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PubMed2025

Causal association between different types of ametropia and risk of diabetic retinopathy: a two-sample Mendelian randomization study.

OBJECTIVE: To investigate the causal link between ametropia and diabetic retinopathy, as well as to offer genetic support for the association between these two conditions. METHODS: This study employed a methodology involving the utilisation of genome-wide association studies data that are publicly accessible. Specifically, single nucleotide polymorphisms (SNPs) that exhibit a strong association with ametropia were employed as instrumental variables, and a two-sample Mendelian randomization (MR) approach was employed to examine the causal relationship between different types of ametropia and diabetic retinopathy. The main findings were derived from the utilisation of inverse variance weighted (IVW), while supplementary results were obtained through the utilisation of MR Egger, weighted median, simple mode and weighted mode. Additionally, a sensitivity analysis was conducted using the 'leave-one-out' method. Cochran's Q statistics were also used to quantify the heterogeneity of SNPs. RESULTS: 38 SNPs were finally included. The results of the IVW analysis indicate that myopia may exert an inhibitory effect on the development of diabetic retinopathy (OR=0.596, 95% CI (0.371, 0.957), p<0.05). Conversely, hypermetropia (OR=8.882, 95% CI (0.389×10-3, 2.06×105), p>0.05) and astigmatism (OR=1.004, 95% CI (0.888, 1.135), p>0.05) do not exhibit a causal relationship with the risk of diabetic retinopathy. CONCLUSION: This two-sample Mendelian randomization study provides evidence that myopia may impede diabetic retinopathy occurrence, while hypermetropia and astigmatism show no significant causal effects. However, our analysis treats refractive errors as independent entities, which may not reflect their clinical interdependence. Further investigations are warranted to elucidate myopia's protective mechanisms.

Humans↗

PubMed1990

Automation and prothrombin time: a United Kingdom field study of two widely used coagulometers.

Current performance in the prothrombin time (PT) of the two main United Kingdom coagulometer/thromboplastin systems was assessed in a field survey. Twenty abnormal samples covering a wide spectrum of International Normalised Ratio (INR) were distributed to users of the KC4/KC10 and Coag-a-Mate instruments. Coagulometer results were compared with those of the manual method. A substantial minority with each system showed good agreement with the manual reference values. There was, however, a considerable variation between instruments, meaningful in clinical terms, evidenced by varying regression slopes and local system International Sensitivity Indices (ISI). For intense anticoagulation (3.0 to 4.5 INR) a larger dose of warfarin is needed with the Coag-a-Mate than with the KC instruments. With a manual INR of 4.0 the KC instruments tended to give longer PT (mean INR + 0.3); the Coag-a-Mate PT was generally shorter (mean INR -0.1). With both systems the mean normal PT were shorter than the manual but the degree of shortening did not parallel that of the abnormal samples. This effect undermines the use of a simple prothrombin ratio and of an INR value derived from it, based on a manual ISI. The use of a system related ISI cannot, however, be recommended until local instrument variables are controlled.

Blood Coagulation Tests↗

PubMed2005

Quality effects of operative delay on mortality in hip fracture treatment.

BACKGROUND: Most hip fracture patients undergo surgery, but there is conflicting evidence on the relation between the timing of surgery and the outcome of treatment. There is considerable variation in the length of surgical delays between hospitals, possibly reflecting the quality of care. AIM: To examine the associations between in-hospital surgical delay and the mortality of hip fracture patients from a practical quality assessment perspective. METHODS: The effects of operative delay on mortality were estimated using various statistical methods applied to observational data from 16 881 first time hip fracture patients aged 65 or older from 47 hospitals (providers) in Finland in 1998-2001. RESULTS: A prolonged in-hospital operative delay was associated with a higher mortality of hip fracture patients in individual level analyses, but the instrumental variable approach indicated that the individual level effect was not caused by the operative delay but by inappropriate methodological assumptions. There was extensive variation between providers in the proportion of late surgery patients. Provider level analyses showed that the effects of the provider of operative delay on mortality are quite small, but there is a clear association between the proportion of late surgery patients and non-optimal treatment. CONCLUSIONS: If provider level heterogeneity is not explicitly taken into account, studies of the effects of surgical delay on outcomes are prone to serious bias. The proportion of patients with prolonged waiting time for surgery at the provider level seems to work as an effective evidence-based quality indicator. Providers should reduce unnecessary delays to surgery and identify more carefully patients not suitable for early surgery.

Age Factors↗

PubMed2026

Standard tea intake is causally associated with a reduced risk of wet age-related macular degeneration: a Mendelian randomization study.

Researchers have posited that increased consumption of tea and coffee may be associated with more favorable treatment outcomes in patients with age-related macular degeneration (AMD). However, there is no clear evidence regarding the causal associations. To delve deeper into this potential connection, scientists used a rigorous method known as Mendelian randomization (MR). This technique was used to explore the causal impact of tea and coffee consumption on the development or progression of AMD. With the aim of investigating the cause-and-effect relationship between 16 tea- and coffee-consuming subtypes and 3 AMD, we designed a two-sample MR study using comprehensive data from genome-wide association studies (GWAS). The major approach adopted was inverse variance weighting (IVW). Furthermore, we implemented complementary methods like the weighted median (WM), weighted mode, and MR-Egger to strengthen our findings. Sensitivity analyses, including MR-Egger, MR-PRESSO, leave-one-out, and Cochran's Q tests, were used to validate results, explore heterogeneity and pleiotropy, and pinpoint potential biases. Two hundred and sixty-eight instrumental variables were selected for MR analysis. The results showed that standard tea intake may be a protective factor for wet AMD [odds ratio (OR) = 0.7076, 95% confidence interval (CI) = 0.5776-0.8668, P = 8 × 10-4, PFDR = 0.0402]. Sensitivity analysis suggests that the results are robust. Our findings provide genetic evidence that standard tea intake is a protective factor against wet AMD, providing new insights into early risk stratification and prevention strategies for the disease.NEW & NOTEWORTHY This study investigates the potential causal relationship between tea and coffee consumption and age-related macular degeneration (AMD) using Mendelian randomization. Analyzing data from genome-wide association studies, we focused on 16 beverage subtypes and 3 AMD conditions. Our findings suggest that standard tea consumption may protect against wet AMD, with robust evidence supporting this link. The results offer new insights into risk stratification and prevention strategies for AMD, highlighting the importance of dietary factors in eye health.

Mendelian Randomization Analysis↗

PubMed2000

Severe disability at hospital discharge in ischemic stroke survivors.

BACKGROUND: Several studies have attempted to identify criteria for predicting functional prognosis after stroke, but often with contradictory results. The purpose of this study was to predict the functional outcome at discharge of first-time stroke patients included consecutively in the Lausanne Stroke Registry. METHODS: We studied 3,628 sequential patients with first-ever stroke who were admitted consecutively to the Centre Hospitalier Universitaire Vaudois. Functional status was evaluated using the Rankin disability scale at discharge. We studied the prognostic value of historical, clinical and instrumental variables related to functional outcome at discharge. The factors studied were age, sex, risk factors, ECG results, occurrence of transient ischemic attacks (TIAs), extension of cerebral infarction, presumed cause of stroke, clinical findings and demographic characteristics. Univariate analysis was performed on each variable by comparing the number of functionally independent with that of dependent patients at the moment of discharge. The significant variables of the univariate analysis were subjected to multivariate analysis with a backward logistic regression procedure to find those with an independent effect on the outcome. RESULTS: A total of 3,156 patients, excluding 117 patients with ischemic stroke who died during hospitalization and 355 with brain hemorrhage, were included; 2,867 patients belonged to the nil, mild or moderate disability groups (modified Rankin score 1-4; functionally at least partially independent patients), while 291 patients belonged to the severe disability group (modified Rankin score 5; functionally dependent patients). The mean duration of stay in hospital of the severe disability group was 31.2 days (SD = 16.2). Multivariate analysis showed that impaired consciousness on admission, limb weakness, progressive worsening, infarct in the superficial and deep territory of the middle cerebral artery, ischemic heart disease and cardiac arrhythmia were predictors of severe disability at discharge. Age was not an independent predictor of poor outcome. Hypercholesterolemia was significantly related to a better outcome. CONCLUSIONS: Some prognostic indicators associated with functional outcome at discharge are available during the first few hours after onset of stroke. This is important for the management of the individual stroke patient and for organizing suitable rehabilitation planning.

Adult↗

PubMed2024

Uric Acid Levels and Cardiovascular and Cerebrovascular Diseases: A Mendelian Randomization Study.

INTRODUCTION: The relationship between uric acid (UA) levels and cardiovascular and cerebrovascular diseases (CCVD) is controversial. A two-sample Mendelian randomization (MR) study was conducted to explore the causal effects of UA levels on CCVD. METHODS: Genetic variants strongly associated with UA levels were selected as instrumental variables from the Genome-Wide Association Study (GWAS) dataset. The GWAS data, sourced from the Global Urate Genetics Consortium (GUGC), comprised a sample size of 110,347 individuals. The selected CCVD outcomes included stroke, coronary artery disease (CAD), as well as atrial fibrillation and flutter. The primary analytical approach employed the inverse-variance weighted (IVW) method, supplemented by MR-Egger and weighted median as complementary methods. Sensitivity analysis was performed to test heterogeneity and pleiotropy. RESULTS: The MR analysis results indicated a causal association between UA levels and stroke (odds ratio [OR]: 1.002; 95% confidence interval [CI]: 1.000-1.003; p = 0.036), CAD (OR: 1.118; 95% CI: 1.044-1.197; p = 0.001), as well as atrial fibrillation and flutter (OR: 1.141; 95% CI: 1.037-1.256; p = 0.007). The results of MR-Egger and weighted median methods confirmed the direction of the IVW results, enhancing the robustness of the findings. No significant anomalies were detected in the sensitivity analysis. CONCLUSION: The MR study suggests that UA levels exert causal effects on stroke, CAD, as well as atrial fibrillation and flutter.

Humans↗

PubMed2005

Association of C-reactive protein with blood pressure and hypertension: life course confounding and mendelian randomization tests of causality.

BACKGROUND: C-reactive protein (CRP) has repeatedly been associated with blood pressure and prevalent and incident hypertension, but whether a causal link exists is uncertain. METHODS AND RESULTS: We assessed the cross-sectional relations of CRP to systolic blood pressure, pulse pressure, and prevalent hypertension in a representative sample of >3500 British women aged 60 to 79 years. For both outcomes, substantial associations were observed. However, these associations were greatly attenuated by adjustment for a wide range of confounding factors acting over the life course. We further investigated causality using a Mendelian randomization approach by examining the association of the 1059G/C polymorphism in the human CRP gene with CRP and with blood pressure, pulse pressure, and hypertension. The polymorphism was associated with a robust difference in CRP, and the expectation would be for higher blood pressure and pulse pressure and greater prevalence of hypertension among those carrying the genetic variant associated with higher CRP levels. This was not observed, and the predicted causal effects of CRP on blood pressure, pulse pressure, and hypertension using instrumental variables methods were close to 0, although with wide CIs. CONCLUSIONS: CRP levels are associated with blood pressure, pulse pressure, and hypertension, but adjustment for life course confounding and a Mendelian randomization approach suggest the elevated CRP levels do not lead to elevated blood pressure.

Aged↗

PubMed2026

Systematic Identification of Therapeutic Targets and Repurposed Drugs for Stroke: From Genome Causal Analysis to Multilevel Validation.

BACKGROUND: Stroke is a severe cerebrovascular disease characterized by narrow time windows and complications. This study aimed to identify novel drug targets and repurposed drugs for stroke. METHODS: This study used expression quantitative trait loci data from druggable genes in brain and blood as instrumental variables. Mendelian randomization, colocalization, and phenome-wide Mendelian randomization were applied to evaluate causal relationships and potential side effects, with stroke and ischemic stroke as primary outcomes. Preclinical validation used oxygen-glucose deprivation/reperfusion and middle cerebral artery occlusion/reperfusion models. Pharmacological and behavioral assessments evaluated the therapeutic potential of candidate targets and drugs. Additionally, proteomic sequencing was performed following GGCX (γ-glutamyl carboxylase) overexpression to explore its biological functions. RESULTS: Elevated GGCX expression in brain and blood was potentially causally associated with reduced risk of stroke and ischemic stroke, supported by colocalization evidence, although potential cardiovascular risks could not be excluded. Drug repositioning identified ifenprodil as a candidate agent that reduced infarction volume, improved motor and cognitive functions, and reversed GGCX downregulation in mice. Ifenprodil treatment and GGCX overexpression alleviated oxygen-glucose deprivation/reperfusion-induced injury and upregulated GGCX expression. Mechanistically, GGCX conferred neuroprotection by regulating protein homeostasis, suppressing inflammation, promoting metabolic recovery, and modulating nuclear transcriptional regulation. CONCLUSIONS: This study established a potential causal link between GGCX and stroke risk, particularly ischemic stroke. GGCX represents a promising therapeutic target for ischemic stroke. Targeted GGCX expression upregulation and drug repurposing, particularly ifenprodil, may offer novel therapeutic avenues. Further validation is warranted to assess clinical efficacy and safety.

Animals↗

PubMed2026

Single-cell expression quantitative trait locus Mendelian randomization reveals immune cell-specific causal regulatory networks and actionable targets in polycystic ovary syndrome.

ObjectiveTo systematically investigate whether the pathogenesis of polycystic ovary syndrome (PCOS) is causally related to dysregulated gene expression in specific immune cell subsets, and to evaluate the potential of these causal genes as actionable drug targets.MethodsThis study employed a two-sample Mendelian randomization (MR) framework using publicly available genome-wide association study (GWAS) summary statistics. The participant data included 797 PCOS cases and 140,558 controls (no direct patient recruitment was involved). Instrumental variables were derived from high-resolution immune cell-specific single-cell expression quantitative trait locus (sc-eQTL) data (OneK1K project) across 14 immune cell types. Primary analyses utilized the inverse-variance weighted (IVW) method. Shared causal variants were validated using Bayesian colocalization. Phenome-wide association analysis (PheWAS), external transcriptomic dataset validation (GSE8157), and DrugBank database screening were conducted for pleiotropy assessment and drug repositioning.ResultsMR analysis revealed genome-wide significant causal associations for GLIPR1 in non-classical monocytes (Mono NC) and XBP1 in CD4+ effector memory T cells (CD4 ET) with PCOS risk. Higher GLIPR1 expression was associated with a decreased PCOS risk (OR = 0.669, P = 4.34×10-6), whereas higher XBP1 expression was associated with an increased risk (OR = 1.406, P = 9.53×10-8). Colocalization analysis confirmed that GLIPR1 shares a causal variant with PCOS (PP.H4 = 96.73%). PheWAS and external validation confirmed the safety profile and significant upregulation (P = 0.03) of GLIPR1. Drug repositioning identified SOT-107, a Phase III protein therapy drug, as a potential interacting agent for GLIPR1.ConclusionsThis sc-eQTL MR study reveals immune cell-specific causal regulatory networks in PCOS. GLIPR1 in non-classical monocytes represents a high-confidence protective target, while XBP1 provides suggestive evidence for immune-mediated pathogenesis. The candidate drug SOT-107 highlights theoretical repositioning opportunities, though rigorous preclinical validation remains required.

Female↗

PubMed2004

Does consumer satisfaction information matter? Evidence on member retention in FEHBP plans.

Taking advantage of a natural experiment, this study explores the crucial link between consumer satisfaction, distribution of consumer satisfaction information, and member retention at open enrollment. Multiple data sources, panel data regression analysis, and instrumental variable techniques inform how retention is affected by consumer satisfaction, before and after free distribution of report card information, controlling for market structure, consumer characteristics, premiums, benefits, and other plan attributes in about 250 Federal Employee Health Benefit Program (FEHBP) plans nationwide. Study results suggest that consumer satisfaction boosts member retention. Free distribution of consumer satisfaction information to federal employees during open enrollment is associated with lower member retention, which may suggest that consumers might have used this newly distributed information and then decided to withdraw from their previous plans.

Consumer Behavior↗

PubMed2006

Quality improvement implementation and hospital performance on patient safety indicators.

This study examines the association between scope of Quality Improvement (QI) implementation in hospitals and hospital performance on patient safety indicators. Secondary data sources included a 1997 survey of hospital QI practices, Medicare Inpatient Database, American Hospital Association's Annual Survey of Hospitals, the Bureau of Health Professions' Area Resource File, and two proprietary data sets. Using a sample of 1,784 community hospitals, the study employed two-stage instrumental variables estimation in which predicted values of four QI scope variables and control variables were used to estimate four patient safety indicators. Involvement by multiple hospital units in the QI effort is associated with worse values on all four patient safety indicators. Percentages of hospital staff and of senior managers participating in QI teams exhibited no statistically significant association with any patient safety indicator. Percentage of physicians participating in QI teams is associated with better values on two patient safety indicators.

Health Care Surveys↗

PubMed2026

Causal Effects of Gut Microbiota on Morning Chronotype, Insomnia and Sleep Duration: A Two-Sample Mendelian Randomization Study.

BACKGROUND: The gut microbiota has been shown to be closely associated with brain function; however, whether it exerts a causal influence on sleep traits remains to be further explored. Mendelian randomization (MR) is an emerging epidemiological approach that uses whole-genome sequencing data to infer causal relationships. In this study, we conducted a two-sample MR analysis to investigate the causal effects of gut microbiota on three domains of sleep traits: morning chronotype, insomnia, and sleep duration. METHODS: Single nucleotide polymorphisms strongly associated with 196 gut microbiota taxa were selected as instrumental variables. Morning chronotype, insomnia, and sleep duration were used as outcomes. MR and sensitivity analyses were performed to assess the causal relationships between gut microbiota and sleep traits. RESULTS: Three taxa (Bifidobacteriales, Bifidobacteriaceae, and Bifidobacterium) were negatively associated with morning chronotype, while Tyzzerella 3 showed a positive causal effect on morning chronotype. Oscillibacter was negatively associated with insomnia, whereas four taxa (Negativicutes, Selenomonadales, the Clostridium innocuum group, and Lachnoclostridium) were identified as risk-increasing factors for insomnia. Lentisphaerae and Victivallaceae were positively associated with sleep duration. Actinobacteria and Alistipes had negative effects on long sleep duration, whereas Ruminiclostridium 6 was positively associated with long sleep duration. Four taxa (Victivallales, Anaerofilum, Lentisphaerae, and Lentisphaeria) were negatively associated with short sleep duration. CONCLUSIONS: Our findings suggest that specific gut microbiota taxa may be positively or negatively associated with sleep traits. These results offer new insights into the potential role of gut microbiota in sleep regulation and provide a basis for future studies aimed at understanding whether modulating microbial composition could influence sleep health.

Mendelian randomization↗

PubMed2026

Causal effects of cholelithiasis on hepatopancreatobiliary diseases: a multi-cohort Mendelian randomization study.

BACKGROUND: Cholelithiasis is commonly associated with multiple hepatopancreatobiliary diseases, yet whether these relationships reflect causal mechanisms or shared risk factors remains unclear. METHODS: We performed a phenome-oriented two-sample Mendelian randomization (MR) analysis to evaluate the causal impact of genetic liability to cholelithiasis across hepatopancreatobiliary outcomes. Independent genome-wide significant variants were selected as instrumental variables. Primary analyses used inverse variance weighting, complemented by sensitivity analyses, reverse MR, and multivariable MR adjusting for body mass index (BMI). RESULTS: Genetic predisposition to cholelithiasis was associated with increased risk of acute pancreatitis and extrahepatic cholangiocarcinoma (eCCA), with consistent directionality across datasets.The association with acute pancreatitis was interpreted as a positive control, whereas the null association with alcohol-induced acute pancreatitis served as a negative control. No causal association was observed for portal vein thrombosis. Sensitivity analyses, including MR-PRESSO and MR Steiger filtering, supported the robustness and directionality of the causal estimates. Reverse MR analyses showed no consistent evidence supporting reverse causality. Multivariable MR indicated that observed effects were not fully explained by BMI-related pathways. CONCLUSION: These findings suggest that cholelithiasis susceptibility may contribute to the broader hepatopancreatobiliary disease network, extending its clinical relevance beyond a localized biliary disorder.

Mendelian Randomization Analysis↗

PubMed2026

Social isolation and 59 common health conditions: insights from observational and genetics analyses.

BACKGROUND: The impacts of social isolation on diverse health conditions and how it contributes to health risks remain unclear. We aimed to investigate the associations of social isolation with 59 health conditions among older adults. METHODS: Participants from the UK Biobank without baseline diagnosis of the included diseases were selected. Social isolation was assessed with three questions. The 59 health conditions included all-cause mortality, 5 cause-specific mortalities, and 53 diseases. We used an instrumental variable from multivariable common factor GWAS in Mendelian randomization (MR) to explore causal links of social isolation with diseases. Omics analyses were conducted to assess the roles of Olink plasma proteins and metabolomics, and PERM was calculated to evaluate the influence of other factors. RESULTS: A total of 489,741 individuals [266,706 (54.5%) women; mean age 56.5 years (SD 8.1)] were included. During a median follow-up of 12.5 years, social isolation was uncorrelated with the majority of 59 health conditions. Significantly, it was associated with increased risks of all-cause [adjusted HR (aHR) 1.28, 95% CI 1.25-1.32], 5 cause-specific mortalities (aHR range, 1.18-1.38), and 11 specific diseases (aHR range, 1.08-1.17). Living alone was the strongest item of isolation in predicting mortality (aHR range, 1.18-1.45) and selected diseases. MR analyses offered little evidence to support a causal link between social isolation and these diseases. The proteins involved in these associations are predominantly related to "response to stimulus". Proteomic signatures (PERM, 36%-49%), health behaviours (32%-59%), and socioeconomic factors (22%-42%) were the main explanatory factors linking social isolation to 8 health outcomes. CONCLUSIONS: Social isolation is associated with elevated risks of 17 out of the 59 examined adverse health outcomes, predominantly mortality-related conditions; however, MR analyses indicate an absence of evidence supporting causality for these associations.

Humans↗

PubMed2025

Severe traumatic brain injury and risk for osteoporosis: a Mendelian randomization study.

BACKGROUND: The influence of nervous system activity on bone remodeling has been widely reported. Patients with traumatic brain injury (TBI) exhibit a high incidence of osteoporosis (OP). Nevertheless, the relationship between severe TBI (sTBI) and OP remains unclear. We performed Mendelian randomization (MR) analysis to assess the potential causal relationship between sTBI and OP. METHODS: Data on exposure and outcomes were acquired from genome-wide association studies (GWAS). Data on OP was obtained from UK Biobank (5,266 cases of OP and 331,893 controls). Data on sTBI was obtained from FinnGen Consortium (6,687 cases and 370,590 controls). Single nucleotide polymorphisms (SNPs) that underwent strict screening were regarded as instrumental variables. We used the inverse variance weighted (IVW), constrained maximum likelihood and model averaging (CML-MA), MR-Egger, and weighted median methods for causal effect estimation. To test the reliability of the results, sensitivity analysis was performed using Cochran's Q, leave-one-out, MR-Egger intercept, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) tests. RESULTS: The IVW analysis indicates that sTBI and OP have a suggestive association (odds ratio [OR] = 1.004, 95% confidence interval [CI] = 1.001,1.007; p = 0.002), and no heterogeneity (Q = 11.536, p = 0.241) or directional pleiotropy was observed (egger_intercept = 7.368 × 10- 5, p = 0.870). The robustness of the results was validated using a leave-one-out sensitivity test. CONCLUSION: According to the MR analysis, sTBI and OP are likely suggestively related. This finding contributes to the prevention of OP in patients with sTBI and provides genetic evidence supporting the theory that the nervous system regulates bone remodeling.

Humans↗

PubMed2025

Causal association between non-steroidal anti-inflammatory drugs use and the risk of benign prostatic hyperplasia: a univariable and multivariable Mendelian randomization study.

BACKGROUND: The results of earlier observational research on the relationships between the usage of non-steroidal anti-inflammatory medicines (NSAIDs) and the risk of benign prostatic hyperplasia (BPH) have been inconsistent. METHODS: To assess these associations, we performed both univariable and multivariable Mendelian randomization (MR) studies. Instrumental variables (IVs) associated with exposures at the significance level (p < 5 × 10-6) were selected from a comprehensive meta-analysis conducted by the United Kingdom Biobank (UKB). Summary data for BPH were obtained from the FinnGen consortium, which comprised 30,066 cases and 119,297 controls. Sensitivity analyses were performed to evaluate heterogeneity and pleiotropy. RESULTS: We found evidence by univariable MR (UVMR) that genetically predicted NSAIDs use increased the risk of BPH (odds ratio [OR] per unit increase in log odds NSAIDs use: 1.164, 95% confidence interval [CI]: 1.041-1.302, p = 0.008). After controlling for inflammation in multivariable MR (MVMR), the link persisted (OR: 1.165, 95% CI: 1.049-1.293, p = 0.004). There were no indications of potential heterogeneity and pleiotropy in UVMR and MVMR analyses. CONCLUSION: The results of the MR estimates suggest that genetically predicted NSAIDs use may elevate the risk of BPH. This outcome prompts the imperative for deeper exploration into potential underlying mechanisms.

Humans↗

PubMed2025

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

BACKGROUND: Recent 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. METHODS: A 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. RESULTS: There 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). CONCLUSION: Our 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.

Humans↗

PubMed2026

Programmed cell death and risk of diabetic retinopathy: a Mendelian randomization study.

BACKGROUND: Programmed cell death (PCD) plays an important role in diabetic retinopathy (DR); however, the underlying genetic mechanisms remain unclear. We used Mendelian randomization (MR) to investigate the causal relationships between PCD-related genes and DR. This study aimed to investigate the effects of PCD on the risk of DR by conducting MR analysis. METHODS: Summary statistics from gene expression quantitative trait loci (eQTL) studies (31,684 Europeans) were analyzed. Genetic instrumental variables were selected using cis-eQTL single-nucleotide polymorphisms (SNPs; P < 5 × 10- 8). Summary data-based MR (SMR) was employed to assess causal associations between PCD-related genes and DR, with three additional MR methods used for sensitivity testing. Bayesian colocalization was used to examine the shared regulatory mechanisms between PCD QTLs and DR risk loci. RESULTS: Sensitivity and colocalization analyses revealed six genes that affected DR: cathepsin H (CTSH), NAD(P)H: quinone oxidoreductase 1 (NQO1), tribbles pseudokinase 3 (TRIB3), and phosphoglycerate mutase 5 (PGAM5), which increased DR risk, and iron-responsive element binding protein 2 (IREB2) and tumor necrosis factor (TNF), which exhibited protective effects. Multivariate MR confirmed significant causal effects for CTSH, IREB2, and PGAM5 (p < 0.050). Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis (including 10 STRING-derived genes) revealed that 13 genes were enriched in necroptosis, apoptosis, mitophagy, and TNF signaling pathways in DR. CONCLUSIONS: This MR study supports the causal involvement of PCD in DR and identifies candidate genes (CTSH, IREB2, PGAM5, NQO1, TRIB3, and TNF) for therapeutic targeting or biomarker development in DR prevention or diagnosis.

Humans↗