 7). The ICU mortality was 32% (n = 53). In multivariate analysis, HHV-6 disease remained independently associated with ICU (OR 4.90) and 90-day (HR 2.25) mortality. Mortality remained significantly higher in the HHV-6 disease group (OR 4.30) when compared to matched ICU patients without HHV-6 DNAemia. Our analysis suggests that HHV-6 disease develops in 10% of patients with HHV-6 detection in the ICU, mostly in the setting of allogeneic HSCT and is independently associated with ICU and 90-day mortality.

Association between gynecological cancers and female infertility: insights from bidirectional Mendelian randomization analysis

PurposeIn recent years, research interest in the potential link between female infertility (FI) and gynecological cancer (GC), including ovarian cancer (OC), endometrial cancer (EC), cervical cancer (CC), and breast cancer (BC), has grown, yet findings remain inconclusive. This study aims to explore the causal relationship between FI and GC using bidirectional two-sample Mendelian randomization (MR) analyses, thereby informing future strategies for FI and GC prevention.MethodsWe utilized SNPs identified from genome-wide association studies (GWAS) on FI and GC. The inverse variance weighted (IVW) method served as the primary approach to assess the causal association between FI and GC. Additionally, five other MR methods—Weighted median, Weighted mode, MR-Egger, Simple mode, and Robust-Adjusted Profile Score—were employed to enhance result robustness and credibility.ResultsIn the forward MR analysis, our IVW results indicated no significant association between FI and GC (FI-BC: OR = 0.95, 95% CI: 0.83–1.09, P = 0.47, P-FDR = 0.775; FI-OC: OR = 1.01, 95% CI: 0.84–1.24, P = 0.789, P-FDR = 0.896; FI-CC: OR = 0.80, 95% CI: 0.61–1.06, P = 0.118, P-FDR = 0.775; FI-EC: OR = 1.07, 95% CI: 0.88–1.30, P = 0.490, P-FDR = 0.775).In the reverse MR analysis, we found a marginal association between BC and FI. However, after adjusting for multiple testing using the FDR method, no significant causal relationship was found between BC and FI, suggesting a marginal association (OR = 1.054, 95% CI: 1.001–1.108, P = 0.043, P-FDR = 0.331). For other cancers, no significant causal relationships were observed between OC, CC and EC with FI(OC-FI: OR = 1.043, 95% CI: 0.999–1.087, P = 0.051, P-FDR = 0.331;CC-FI: OR = 0.992, 95% CI: 0.956–1.028, P = 0.654, P-FDR = 0.836; EC-FI: OR = 1.006, 95% CI: 0.956–1.055, P = 0.809, P-FDR = 0.885).ConclusionsOur study found no significant causal relationship between FI and GC. However, a potential marginal association between BC and FI was observed. These findings underscore the need for further research to confirm this association and emphasize the importance of reproductive protection for young breast cancer patients to preserve fertility.

Association between type 2 diabetes and gastric cancer in Europeans and East Asians based on two sample Mendelian randomization

BackgroundThere are conflicting results and potential methodological flaws of previous observational studies on the association between T2DM and the risk of gastric cancer.This two-sample Mendelian randomization (MR) study aimed to investigate the causal association between type 2 diabetes mellitus (T2DM) and gastric cancer in different ethnic populations.MethodsExposure variables were obtained from genome-wide association studies (GWAS) of T2DM in European population (finn-b-E4_DM2; 32,469) and East Asian population (ebi-a-GCST90018706; n = 45,383). Concomitantly, we utilized summary-level genetic data for gastric cancer in Europeans population (ebi-a-GCST90018849; n = 1029) and East Asians population (ebi-a-GCST90018629; n = 7,921) as the outcome measure. Causal associations between T2DM and gastric cancer in the same ethnic groups were primarily determined using the inverse-variance weighted (IVW) method.ResultsA total of 62 and 106 single nucleotide polymorphisms associated with T2DM were selected for in Europeans and East Asians, respectively. The IVW analysis indicated that there was a significant inverse association between T2DM and gastric cancer in Europeans (odds ratio [OR] 0.917; 95% confidence interval [CI] 0.855–0.984) and East Asians (OR 0.881; 95% CI 0.845–0.918). The weighted median and Weighted mode regression models produced similar results. MR-Egger regression analysis suggested the absence of horizontal pleiotropy. The leave-out sensitivity analysis demonstrated that the results were stable.ConclusionThis MR study revealed that T2DM may be associated with a reduced risk of gastric cancer in European and East Asian population.

Causal associations between inflammatory bowel disease and sepsis: a two-sample Mendelian randomization study

BackgroundRecent observational studies have revealed an inconclusive correlation between inflammatory bowel disease (IBD) and sepsis, accompanied by an uncertain understanding of the causal relationship between the two. To investigate the causality between IBD and sepsis, we employed a two-sample Mendelian randomization (MR) approach.MethodsA genome-wide significant threshold (P < 5 × 10–8) was achieved in order to identify single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for two types of IBD, such as Crohn's disease (CD) and ulcerative colitis (UC). Subsequently, the selected SNPs were assessed in relation to three categories of sepsis, namely sepsis, sepsis (critical care), and sepsis (28-day death in critical care). An inverse-variance weighted (IVW) estimation of MR was conducted, followed by sensitivity analysis on multiple dimensions.ResultsThere was a significant association between genetic liability to CD (IVW: OR, 1.246; 95% CI, 1.090–1.423; P = 0.0012) with sepsis (28-day death in critical care), but not with sepsis (critical care) and sepsis. Whereas UC showed slightly, yet statistically insignificant, higher risk for sepsis (IVW: OR, 1.031; 95% CI, 0.988–1.064; P = 0.064).ConclusionOur study offers genetic evidence that supports a substantial causal relationship between CD and sepsis (28-day death in critical care). To enhance the specificity and objectivity of future research findings, it is recommended to specify the types of IBD and the severity of sepsis. Furthermore, the genetic risk loci related may become potential drug development targets.

A 7-Year Active Surveillance Experience for Occupational Lung Cancer in Bologna, Italy (2017-2023).

In Italy, lung cancer is the second most frequent neoplasm in men and the third in women. Exposure to carcinogens in workplaces plays a significant role. Still, cases attributable to occupational exposure are currently under-reported as occupational diseases: the current National Prevention Plan also encourages active research projects for the detection of cancers attributable to occupational exposure. The Unit of Prevention and Safety in the Workplace of Bologna Local Health Authority (Azienda Unità Sanitaria Locale-AUSL-)created a network for active surveillance of occupational lung cancer cases with the dedicated Diagnostic and Therapeutic Care Pathways(PDTA). Possible occupational exposure cases were selected within all incident PDTA cases using a self-completed patient filter form. Only patients selected through the form were interviewed; occupational physicians collected personal, occupational, and clinical history. Definition of a cooperation system with the local office of the National Institute for Insurance(INAIL)for monitoring the process during the medico-legal assessments conducted by the insurance institute up to resolution. 453 cases completed the filter form, 177 had a potential occupational exposure. Of these, 140 accepted the direct interview with occupational physicians. One hundred eleven cases interviewed were assessed with sure or suspect occupational origin: for 82, a claim for recognition was sent to the INAIL, while for the other 29 was sent to INAIL a report for epidemiological purposes. Out of 82 compensation claims, 18 individuals (4 females and 14 males) received compensation, while 4 cases remain under investigation. A total of 53 claims were rejected: 54.7% for lack of exposure to risk factors, 24.5% for insufficient exposure, 9.4% due to inadequate administrative documentation, 7.5% because of insufficient clinical documentation, and 3.8% for the absence of causal association. Several occupational lung cancers were found that otherwise would have been unrecognized. Asbestos was the most frequent agent occurring in the most widespread work sectors-construction and manufacture of metalworking products-and in the period of exposure from 1970 to 1980. Other relevant agents were welding fumes and polycyclic aromatic hydrocarbons. Active surveillance, direct patient interviews, and claims for recognition integrated by a complementary report are essential to increase the INAIL compensation rate.

Causal inference methodologies to assess the effect of missed clinic visits on treatment success rate among people with tuberculosis in rural Uganda

BackgroundAlthough randomized controlled trials are the gold standard design for cause-effect analysis, high costs and challenges around practicability, feasibility, and ethics may limit their use. In such situations, causal inference methods can improve the rigor of cause-effect analysis using observational data but such methods have infrequently been applied in tuberculosis (TB) research. We conducted a parallel comparison across three causal inference methods in order to assess the causal association between missed clinic visit/s and treatment success among people with drug-susceptible bacteriologically confirmed pulmonary TB.MethodsWe used causal inference methods to analyze cross-sectional data of adults with drug-susceptible bacteriologically confirmed pulmonary TB at clinics in rural eastern Uganda. We compared effect estimates from three causal inference methods, namely instrumental variable analysis, propensity-score analysis (adjustment, matching, weighting, and stratification), and double-robust estimation for cause-effect analysis. The exposure was missing a TB clinic visit/s and the outcome was treatment success defined as cure or treatment completion, both measured on a binary scale. Covariates were selected based on the literature, and their social and biological relevance to the outcome. We report the odds ratio and 95% confidence interval from each causal analysis.ResultsOf 762 participants (mean age of 39.3 ± 15.8 years) included, 186 (24.4%) had missed a clinic visit/s while 687 (90.2%) were successfully treated for TB. Missed clinic visit/s lowered treatment success across all analyses with instrumental variable analysis (OR 0.41, 95% CI 0.20–0.82), propensity-score analysis (adjustment [OR 0.49, 95% CI 0.30–0.82], matching [OR 0.43, 95% CI 0.21–0.91)], weighting [OR 0.52, 95% CI 0.30–0.91], and stratification [OR 0.34, 95% CI 0.19–0.62]), and double-robust estimation (OR 0.49, 95% CI 0.28–0.85).ConclusionsMissed clinic visit/s reduced the likelihood of TB treatment success rate across all causal inference methods, supporting a causal relationship. Studies are needed to examine interventions that enhance retention in TB treatment.

Association of FGF21 with Metabolic and Cardiovascular Diseases: A Mendelian Randomization Analysis.

Studies have covered a possible relevance between fibroblast growth factor 21 (FGF21) and obesity-related metabolic complications and cardiovascular disease (CVD). Nevertheless, whether FGF21 is a causative factor in these diseases is not known. Using a bidirectional, two-sample Mendelian randomization (MR) approach, this study sought to establish a causal relationship between FGF21 and seven metabolic diseases and six CVDs. A large-scale meta-analysis dataset of genome-wide association studies (GWAS) was analyzed to generate summary-level statistics for FGF21. The diseases we studied included non-alcoholic fatty liver disease (NAFLD), obesity, type 2 diabetes (T2DM), hypertension, gestational diabetes (GDM), gestational hypertension (GHTN), pre-eclampsia or eclampsia (PE), atherosclerosis, cardiomyopathy (CMP), coronary heart disease (CHD), coronary atherosclerosis, heart failure (HF), myocardial infarction (MI) and the corresponding summary GAWS data were retrieved from the FinnGen Biobank and IEU Open GWAS Project database. The inverse variance-weighted (IVW) algorithm was the primary approach utilized for the MR analysis. The MR-Egger regression and MR-PRESSO tests were implemented to evaluate horizontal pleiotropy. The heterogeneity of instrumental variables was subsequently assessed utilizing Cochran's Q statistics.When diseases are used as exposures, MR analysis results of the IVW method indicated that NAFLD (Beta=- 0.047, 95% CI=- 0.08 to - 0.014; p=0.006), obesity (Beta=0.087, 95% CI=0.021-0.153; p=0.009), T2DM (Beta=0.071, 95% CI=0.037-0.106; p<0.001) correlated causally with FGF21. Nevertheless, FGF21 was not causally related to the remaining metabolic diseases and CVDs, according to the results of the MR analysis (p>0.05). It was demonstrated that the aforementioned results were robust and devoid of pleiotropy.Our study supports a causal association between NAFLD, obesity, and T2DM with FGF21. No substantial evidence exists to establish a causal relationship between FGF21 and other diseases. This study provides opportunities for the early prevention and innovative therapy of NAFLD, obesity, and T2DM.

Integrative metabolomics and genomics reveal molecular signatures for type 2 diabetes and its cardiovascular complications

BackgroundMetabolites are pivotal in the biological process underlying type 2 diabetes (T2D) and its cardiovascular complications. Nevertheless, their contributions to these diseases have not been comprehensively evaluated, particularly in East Asian ancestry. This study aims to elucidate the metabolic underpinnings of T2D and its cardiovascular complications and leverage multi-omics integration to uncover the molecular pathways involved.MethodThis study included 1180 Chinese participants from the Zhejiang Metabolic Syndrome Cohort (ZMSC). A total of 1912 metabolites were profiled using high-coverage widely targeted and non-targeted metabolic techniques. Multivariable logistic regression models and orthogonal partial least squares discriminant analysis were used to identify T2D-related metabolites. A metabolome-wide genome-wide association study (GWAS) in ZMSC, followed by two-sample Mendelian randomization (MR) analyses, was conducted to explore potential causal metabolite-T2D associations. To enhance cross-ancestry generalizability, MR analyses were conducted in European ancestry to explore the potential causal effects of serum metabolites on T2D and its cardiovascular complications. Furthermore, multi-omics evidence was integrated to explore the underlying molecular mechanisms.ResultsWe identified six metabolites associated with T2D in Chinese, supported by metabolome analysis and genetic-informed causal inference. These included two potential protective factors (PC [O-16:0/0:0] and its derivative LPC [O-16:0]) and four potential risk factors ([R]-2-hydroxybutyric acid, 2-methyllactic acid, eplerenone, and rauwolscine). Cross-ancestry metabolome-wide analysis further revealed four shared potential causal metabolites, highlighting the potential protective role of creatine for T2D. Through multi-omics integration, we revealed a potential regulatory path initialized by a genetic variant near CPS1 (coding for a urea cycle-related mitochondrial enzyme) influencing serum creatine levels and subsequently modulating the risk of T2D. MR analyses further demonstrated that nine urea cycle-related metabolites significantly influence cardiovascular complications of T2D.ConclusionOur study provides novel insights into the metabolic underpinnings of T2D and its cardiovascular complications, emphasizing the role of urea cycle-related metabolites in disease risk and progression. These findings advance our understanding of circulating metabolites in the etiology of T2D, offering potential biomarkers and therapeutic targets for future research.Research insightsWhat is currently known about this topic?Metabolites are crucial for understanding diabetes biology.Multi-omics integration aids in revealing complex mechanisms.What is the key research question?How do serum metabolites affect diabetes and its cardiovascular outcomes?What is new?Novel diabetes-related metabolites identified in Chinese populations.Consistent metabolites associated with diabetes and glycemic traits in East Asians and Europeans.Emphasizing the role of urea cycle pathway in cardiometabolic disease.How might this study influence clinical practice?Findings could guide diabetes prevention and personalized management strategies.

The role of the hippocampus and SLC39A8 in chronic musculoskeletal pain-induced dementia: a Mendelian randomization study

Despite observational studies suggesting a link between chronic musculoskeletal pain (CMP) and increased risk of cognitive decline and dementia, the causal nature of this relationship remains uncertain due to potential confounding factors and reverse causality. We employed two-sample Mendelian Randomization (TSMR), bidirectional MR, mediation MR, drug-target MR, and colocalization analysis, along with gene set enrichment and protein–protein interaction (PPI) analyses. TSMR assessed the causal associations between CMP and the risk of dementia and its subtypes, including Alzheimer’s disease (AD), vascular dementia (VaD), Lewy body dementia (LBD), frontotemporal dementia (FTD), and Parkinson’s disease (PD). Bidirectional MR evaluated reverse causality, while mediation analyses identified potential mediators, focusing on neuroimaging and cognitive phenotypes. Drug-target MR investigated the role of the SLC39A8 gene, and colocalization analysis determined shared causal genetic variants. Gene set enrichment and PPI analyses elucidated the biological pathways implicated in the CMP-dementia relationship. Robust evidence established a causal relationship between chronic low back pain (LBP) and increased risk of PD, with knee osteoarthritis identified as a partial mediator, suggesting a pathway involving chronic inflammation. Bidirectional MR analysis revealed no evidence of reverse causality, further supporting the unidirectional causal link from LBP to PD. Colocalization analysis confirmed distinct genetic architectures for LBP and PD, while drug-target MR implicated the SLC39A8 gene as a potential mediator. Gene set enrichment and PPI analyses highlighted critical biological pathways, such as purine metabolism and glutamate receptor signaling. Suggestive evidence indicated potential causal links between limb pain and overall dementia, myalgia and VaD, as well as potential protective effects of Polymyalgia Rheumatica (PMR) against AD and rheumatism against PD. This study reveals a complex causal relationship between CMP and neurodegenerative diseases, particularly the robust link between LBP and PD. The findings underscore the need for further research to elucidate the underlying mechanisms and inform targeted prevention and treatment strategies.

Mapping the role of macro and micronutrients in bone mineral density: a comprehensive Mendelian randomization study

BackgroundMacro and micronutrients may play an important role in osteoporosis development; however, observational studies have yielded inconsistent results. Clarifying these associations is vital to the development of nutritional recommendations aimed at preventing osteoporosis.MethodsUtilizing the largest available genome-wide association study (GWAS) summary statistics to date, we performed a two-sample Mendelian randomization (MR) analysis to investigate the causal effects of energy-adjusted macronutrient intake (fat, protein, carbohydrate, and sugar) and circulating levels of 20 micronutrients (ten each for vitamins and minerals) on heel estimated bone mineral density (eBMD), a promising marker for osteoporosis risk and fracture susceptibility. Sensitivity, sex-specific, and one-sample MR analyses were applied to further validate and annotate the results.ResultsAmong all nutrients, four genetically predicted circulating levels of micronutrients were suggestively associated with eBMD (vitamin A: βIVW = − 0.054, PIVW = 3.70 × 10–2; vitamin B12: βIVW = − 0.020, PIVW = 3.71 × 10–6; vitamin E: βIVW = 0.277, PIVW = 3.22 × 10–2; selenium: βIVW = 0.023, PIVW = 5.37 × 10–3; all Pintercept > 0.05). All these results were also considered robust, as sensitivity analyses yielded directionally consistent results. However, only the causal effects of vitamin B12 and selenium on eBMD remained significant after Bonferroni correction and were not confounded by obesity, smoking status, or alcohol consumption. Sex-specific analysis revealed a male-specific causal association between vitamin E and eBMD (βIVW = 0.275, PIVW = 9.81 × 10–14). Additionally, using individuallevel data from the UK Biobank cohort, one-sample MR analysis found no causal relationships between diet-derived nutrient intake and eBMD in the overall population, as well as in the females or the males.ConclusionsOur findings suggest that appropriate levels of plasma vitamin B12 and adequate levels of serum selenium are crucial for delaying bone loss and promoting bone health, emphasizing the need for nutritional recommendations to maintain optimal levels of these nutrients to promote eBMD and prevent osteoporosis.

Inferring causal associations in hydrological systems: a comparison of methods

Inferring causal associations in hydrological systems: a comparison of methods

Causal association between gut microbiota and food allergy: a Mendelian randomization analysis

To analyze the potential causal relationship between gut microbiota and food allergy (FA) using two-sample Mendelian randomization (MR) methods. Data from genome-wide association studies on gut microbiota and FA were utilized. MR analysis was conducted employing inverse variance weighting, MR-Egger regression, and weighted median methods to assess the causal relationship between gut microbiota and FA. Cochrane's Q test was used to evaluate heterogeneity of instrumental variables, MR-PRESSO analysis was conducted to test for outliers and pleiotropy, and MR-Egger regression was employed to assess horizontal pleiotropy. The "leave-one-out" method was used to evaluate the impact of removing individual single nucleotide polymorphisms on the causal relationship. Inverse variance weighting analysis revealed that the phylum Verrucomicrobia, family Verrucomicrobiaceae, order Verrucomicrobiales, genus Ruminococcaceae UCG013, and genus Akkermansia were negatively associated with FA (P<0.05). Sensitivity analyses confirmed the reliability of the findings, indicating no heterogeneity or pleiotropy present. There is a causal relationship between gut microbiota and FA, with Verrucomicrobia, Verrucomicrobiaceae, Verrucomicrobiales, Ruminococcaceae UCG013, and Akkermansia potentially reducing the risk of developing FA. These findings provide potential targets for the treatment and prevention of FA; however, further research is needed to explore the specific mechanisms by which the microbiota influence FA.

Exploring causal relationship between 41 inflammatory cytokines and marginal zone lymphoma: A bidirectional Mendelian randomization study

Abstract Purpose Marginal zone lymphoma (MZL) is a rare subtype of non-Hodgkin lymphoma, and its diagnosis primarily relies on pathological biopsy. The study aims to investigate the causal relationships between 41 inflammatory cytokines and MZL using a two-sample bidirectional Mendelian randomization (MR) approach, providing new insights and methodologies for rapid differential diagnosis and treatment strategies. Methods Causal associations between 41 inflammatory cytokines and MZL were examined using genetic variant data from two large-scale genome-wide association studies. The inverse variance weighting method was employed, and multiple sensitivity analyses, including MR-Egger, weighted median, simple model, and weighted model methods, were conducted to strengthen the robustness of the findings. Results Elevated levels of MIG and IL-10 were associated with an increased risk of MZL (MIG: OR = 1.57, p = 0.035; IL-10: OR = 1.69, p = 0.021), while higher B-NGF levels exhibited a protective effect (OR = 0.46, p = 0.027). Reverse MR analysis revealed a negative correlation between MZL and IFN-γ levels (OR = 0.97, p = 0.015). Conclusions MIG, IL-10, B-NGF, and IFN-γ are potential biomarkers and therapeutic targets for MZL. IFN-γ likely acts as a downstream molecule in MZL pathogenesis, offering novel insights into MZL-related research, clinical diagnosis, and treatment strategies.

Cross-sectional and longitudinal trajectory analyses of sleep duration and frailty among middle-aged and older Chinese adults

The relationship between sleep duration and frailty remains unclear, particularly regarding their bidirectional nature and temporal dynamics in the Chinese population. This study aimed to investigate the cross-sectional association, developmental trajectories, and interactions between sleep duration and frailty in Chinese middle-aged and older adults. Data were obtained from the China Health and Retirement Longitudinal Study (CHARLS), which included 12,942 participants for cross-sectional analysis and 11,192 participants for the longitudinal trajectory study. Latent growth models and cross-lagged panel models were utilized to explore the temporal effects of sleep duration on frailty and vice versa. Participants’ mean age was 59.29 ± 9.48 years, comprising 47.73% men and 52.27% women. Cross-sectional analysis revealed that, compared with participants with normal sleep duration (6–8 h), both Q1 (≤ 5 h, OR = 1.99, 95% CI 1.64–2.41, P < 0.001) and Q4 (> 8 h, OR = 1.50, 95% CI 1.12–2.02, P = 0.01) showed increased risks of frailty. The parallel latent growth model demonstrated that the initial level of sleep duration significantly negatively predicted the initial level of frailty (β = − 0.34, P < 0.001), while the rate of change in sleep duration negatively predicted the rate of change in frailty (β = − 0.61, P < 0.001). Conversely, the initial level of frailty significantly negatively predicted the initial level of sleep duration (β = − 0.36, P < 0.001), and the rate of change in frailty negatively predicted the rate of change in sleep duration (β = − 0.71, P < 0.001). Cross-lagged analysis indicated a bidirectional causal association between sleep duration and frailty, with the negative predictive effect of frailty on sleep duration being relatively stable, while sleep duration had a short-term effect on frailty. Our study revealed a U-shaped correlation between sleep duration and frailty risk in cross-sectional analysis and established a bidirectional relationship through longitudinal investigation. These findings underscore the importance of balanced sleep patterns and early screening for both conditions in middle-aged and older adults.

Association of Immune Cell Phenotypes With Oral Cancer: A Two-Sample Mendelian Randomisation Study.

Association of Immune Cell Phenotypes With Oral Cancer: A Two-Sample Mendelian Randomisation Study.

Peripheral blood immune cell phenotypes and Alzheimer's disease: A mediation Mendelian randomization study.

BackgroundAlzheimer's disease (AD) is a debilitating neurodegenerative disorder. Although peripheral immune cells have been implicated in the pathology of AD, the causal relationship between peripheral blood immune cells and AD remains to be fully elucidated.ObjectiveTo examine the association between peripheral blood immune cell phenotypes and AD, mediated by peripheral blood metabolite, a two-step Mendelian randomization (MR) analysis was performed.MethodsSummary statistics were obtained from the two largest independent cohorts. We explored bidirectional univariable MR analysis to explore causal associations and assessed the mediated proportion of peripheral blood metabolite phenotypes.ResultsThe proportion of IgD + CD38- B cells (Bm1) were found to increase the risk of AD in both the FinnGen database (p = 0.033) and the UK Biobank (p = 0.034). Conversely, hematopoietic stem cells were associated with a decreased risk of AD in the FinnGen database (p = 0.045) and the UK Biobank (p = 0.017). Mediation analysis revealed indirect effects of the proportion of Bm1 on AD through cysteine levels (β = 5 × 10-3), Acetylcarnitine (C2) to propionylcarnitine (C3) ratio (β = 4.5 × 10-3), and Gamma-glutamyl-alpha-lysine levels (β = 2.6 × 10-3), with mediated proportion of 19.4%, 16.9% and 9.6% of the total effect, respectively. Additionally, hematopoietic stem cells influenced AD through Glycolithocholate sulfate levels (β = 1.5 × 10-3), with a mediated proportion of 3.5%.ConclusionsOur findings demonstrate that two peripheral blood immune cell phenotypes impact the risk of AD. These immune cells may influence AD through various peripheral blood metabolite, identifying potential intervention targets for individuals at risk.

Decoding the causal association between immune cells and three chronic respiratory diseases: Insights from a bi-directional Mendelian randomization study

BackgroundNumerous studies have indicated the correlations of immune traits and chronic respiratory diseases (CRDs). Whereas, causality is still implicative. Hence, our study was designed to investigate the causal relations utilizing bidirectional Mendelian randomization (MR) and to identify the immune traits of potential significance.MethodsUsing GWAS datasets, we performed Mendelian randomization (MR) analyses to examine 731 immune traits associated with three CRDs: asthma, bronchiectasis and chronic obstructive pulmonary disease (COPD). Six widely applied MR approaches, along with Bayesian weighted Mendelian randomization analysis, were utilized to assess causality. Through extensive sensitivity assessments, heterogeneity and pleiotropy have been examined. For integrity, leave-one-out analysis was implemented as the final step.ResultsOur study reveals 13 immune traits that may have a genetic basis for predicting the occurrence of CRDs, which include two risk traits (CD62L− myeloid dendritic cell (DC) absolute count (AC), CD8 on CD28+ CD45RA− CD8+ T cell) and four protective traits (CD39+ CD8+ %T cell, CD4 on CD39+ activated CD4 regulatory T (Treg) cell, herpes virus entry mediator (HVEM) on Central Memory (CM) CD8+ T cell, CD16 on CD14+ CD16+ monocyte) in COPD, three protective traits (IgD− CD27− %B cell, CD3 on CM CD8+ T cell, CD16 on CD14+ CD16+ monocyte) and one risk trait (CD62L− %DC) in bronchiectasis. Additionally, two risk traits (CD14− CD16− AC monocyte, CD19 on IgD+ CD38+ B cell) and one protective trait (HVEM on CD45RA− CD4+ T cell) were identified in asthma. Sensitivity analyses showed no indications of pleiotropy or signs of heterogeneity. The inverse MR assessment results gave no evidence of reverse causations, ultimately validating the soundness of the findings.ConclusionsOur investigation identifies latent correlations of immune traits and three major CRDs, offering novel perspectives on the preventive and therapeutical strategies for CRDs.Graphical abstract

Causal atlas on comorbidities in cardiomyopathy: a Mendelian randomization study of European ancestry.

Cardiomyopathy (CM) is often accompanied by comorbidities that increase the risk of death. Our aim is to explore the causal association between CM and its subtypes and various related comorbidities. Bidirectional Mendelian randomization (MR) was used to explore the causal association between 39 comorbidities and CM, 13 comorbidities and hypertrophic cardiomyopathy (HCM), 25 comorbidities and dilated cardiomyopathy (DCM), and 13 comorbidities and restrictive cardiomyopathy (RCM). Besides, we explored the causal associations between systolic, diastolic, and pulse pressure with CM and DCM, respectively. MR Mediation analysis was used to explore whether atrial fibrillation (AF) or hypertension was as mediating variable mediating the causal association between each other and CM. By MR analysis, we found that AF (OR = 1.28) and hypertension (OR = 3.58) were associated with an increased risk of CM, and CM was causally associated with an increased risk of heart failure (OR = 1.40). In addition, hypertension was causally associated with a lower risk of DCM (OR = 0.22). The results of the causal association of systolic, diastolic, and pulse pressure with CM and DCM were consistent with the direction of the causal association of hypertension with CM and DCM. Through MR Mediation analysis, we found AF as a mediating factor mediates the causal association between hypertension and CM, with a mediating proportion of about 16.22%. This study is the first to reveal the causal association between certain comorbidities and CM and DCM, and to find possible mediating effects among them.