Causal Association Research Articles

Sex hormones and risk of lung and colorectal cancers in women: a Mendelian randomization study

The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies on sex hormones and from the Trøndelag Health Study (HUNT) and large consortia on cancers. There was suggestive evidence of 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio 0.60, 95% confidence interval 0.37–0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry.

Partnership quality and maternal depressive symptoms in the transition to parenthood: a prospective cohort study

BackgroundPregnancy and childbirth are critical life events which lead to significant changes in family structures and roles, thus having a substantial impact on partner relationship and maternal wellbeing. A dysfunctional partnership during this critical time of life has been associated with maternal depressiveness. However, sub-components of partnership quality and the causal relation with maternal symptoms of depression in the perinatal period have been sparsely studied so far. The current study aims to longitudinally assess the course of relationship quality and its sub-components from pregnancy to postpartum and to test a potential causal association with maternal symptoms of depression in the perinatal period.MethodsDiffering from previous studies, partnership quality and symptoms of depression have been assessed prospectively and longitudinally from an early stage of pregnancy (second trimester) until six months postpartum. Cross-lagged panel models were applied to investigate a potential causal relationship between partnership quality and maternal depressive symptoms.ResultsRelationship quality decreased significantly during the transition to parenthood (p < .05) with the steepest decline referring to tenderness (p < .001). We also found a substantial association of relationship quality and maternal depressiveness, but no indication for a clear causal direction of this association.ConclusionsOur results suggest that relationship quality and maternal depressiveness are substantially related in the perinatal period, thus pointing to the need of early prevention and intervention programs for peripartum women and their partners to prevent adverse outcome for the couple and the family.

Association between brain resting-state functional activities and migraine: a bidirectional mendelian randomization study

Researchers have conducted extensive research on the correlation between brain resting-state functional activities (RSFA) and migraine. However, we still do not fully understand the exact nature of the causal relationship between these RSFA and migraine. We conducted a bidirectional two-sample Mendelian randomization (MR) study to investigate the causal association between migraine and RSFA. We gathered summary statistics from genome-wide association studies for 191 resting-state functional magnetic resonance imaging phenotypes. We employed various analytical methods for bidirectional two-sample MR analyses. This included inverse variance weighted, weighted median, MR Egger, and the constrained maximum likelihood approaches. We also conducted pleiotropy and heterogeneity analyses to evaluate the robustness and reliability. We found the functional connectivity between the default mode and the central executive network (OR = 1.39, p = 4.77 × 10−4, FDR corrected p value = 0.040) and the intensity of spontaneous brain activity in the calcarine or lingual gyrus within the visual network (OR = 0.74, p = 5.94 × 10−4, FDR corrected p value = 0.040) having a causal effect on the risk of migraine. Our MR analysis provided genetic support for these networks, which may play an important role in influencing migraine susceptibility.

Multi-Ancestry Causal Association between Rheumatoid Arthritis and Interstitial Lung Disease: A Bidirectional Two-Sample Mendelian Randomization Study.

Background: Rheumatoid arthritis (RA) is associated with diverse extra-articular manifestations, including interstitial lung disease (ILD). No previous studies have examined the bidirectional relationship between RA and ILD using the Mendelian randomization (MR) analyses. Therefore, we aimed to investigate this subject using a two-sample bidirectional MR method. Methods: We performed bidirectional two-sample MR using summary statistics from genome-wide association studies (GWASs). The data are publicly available, de-identified, and from European (EUR) and East Asian (EAS) ancestries. Results: A total of 474,450 EUR participants and 351,653 EAS participants were included for either forward or reverse MR analysis. In our primary analysis, we found significant evidence of an increased risk of ILD associated with RA among individuals of EUR ancestry (ORMR-cML = 1.08; 95% confidence interval [CI] = 1.03-1.14; p = 0.003) and EAS ancestry (ORMR-cML = 1.37; 95% CI = 1.23-1.54; p < 0.001). Additionally, the reverse MR showed significant evidence of an increased risk of RA associated with ILD among those of EUR ancestry (ORMR-cML = 1.12; 95% CI = 1.05-1.19; p < 0.001). However, only one instrumental variable was selected in the EAS ILD GWAS, and there was no increased risk of RA associated with ILD in those of EAS ancestry (ORMR-cML = 1.02; 95% CI = 0.91-1.14; p = 0.740). Conclusions: Our findings indicate that RA and ILD have a bidirectional causal inference when using the MR analysis of GWAS datasets. The findings are only relevant for genetic predisposition; thus, further research is needed to determine the impact of non-genetic predispositions.

Infective Endocarditis Outcomes in Congestive Heart Failure Patients.

The aim of this study is to analyze the difference in hospital outcomes for infective endocarditis (IE) admissions with and without comorbid congestive heart failure (CHF). The National Inpatient Sample (NIS) was the database we used to find and sort patient data from inpatient hospitalizations. We then used logit probit regression to analyze the association between patients admitted for IE with and without CHF and their all-cause mortality rates. After collecting our sample population, we used propensity score matching to create our comparative cohorts of IE patients which were then analyzed to determine if there was an association between inpatient hospital outcomes and the presence of CHF. Among the patients admitted for IE, there was a statistically significant association between comorbid CHF diagnoses and an increase in all-cause mortality during hospital admission. The proportion of mortality was 7.8% during the hospitalization for IE admissions with comorbid CHF, while the proportion was 4.16% for the subset of IE admissions without comorbid CHF. The association of comorbid CHF and all-cause mortality during the hospital stay for IE admissions was significant with an odds ratio of 3.197 (2.089-4.891) after adjusting for age, sex, race, income, and other comorbidities. The association between the requirement for either temporary or continuous pacing during the hospital stay and co-existing CHF diagnosis in IE admissions was also significant with an odds ratio of 2.86 (1.720-4.761). Among the propensity-matched cohort analysis, there was a significantly higher proportion of IE admissions with co-existing CHF needing pacing (either temporary or continuous), 5.74% (3.96%-8.25%) compared to the IE cohort without comorbid CHF: 1.48% (0.71%-3.09%). With the results of our analyses proving a significant association between the presence of CHF and adverse in-hospital outcomes in IE admissions, it calls for further prospective and real-world studies to analyze the finer aspects of the association. This becomes important for clinicians in stratifying at-risk patients for a higher level of care and prognostication aspects of the treatment. Our study results prove a causative association between the presence of CHF and heart block in IE admissions. This could be useful for clinicians in planning appropriate management plans in the event of initial signs of bradycardia and hypotension developing in this patient population.

Dissecting shared genetic architecture between depression and body mass index

BackgroundA growing body of evidence supports the comorbidity between depression (DEP) and obesity, yet the genetic mechanisms underlying this association remain unclear. Our study explored the shared genetic architecture and causal associations of DEP with BMI.MethodsWe investigated the multigene overlap and genetic correlation between DEP (N > 1.3 million) and BMI (N = 806,834) based on genome-wide association studies (GWAS) and using the bivariate causal mixture model and linkage disequilibrium score regression (LDSC). The causal association was explored by bi-directional Mendelian randomization (MR). Common risk loci were identified through cross-trait meta-analyses. Stratified LDSC and multi-marker gene annotation analyses were applied to investigate single-nucleotide polymorphisms enrichment across tissue types, cell types, and functional categories. Finally, we explored shared functional genes by Summary Data-Based Mendelian Randomization (SMR) and further detected differential expression genes (DEG) in brain tissues of individuals with depression and obesity.ResultsWe found a positive genetic correlation between DEP and BMI (rg = 0.19, P = 4.07 × 10−26), which was more evident in local genomic regions. Cross-trait meta-analyses identified 16 shared genetic loci, 5 of which were newly identified, and they had influence on both diseases in the same direction. MR analysis showed a bidirectional causal association between DEP and BMI, with comparable effect sizes estimated in both directions. Combined with gene expression information, we found that genetic correlations between DEP and BMI were enriched in 6 brain regions, predominantly in the nucleus accumbens and anterior cingulate cortex. Moreover, 6 specific cell types and 23 functional genes were found to have an impact on both DEP and BMI across the brain regions. Of which, NEGR1 was identified as the most significant functional gene and associated with DEP and BMI at the genome-wide significance level (P < 5 × 10−8). Compared with healthy controls, the expression levels of NEGR1 gene were significant lower in brain tissues of individuals with depression and obesity.ConclusionsOur study reveals shared genetic basis underpinnings between DEP and BMI, including genetic correlations and common genes. These insights offer novel opportunities and avenues for future research into their comorbidities.

Systematic evaluation of multifactorial causal associations for Alzheimer's disease and an interactive platform MRAD developed based on Mendelian randomization analysis.

Alzheimer's disease (AD) is a complex degenerative disease of the central nervous system, and elucidating its pathogenesis remains challenging. In this study, we used the inverse-variance weighted (IVW) model as the major analysis method to perform hypothesis-free Mendelian randomization (MR) analysis on the data from MRC IEU OpenGWAS (18,097 exposure traits and 16 AD outcome traits), and conducted sensitivity analysis with six models, to assess the robustness of the IVW results, to identify various classes of risk or protective factors for AD, early-onset AD, and late-onset AD. We generated 400,274 data entries in total, among which the major analysis method of the IVW model consists of 73,129 records with 4840 exposure traits, which fall into 10 categories: Disease, Medical laboratory science, Imaging, Anthropometric, Treatment, Molecular trait, Gut microbiota, Past history, Family history, and Lifestyle trait. More importantly, a freely accessed online platform called MRAD (https://gwasmrad.com/mrad/) has been developed using the Shiny package with MR analysis results. Additionally, novel potential AD therapeutic targets (CD33, TBCA, VPS29, GNAI3, PSME1) are identified, among which CD33 was positively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. TBCA and VPS29 were negatively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. GNAI3 and PSME1 were negatively associated with the main outcome traits of AD, as well as with LOAD, but had no significant causal association with EOAD. The findings of our research advance our understanding of the etiology of AD.

A MR-PheWAS and bidirectional Mendelian randomization study: Exploring for causal relationships of pancreatic cancer.

It is unknown what causes pancreatic cancer. We conducted a phenome-wide Mendelian randomization analysis (MR-pheWAS), a bidirectional Mendelian study, and a systematic review of research in order to thoroughly investigate any causal association between pancreatic cancer and Atlas. We used phenome-wide Mendelian randomization analysis to test for associations between pancreatic cancer and 776 phenotypes (n = 452,264) of Atlas in the UK Biobank. Causality is confirmed by two-sample Mendelian randomization (MR) analysis using correlation found by false discovery rate correction. Simultaneously, a comprehensive evaluation of pancreatic cancer MR studies was conducted in order to complement our findings and harmonize the existing evidence. According to the inverse-variance-weighted model, a total of 41 out of 776 phenotypes had a nominal significance level (P < .05) genetic prediction association with pancreatic cancer. Only genetically predicted pancreatic cancer was shown to be linked with elevated eosinophil counts following false discovery rate correction (P = .031) when several tests were taken into account. Pancreatic cancer and eosinophils were shown to be positively causally associated to one another, establishing a self-loop, according to two-sample MR validation in the IEU database (OR = 1.011, 95% CI: 1.002-1.020, P = .010) (OR = 1.229, 95% CI: 1.037-1.458, P = .017). Although MR-pheWAS found a strong causal relationship between eosinophils and pancreatic cancer, it also found a negative exclusion value for each phenotype and a significant number of suggestive association phenotypes that offered guidance for further research.

Systematic evaluation of multifactorial causal associations for Alzheimer’s disease and an interactive platform MRAD developed based on Mendelian randomization analysis

Alzheimer’s disease (AD) is a complex degenerative disease of the central nervous system, and elucidating its pathogenesis remains challenging. In this study, we used the inverse-variance weighted (IVW) model as the major analysis method to perform hypothesis-free Mendelian randomization (MR) analysis on the data from MRC IEU OpenGWAS (18,097 exposure traits and 16 AD outcome traits), and conducted sensitivity analysis with six models, to assess the robustness of the IVW results, to identify various classes of risk or protective factors for AD, early-onset AD, and late-onset AD. We generated 400,274 data entries in total, among which the major analysis method of the IVW model consists of 73,129 records with 4840 exposure traits, which fall into 10 categories: Disease, Medical laboratory science, Imaging, Anthropometric, Treatment, Molecular trait, Gut microbiota, Past history, Family history, and Lifestyle trait. More importantly, a freely accessed online platform called MRAD (https://gwasmrad.com/mrad/) has been developed using the Shiny package with MR analysis results. Additionally, novel potential AD therapeutic targets (CD33, TBCA, VPS29, GNAI3, PSME1) are identified, among which CD33 was positively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. TBCA and VPS29 were negatively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. GNAI3 and PSME1 were negatively associated with the main outcome traits of AD, as well as with LOAD, but had no significant causal association with EOAD. The findings of our research advance our understanding of the etiology of AD.

A Mendelian randomization study of the association between serum uric acid and osteoporosis risk.

The relationship between serum uric acid (SUA) and osteoporosis (OP) has yielded conflicting results in observational studies. This Mendelian randomization (MR) study aims to elucidate the causal association between SUA and OP. A two-sample MR analysis was conducted using summary-level data from genome-wide association studies (GWAS). Two sets of polygenic instruments strongly associated (p < 5 × 10-8) with SUA were extracted from the CKDGen consortium and UK biobank. Polygenic instruments associated with OP (p < 5 × 10-8) were derived from FinnGen biobank and UK biobank. Inverse variance weighting (IVW) was employed as the primary analysis method. Additionally, we utilized MR-Egger, weighted median, the simple mode method, and the weighted mode as complementary analyses. Cochran's Q statistics were used to assess heterogeneity, with MR-Egger intercept testing and MR pleiotropy residual sum and outlier (MR-PRESSO) to examine horizontal pleiotropy. Sensitivity analysis was performed using the leave-one-out method. The IVW analysis conducted across four groups confirms no significant causal relationship between SUA concentration and OP: UKB-UKB (OR: 1.001, 95% CI: 0.999-1.003, p=0.464), CKD-UKB (OR: 1.001, 95% CI: 0.999-1.003, p=0.349), UKB-Fin (OR: 0.934, 95% CI: 0.747-1.168, p=0.549), CKD-Fin (OR: 1.041, 95%CI: 0.934-1.161, p=0.470). Furthermore, additional four MR analyses corroborated these findings. Upon excluding all outliers identified by the MR-PRESSO test, no significant directional pleiotropy was observed, except for some data heterogeneity noted in the UKB-UKB group (Q=50.65, P=0.002). Additionally, a leave-one-out analysis indicated that no single SNP exerted undue influence on the results. This MR analysis provides convincing genetic evidence that there is no causal association between SUA and OP, SUA is unlikely to increase or reduce the risk of OP.

Mendelian randomization study reveals a causal relationship between body mass index in children and risk of autoimmune diseases.

Newly emerging evidence indicates that body mass index (BMI) is a potential risk factor for autoimmune diseases (ADs). Nevertheless, the exact causal connection between ADs and BMI in children remains uncertain. To investigate the relationship between BMI in children and ADs, a 2-sample Mendelian randomization (MR) analysis was conducted. In this analysis, several regression methods were utilized, including the inverse-variance weighted (IVW), weighted mode, weighted median, and MR-Egger regression. Publicly available summary statistics datasets from meta-analyses of genome-wide association studies (GWAS) were employed, specifically focusing on BMI in children of European descent (n = 39,620) from the UK Biobank (ebi-a-GCST90002409) as the exposure group. The outcomes were derived from individuals included in the Finnish biobank study FinnGen, with 42,202 cases and 176,590 controls representing the ADs group (finngen_R5_AUTOIMMUNE). For instrumental variables, we carefully selected 16 single nucleotide polymorphisms (SNPs) from GWAS on BMI in children. Our analysis implemented the IVW method, which demonstrated supporting evidence for a causal association between BMI in children and ADs. The results indicated a significant effect with a beta coefficient of 0.22, standard error (SE) of 0.05, odds ratio (OR) of 1.25, and a 95% confidence interval (CI) ranging from 1.13 to 1.38, with a P-value of <.05. We also utilized the weighted median method, which yielded similar findings to the IVW method. The OR estimates from the weighted median analysis showed a beta coefficient of 0.20, SE of 0.06, OR of 1.22, and a 95% CI ranging from 1.08 to 1.36, with a P-value of <.05. No significant association was observed in the MR-Egger and Weighted mode analyses. The findings from the MR analysis suggest that there is evidence supporting a potential causal link between BMI in children and an increased susceptibility to ADs.

Decoding skin mysteries: Unveiling the link between microbiota and keloid scars through a Mendelian randomization study.

The cause of keloids remains unclear, but studies suggest a link between skin microbiota and keloid formation. However, the causal relationship has not been confirmed. This study utilized Genome-Wide Association Studies (GWAS) data from 2 population-based German cohorts, comprising a total of 1656 skin samples. To bolster the reliability of our results, we incorporated GWAS data from 3 keloid cohorts, encompassing 2555 patients and 870,556 controls (GWAS ID: keloid1, ebi-a-GCST90018874; keloid2, bbj-a-131; keloid3, ebi-a-GCST90018654). Subsequently, we employed bidirectional 2-sample Mendelian randomization (MR) analysis to probe the causal relationship between the variables. The primary method employed was the inverse-variance weighted (IVW) method, supported by heterogeneity analysis, horizontal pleiotropy testing, outlier detection, and "leave-one-out" sensitivity analysis. By synthesizing the results from 3 groups of MR analyses, we discovered a negative causal association between a.ASV063 [Finegoldia (unc.)] located on the volar forearm and keloid disease (IVW (keloid1) odds ratio (OR): 0.939, 95% confidence interval (CI): 0.886-0.994, P = .032; IVW (keloid2) OR: 0.897, 95% CI: 0.813-0.990, P = .031; IVW (keloid3) OR: 0.900, 95% CI: 0.825-0.981, P = .017). Similarly, a negative causal relationship may also exist between the genus: Bacteroides from the antecubital fossa and keloid disease (IVW (keloid1) OR: 0.928, 95% CI: 0.884-0.973, P = .002; IVW (keloid2) OR: 0.891, 95% CI: 0.820-0.968, P = .007; IVW (keloid3) OR: 0.918, 95% CI: 0.849-0.992, P = .030). Additionally, no reverse causation was found, with all analyses showing no signs of horizontal pleiotropy or heterogeneity. This study offers new insights for the prevention and treatment of keloids.

Novel Insights into Causal Effects of Serum Lipids and Apolipoproteins on Cardiovascular Morpho-Functional Phenotypes.

Previous observational studies have explored the association between serum lipids, apolipoproteins, and adverse ventricular/aortic structure and function. However, whether a causal link exists is uncertain. This study employed a two-sample Mendelian randomization (MR), colocalization, reverse, and multivariable MR (MVMR) approach to examine the causal associations among five serum lipids, two apolipoproteins, and 32 cardiac magnetic resonance (CMR) traits. Utilizing single-nucleotide polymorphisms (SNPs) linked to serum lipids and apolipoproteins as instrumental variables. CMR traits from seven independent genome-wide association studies served as preclinical endophenotypes, offering insights into aortic and cardiac structure/function. The primary analysis utilized a random-effects inverse variance method (IVW), followed by sensitivity and validation analyses. In the primary IVW MR analyses, genetically predicted low-density lipoprotein cholesterol (LDL-C) levels were positively correlated with increased descending aorta strain (DAo strain) (β = 0.098; P = 2.69E-07) and ascending aorta strain (AAo strain) (β = 0.079; P = 5.19E-05). Genetically predicted high-density lipoprotein cholesterol (HDL-C) levels were positively correlated with left ventricular radial peak diastolic strain rate (LV-PDSRll) (β = 0.176; P = 2.89E-05) and the left ventricular longitudinal peak diastolic strain rate (LV-PDSRrr) (β = 0.059; P = 2.44E-06), and negatively correlated with left ventricular regional wall thickness (LVRWT). While apolipoprotein B (ApoB) levels were positively correlated with AAo strain (β = 0.076; P = 1.16E-05), DAo strain (β = 0.065; P = 2.77E-05). A shared causal variant was identified to demonstrate the associations of ApoB with AAo strain and DAo strain using colocalization analysis. Sensitivity analyses confirmed the robustness of these associations. Targeting lipid and apolipoprotein levels through interventions may provide novel strategies for the primary prevention of CVDs.

Causality of visceral adipose tissue on chronic kidney disease and renal function measure indicators, and mediation role of hypertension: Mendelian randomization study.

Although chronic kidney disease (CKD) is associated with obesity, few studies have used visceral adipose tissue (VAT) as an indicator to investigate its causal effect on CKD. Therefore, Mendelian randomization (MR) was employed to study the causal effects of VAT on CKD and its potential mediation by hypertension. Genome-wide association study (GWAS) statistics on VAT exposure were obtained from the UK Biobank, while GWAS datasets of CKD outcomes were obtained from CKDGen and FinnGen (validation study). Furthermore, VAT was considered the exposure, with the estimated glomerular filtration rate based on creatinine (eGFR (crea)), estimated glomerular filtration rate based on cystatin C (eGFR(cys)), and blood urea nitrogen (BUN) employed to assess the causal effect of VAT on kidney test indicators. Lastly, a two-step MR method was used to study the mediating role of hypertension in the pathogenesis of VAT among patients with CKD. VAT exhibited a positive causal association with CKD, irrespective of whether the GWAS datasets from CKDGen (odds ratio [OR] = 1.18, 95% CI: 1.08 to 1.29, P = 1.433140e-04) or FinnGen (1.47, 1.30 to 1.67, p = 2.500000e-09). VAT was not causally associated with eGFR (crea) (1.00, 0.99 to 1.00, p = 0.53), was negatively associated with eGFR (cys) (0.95, 0.93 to 0.97, P = 5.070000e-10), and was positively associated with BUN (1.02,1.01 to 1.02, P = 7.824860e-04). The mediating effect of VAT on CKD via hypertension was 45.8% (95% CI: 26.4 65.1). VAT has a positive causal effect on CKD, with hypertension playing a significant role. However, the effects of VAT on renal function indicators require further investigation.

Ionizing radiation and skin cancer—a review of current evidence

Cancer of the skin represents a challenge for radiological protection, as it is very common and involves the largest organ of the human body, which is exposed to environmental stress, including ionizing radiation. The most common subtypes, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) have very low mortality. Current consideration of skin cancer in radiological protection is mainly based on data from the 1990s, which indicate that BCC may be induced by ionizing radiation, SCC is only weakly associated with ionizing radiation, and malignant melanoma (MM) is not considered as ionizing radiation-induced. In a semi-systematic review of the evidence between 1990 and 2023, we snowballed 19 index articles. We identified 29 articles with information on a potential dose-response relationship between skin cancer and ionizing radiation exposure and assessed the evidence for a causal association. Exposure situations included a-bomb survivors, therapeutic and occupational exposure (airlines, nuclear and medical facilities) and residents exposed to radon. There is currently no epidemiological evidence that MM or SCC are caused by ionizing radiation. The only skin cancer type with evidence for a causal relationship is BCC, and evidence is limited to exposures above 0.5 Gy with a wide range of risk levels per dose. Thus, ionizing radiation-inducible skin cancer refers to BCC only and only at levels of exposure beyond those experienced by the vast majority of people exposed today.

Circulating levels of cytokines and risk of urologic cancers: a two-sample Mendelian randomization study

BackgroundChronic inflammation is associated with the etiology of various cancers. However, there is a lack of systematic research in urologic cancers. This study aims to use a two-sample Mendelian randomization (MR) approach to evaluate the role of circulating cytokines in the development of urologic cancers.MethodsWe obtained the summary-level data for bladder cancer (373,295 cases and 372,016 controls), prostate cancer (462,933 cases and 459,664 controls), and kidney cancer (463,010 cases and 461,896 controls) from the UK Biobank. Genetic variations linked to 41 circulating cytokines were used as instrumental variables (IVs) in meta-analyses of genome-wide association studies (GWASs) involving 8,293 individuals from Finland. We primarily used the inverse-variance weighted (IVW) method to assess the potential associations between the 41 cytokines and the risk of 3 common urologic cancers. Weighted-median method, weighted mode and simple-median method were used to assess the sensitivity. Heterogeneity and pleiotropic outlier were evaluated by Cochran's Q test and MR-Egger regression. Genetic correlation, colocalization analysis and multivariable MR analysis were used to further validate the potential pleiotropy.ResultsAfter the Bonferroni correction, there was an observed association between elevated genetically predicted levels of CCL27 and a heightened risk for bladder cancer. Conversely, IL-12p70 levels were found to have a protective association against the risk of bladder cancer. Sensitivity analyses utilizing various IV sets and MR approach remained robust. Furthermore, we found potential associations of 7 cytokines with urologic cancers (4.07 × 10−4 ≤ P < 0.05).ConclusionOur study supported causal associations between CCL27, IL-12p70 and bladder cancer risk and potential associations of 7 cytokines with the risk of urologic cancers, helping us to further understand the pathogenesis of urologic cancers and providing clues for improving diagnostic accuracy and therapies.

Association between circulating inflammatory proteins and benign prostatic disease: a Mendelian randomization study

Previous research has suggested that circulating inflammatory proteins are associated with benign prostatic disease (BPD). This Mendelian randomization (MR) study was conducted to further investigate the causal relationship between 91 inflammatory proteins and BPD. Genome-wide association study (GWAS) summarized data of benign prostatic hyperplasia (BPH) and prostatitis were obtained from the FinnGen Biobank. The latest study offered the GWAS data on 91 proteins related to inflammation. We performed a bidirectional MR to investigate the causal association between inflammatory proteins and BPD. The outcomes of the IVW method indicated that decreased levels of circulating interleukin-17 C (IL-17 C) (OR = 0.92, 95%CI = 0.85–0.99, p-value = 0.0344) were suggestively associated with a higher risk of BPH and elevated levels of interleukin-10 receptor subunit alpha (IL-10RA) (OR = 1.24, 95%CI = 1.05–1.47, p-value = 0.0132) and urokinase-type plasminogen activator (uPA) (OR = 1.13, 95%CI = 1.00–1.28, p-value = 0.0421) were suggestively related to a higher risk of prostatitis. Furthermore, reverse MR revealed that BPH may promote the expression of circulating factors, including natural killer cell receptor 2B4 (CD244) (OR = 1.07, 95%CI = 1.01–1.13, p-value = 0.0192), T-cell surface glycoprotein CD6 isoform (CD6) (OR = 1.07, 95%CI = 1.01–1.13, p-value = 0.0192), and leukemia inhibitory factor receptor (LIF-R) (OR = 1.07, 95%CI = 1.01–1.15, p-value = 0.0163). Moreover, the results of sensitivity analyses indicate that heterogeneity and horizontal pleiotropy are unlikely to distort the findings. The results of this study indicate a potential association between circulating inflammatory proteins and BPD, which may become new diagnostic indicators or drug targets for clinical application in the prevention and treatment of BPD. However, further investigation is required.

Investigating the dynamic nexus between fiscal deficit and inflation: empirical evidence from BRICS economies

PurposeThe debate surrounding whether fiscal actions are responsible for inflation has been a central focus in macro-public finance. In this regard, the present study makes a novel attempt to assess the nexus between fiscal deficit and inflation in the presence of output growth, trade openness and money supply using a balanced panel dataset from Brazil, Russia, India, China, and South Africa (BRICS) economies.Design/methodology/approachIn conducting the empirical analysis, the study initially addresses the issues of cross-section dependency, heterogeneous slope coefficients and nonstationarity. The assessment of long-run cointegration was carried out by using novel third-generation cointegration tests introduced by Westerlund and Edgerton (2008) and Banerjee and Carrion-i-Silvestre (2017). The authors utilise the advanced and latest estimation technique, the cross-section augmented autoregressive-distributed lag (CS-ARDL) model, for long-run and short-run analyses. Finally, to investigate the causal relationship between fiscal deficit and inflation within a panel framework, this study employs the novel test (JKS) introduced by Juodis et al. (2021).FindingsUsing recent econometric tests, the study validates the existence of cross-sectional dependency and slope heterogeneity. The results of the third-generation cointegration test by Westerlund and Edgerton (2008) and Banerjee and Carrion-i-Silvestre (2017) show that the variables are cointegrated in the long run. The CS-ARDL model revealed a positive relationship between inflation and fiscal deficit. The implication of this finding suggests that the fiscal deficit plays an inflationary role in BRICS economies. Finally, the JKS causality test results found a bi-directional causal association between fiscal deficit and inflation.Practical implicationsThe findings suggest several significant policy recommendations. It is recommended that a well-executed fiscal consolidation strategy be adopted to attain sound fiscal health and lower inflation. A disciplined fiscal approach is not only vital for effective monetary policy but also essential for maintaining macroeconomic stability. Monetary authorities must establish credible practices to effectively manage the macroeconomic system, and policy stances should align with the specific needs of the economy. The bidirectional causality between fiscal deficit and inflation suggests that relying solely on fiscal measures is inadequate for managing inflationary pressures or stabilising fiscal balances. Thus, a more comprehensive approach is required, including measures such as sustaining economic growth, reducing import dependency, diversifying exports and ensuring exchange rate stability.Originality/valueNumerous empirical studies have explored the link between fiscal deficit and inflation. However, most research studies within BRICS economies have focused on individual countries rather than considering the group as a whole. This limited scope may fail to capture the unique characteristics and interactions within these economies. To the best of the author’s knowledge, the present study is the first attempt to examine the issue from a panel perspective across BRICS economies. The methodological novelty of the present study is that it represents the first attempt, at least within emerging market economies, to investigate the nexus between fiscal deficit and inflation using second- and third-generation econometric models. From a policy perspective, the authors highlight that BRICS economies must prioritise fiscal discipline through measures such as reducing unproductive expenditure and improving tax collection. Close coordination between fiscal and monetary authorities is essential to ensuring that monetary policy supports fiscal consolidation efforts while maintaining price stability.

Plasma metabolome mediates the causal relationship between immune cells and heart failure: a two-step bidirectional Mendelian randomization study.

Prior research has established a correlation between immune cell activity and heart failure (HF), but the causal nature of this relationship remains unclear. Furthermore, the potential influence of metabolite levels on this interaction has not been comprehensively explored. To address these gaps, we employed a bidirectional Mendelian randomization (MR) approach in two stages to examine whether metabolite levels can mediate the causal relationship between immune cells and HF. Genetic information was extracted from summary data of genome-wide association studies. By applying a two-sample, two-step MR approach, we investigated the causal relationships among immune cells, metabolite levels, and HF, with a specific focus on the mediating effects of metabolites. Sensitivity analysis techniques were implemented to ensure the robustness of our findings. MR analysis revealed significant causal associations between HF and eight specific immune cells and five metabolites. Mediation analysis further identified three mediated relationships. Particularly, hexadecenedioate (C16:1-DC) mediated the influence of both the CD28- CD127- CD25++ CD8br%CD8br (mediation proportion: 19.2%) and CD28+ CD45RA + CD8br%T cells (mediation proportion: 11.9%) on HF. Additionally, the relationship between IgD + CD38br AC cells and HF appeared to be mediated by the phosphate to alanine ratio (mediation proportion: 16.3%). Sensitivity analyses validated that the used instrumental variables were free from pleiotropy and heterogeneity. This study provides evidence that certain immune cell levels are associated with the risk of HF and that metabolite levels may mediate these relationships. However, to strengthen these findings, further validation using MR analyses with larger sample sizes is essential.

The Relationship between Negative Emotions and Atrial Fibrillation: A Mendelian Randomization Study.

The relationship between negative emotions and atrial fibrillation (AF) has garnered significant attention, yet observational studies have yielded contradictory findings regarding the causal associations between the two. Our study sought to provide genetic evidence for a causal relationship between negative emotions and AF through Mendelian randomization (MR) study. Utilizing genetic variations associated with negative emotions and AF as instrumental variables (IVs), a two-sample MR study was implemented. The potential causality between the two was initially assessed by using negative emotions as exposure and AF as outcome. Subsequently, potential reverse causality was evaluated by using AF as exposure and negative emotions as outcome. The inverse variance weighted (IVW) method served as the primary analysis for the two-sample MR, supplemented by weighted median method, MR-Egger regression, Simple mode method, and Weighted mode method. Sensitivity analyses were performed using the MR pleiotropy residual sum and outlier test (MR-PRESSO), Cochran Q test, and leave-one-out analysis to ensure the robustness of the results. The two-sample MR analyses revealed that genetic susceptibility to AF had no potential causal effect on negative emotions (p > 0.05). Conversely, genetic susceptibility to negative emotions was positively correlated with an increased relative risk of AF [odds ratio (OR), 1.173, 95% confidence interval (CI): 1.115-1.235, p = 8.475 × 10-10]. Furthermore, neither horizontal pleiotropy nor heterogeneity was detected in the analysis. Genetic evidence from the study supports a potential causal link between negative emotions and AF. The study suggests that negative emotions may elevate the risk of AF, and the escalation of negative emotions in AF patients is more likely attributable to modifiable factors rather than genetically related factors.