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Background: The liver‒brain axis is critical in neurodegenerative diseases (NDs), with lipid metabolism influencing neuroinflammation and microglial function. A systematic investigation of the genetic relationship between lipid metabolism abnormalities and ND, namely, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), is lacking. To assess potential causal links between ND and six lipid parameters, two-sample Mendelian randomization (MR) was used. Methods: Large-scale European ancestry GWAS data for lipid parameters and ND (AD, ALS, PD, and MS) were used. Genetic variants demonstrating significant correlations (P < 5 × 10−8) with lipid metabolism parameters were identified and employed as instrumental variables (IVs) after proper validation. The research incorporated UK Biobank genomic data to examine associations between genetic variants and lipid metabolism parameters. The analysis included primary MR, sensitivity analyses, and multivariable MR, which considered potential mediators. Results: MR via the inverse-variance weighted method revealed causal effects of cholesterol (CHOL, OR = 1.10, 95% CI: 1.03–1.18, P = 4.23 × 10⁻3) and low-density lipoprotein cholesterol (LDLC, OR = 1.10, 95% CI: 1.03–1.17, P = 3.28 × 10⁻3) on the risk of ALS, which were validated across multiple methods. Potential correlations were observed between ApoB and ALS and inversely correlated with AD, whereas no significant associations were found for PD or MS. CHOL and LDLC associations with ALS demonstrated no significant heterogeneity or pleiotropy, supporting their reliability. Conclusions: Higher CHOL and LDLC levels were associated with increased ALS risk, suggesting a potential causal link, and supporting the liver‒brain axis hypothesis in ND. Current genetic evidence does not support a significant role for lipid metabolism in PD and MS etiology, suggesting the relationship between lipid metabolism and other NDs may be more complex and warrants further investigation. [ABSTRACT FROM AUTHOR]

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with unique lesional dysbiotic features. However, the role of the microbiology in the pathogenesis of HS remains in dispute. We aimed to conduct a two-sample Mendelian randomization study to investigate the relationship between skin microbiota and HS. A two-sample Mendelian randomization study was performed using the summary statistics of skin microbiota from summary GWAS data of the European descent from two cross-sectional, population-based German cohorts, KORA FF4 (n = 324) and PopGen (n = 273). The summary statistics of hidradenitis suppurativa were obtained from the FinnGen DF10 (1,070 cases and 394,105 controls). Inverse variance weighted (IVW), MR-Egger regression, weighted median, simple mode, weighted mode, and MRPRESSO were used to examine the causal association between skin microbiota and hidradenitis suppurativa. Cochran's Q statistics were used to quantify the heterogeneity of instrumental variables. Our study suggested that genus Corynebacterium in dry skin is significantly associated with HS after false discovery rate (FDR) correction (odds ratio (OR) = 1.04, 95% confidence interval (CI): 1.02–1.06, P = 0.0002, FDR adjusted P = 0.035). Additionally, we found genus Micrococcus in moist skin (OR = 1.10, 95% CI: 1.03–1.18, P = 0.0060, FDR adjusted P = 0.360), species Streptococcus salivarius in dry skin (OR = 1.03, 95% CI: 1.01–1.05, P = 0.0070, FDR adjusted P = 0.360), and species Propionibacterium granulosum (OR = 1.02, 95% CI: 1.00–1.04, P = 0.0460, FDR adjusted P = 0.970) are potentially associated with HS before FDR adjustment. No evidence of the effect in the reverse direction for HS on skin microbial features. This two-sample Mendelian randomization study found that genus Corynebacterium was causally associated with HS. Further studies are needed to clarify the protective effect of prebiotics, probiotics or microbiome transplants on HS. [ABSTRACT FROM AUTHOR]

Background: hyperthyroidism characterized by low thyrotropin, highlighting complications and risks, including cardiac issues, osteoporosis, adverse pregnancy outcomes, unintentional weight loss, and increased mortality associated with untreated hyperthyroidism. However, the casual association between telomere length (TL) and hyperthyroidism remains unclear. Objective: We aim to explore the casual relationship between TL and hyperthyroidism. Methods: A two-sample bidirectional Mendelian randomization (MR) analysis employed the inverse variance weighted (IVW) method, supplemented by additional approaches such as Weighted Median (WM), and MR Egger. Results: The summary statistics for TL were derived from the UK Biobank, comprising 472,174 individuals, while the data for hyperthyroidism were sourced from the GWAS Catalog and the FinnGen database, encompassing cohorts of 460,499 and 173,938 individuals, respectively. Utilizing 139 genome-wide significant single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for TL, forward MR analyses indicated a negative causal effect of TL on hyperthyroidism. The risk of hyperthyroidism decreased as genetically predicted TL increased by one standard deviation, as determined by the IVW form GWAS Catalog (OR:0.659,95%CI: 0.541-0.802, p < 0.001) and IVW from FinnGen(OR:0.634, 95%CI: 0.479-0.840, p = 0.001). Other MR methods exhibited a consistent trend in the impact of TL on hyperthyroidism. Reverse MR analysis suggested no causal association between TL and hyperthyroidism (p > 0.05). Sensitivity analyses confirmed the robustness of these results, suggesting minimal susceptibility to confounding factors and bias. Conclusion: The finding that longer telomeres reduce hyperthyroidism risk highlights the need to validate hyperthyroidism's impact on telomere length, offering valuable insights for prevention and treatment. [ABSTRACT FROM AUTHOR]

Background: With the development of the economy, the number of obese patients has been increasing annually worldwide. The proportion of asthma patients associated with obesity is also gradually rising. However, the pathogenesis of obesity-related asthma remains incompletely understood, and conventional pharmacological treatments generally show limited efficacy. Objective: This study aims to explore the causal relationship between obesity and allergic asthma, elucidate the pathogenesis of obesity-related asthma, and identify the plasma proteins involved in its development, providing new insights for clinical interventions. Methods: In this study, we employed a two-step approach for mediation Mendelian randomization (MR) analysis, utilizing stringent selection criteria to identify instrumental variables (IVs). This approach was used to assess the causal impact of obesity on allergic asthma and to validate the plasma proteins identified as mediating factors. We further explored the functions and enriched pathways of the mediating proteins using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Finally, we conducted drug-targeted MR analysis to evaluate the potential of each mediator plasma proteins as a drug target gene. If significant heterogeneity remained among the IVs, we applied the weighted median method as the primary analytical tool. Otherwise, we utilized the inverse variance weighted (IVW) method as the main analytical approach. Additionally, we conducted various sensitivity analyses and statistical tests to further illustrate the robustness of the observed associations. Results: The research findings indicate a causal relationship between obesity and allergic asthma. Plasma proteins such as TPST1, ROR1, and DAPK1 mediate this relationship, with TPST1 accounting for over 10% of the mediation effect. GO and KEGG analyses show that the genes corresponding to these mediator proteins are primarily enriched in pathways related to responses to stimuli, carbohydrate synthesis and metabolism, regulation of certain protein activities, and synaptic connections. The drug-targeted MR analysis suggests that SIGLEC12, BOLA1, HOMER2, and TPST1 all have the potential to be drug target genes. Conclusion: This study suggests that obese patients defined by BMI may promote the development of allergic asthma by influencing the expression of plasma proteins such as TPST1, ROR1, and DAPK1. Furthermore, some of these plasma proteins, including TPST1, could potentially serve as therapeutic targets for treating allergic asthma in these patients. However, further research is needed to explore their therapeutic potential and the mechanisms underlying their effects. Clinical trial number: Not applicable. [ABSTRACT FROM AUTHOR]

An abundant amount of colon cancers is diagnosed every year, accounting for 9% of malignant tumors. Even with the progress of relevant research, the 5-year survival rate for colon cancer is still less than 60%, indicating that improving the prognosis of colon cancer is still a challenge that needs to be overcome. This study employed the algorithm "scissor" to integrate the single-cell sequencing data and bulk transcriptome data with prognosis information to predict prognosis-associated cells (PAC). Summary-data-based Mendelian randomization (SMR) analysis was conducted using expression quantitative trait loci data and GWAS data to identify genes having causal associations with prognosis phenotype in colon cancer patients and five traditional two-sample Mendelian randomization methods were utilized to confirm the results. Finally, our findings were validated based on two independent external validation datasets, GSE17536 and GSE39582. The real-world tissue dataset with corresponding immunohistochemical (IHC) experiments was utilized to confirm our findings. We determined that the majority of PACs were fibroblasts. On top of that, this study identified ADAMDEC1 as a gene that has a significant causal association with overall survival. ADAMDEC1, highly expressed in highly differentiated fibroblasts, was ascertained its high expression was linked with a better prognosis of patients with colon cancer by the related bulk transcriptome analysis. Our dataset presented that higher IHC scores were associated with a better prognosis for colon cancer, further validating our results. This study has identified ADAMDEC1 as a prognostic protective factor for patients with colon cancer, providing clues for clinical trials and drug experimental target research. [ABSTRACT FROM AUTHOR]

Arterial stiffness is an emerging indicator of cardiovascular risk, but its causal relationship with a variety of age-related diseases is unclear. The objective is to assess the causal relationship between arterial stiffness index (ASI) and age-related diseases by Mendelian randomization (MR) analysis. We obtained instrumental variables associated with age-related diseases from genome-wide association studies (GWAS) of 484,598 European individuals, and data for ASI were obtained from the UK Biobank GWAS of 127,127 participants. We used the inverse variance-weighted as the primary analysis method. In addition, several sensitivity analyses including MR-Egger, weighted-median (WM), Mendelian randomization pleiotropy residual sum and outlier, and Cochran's Q test were performed to test the robustness of the results. Reverse MR analysis was also performed to assess reverse causal relationships between age-related diseases and ASI. We verified the causal relationship between eight age-related diseases and ASI, of which cardiovascular disease (β = 0.19), gallbladder disease (β = 0.85), liver, biliary, or pancreas problem (β = 1.02), hypertension (β = 0.19), joint disorder (β = 0.53), and esophageal disorder (β = 2.10) elevated ASI. In contrast, hyperthyroidism or thyrotoxicosis (β = −2.17) and bowel problems (β = −1.83) may reduce ASI. This MR analysis reveals causal relationships between ASI and several age-related diseases. ASI is expected to be a potential indicator of health conditions for older populations. [ABSTRACT FROM AUTHOR]

BACKGROUND: Circulating proteins in blood are involved in various physiological processes, but their contributions to blood pressure regulation remain partially understood. In traditional observational studies, identifying circulating proteins causally associated with blood pressure is challenging because of potentially unmeasured confounding and possible reverse causality. METHODS: Two-sample Mendelian randomization analyses were conducted to estimate the causal effects of 2270 circulating proteins (data sourced from 8 genome-wide association studies) on diastolic blood pressure, systolic blood pressure, and pulse pressure. Colocalization analyses were then used to investigate whether the circulating proteins and blood pressure traits shared causal genetic variants. To further verify the findings, we subsequently performed Steiger filtering analyses, annotation of protein-altering variants, assessment of overlap between protein quantitative trait loci and expression quantitative trait loci, protein-protein interaction and functional enrichment analyses, and drug target evaluation. To provide more potential biomarkers, we further evaluated the epidemiological associations of 2923 circulating proteins with blood pressure and hypertension by cross-sectional and longitudinal analyses using individual data in the UK Biobank. RESULTS: Mendelian randomization and colocalization analyses identified 121 circulating proteins with putative causal effects on at least 1 blood pressure trait. Many of the identified proteins are enriched in the pathways relevant to blood pressure regulation, and a majority of these proteins are either known drug targets or druggable candidates. CONCLUSIONS: This study has uncovered numerous circulating proteins potentially causally associated with blood pressure, providing insights into the regulatory mechanisms of blood pressure and potential therapeutic targets to facilitate blood pressure management. [ABSTRACT FROM AUTHOR]

Blood cells are crucial components of the human body, closely linked to the aging process. This study aims to explore the causal relationship between 91 blood cell phenotypes and aging through Mendelian randomization (MR) analysis. Exposure data from genome-wide association studies (GWAS) was extracted from the GWAS of blood cell perturbation phenotypes in 2,600 European individuals. Initial analysis utilized GWAS data related to aging from the GWAS Catalog database GCST90014288, with inverse-variance weighting as the primary method for causal analysis. Sensitivity analyses included Cochran's Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis. For significant associations, replication and meta-analysis were conducted using independent aging GWAS data from GCST90014300. Initial analysis revealed that environmental peroxide-impacted red blood cells and ciprofloxacin-impacted reticulocytes accelerated aging. Additionally, elevated neutrophil levels were found to accelerate aging, while LiCl-impacted neutrophils reduced aging risk. Replication and meta-analysis showed consistent results: ciprofloxacin-impacted reticulocytes and elevated neutrophil levels increased the risk of aging, while LiCl-impacted neutrophils reduced the risk. RBCs showed no significant impact on aging progression. Sensitivity analyses confirmed the robustness and reliability of these positive findings. Our study provides evidence of a causal relationship between three blood cell disturbance phenotypes and human aging. [ABSTRACT FROM AUTHOR]

Observational studies have linked selenium and metabolic syndrome (MetS), but the causality remains unclear. Therefore, this study intends to determine the causal relationship between selenium and the risk of MetS and its component features [body mass index (BMI), waist circumference adjusted for BMI (WCadjBMI), triglycerides (TC), HDL-cholesterol (HDL-C), fasting blood glucose (FBG), fasting blood insulin (FBI), systolic blood pressure (SBP), and diastolic blood pressure (DBP)]. This study was designed as the two-sample Mendelian randomization (MR), and genetic variants were obtained from the genome-wide association studies. The inverse variance weighted (IVW) was applied as the primary method, and the MR-Egger, weighted median, and MR-PRESSO were supplemented to assess its robustness. The Bonferroni method was used to correct p-values for multiple tests. Genetically incremented selenium level was related to higher odds ratios of developing the MetS (OR = 1.054, 95% CI = 1.016–1.094, p = 0.0049). As for components, significant causal links were identified between selenium and BMI (β = 0.015, p = 1.321 × 10−5), WCadjBMI (β = 0.033, p = 2.352 × 10−4), HDL-C (β = −0.036, p = 1.352 × 10−8), FBG (β = 0.028, p = 0.001), and FBI (β = 0.028, p = 0.002). No significant association was discovered for SBP (β = −0.076, p = 0.218) and DBP (β = 0.054, p = 0.227). These results were generally supported by the weighted median and MR-PRESSO methods. Our study provided evidence of the causal effect of selenium on MetS risk from the genetic perspective in the European population, and further investigation across diverse populations was warranted. [ABSTRACT FROM AUTHOR]

Background: Dyslipidemia is closely related to diabetic neuropathy. This study examined the potential causal relationship involving 179 lipid species and the disease. Methods: The pooled data on 179 lipid species and diabetic neuropathy were obtained from previous genome-wide association studies (GWAS). A Mendelian Randomization (MR) method was employed to investigate the potential causal link, and the robustness of the findings was confirmed through comprehensive sensitivity analyses. Results: Genetically, phosphatidylcholine might be associated with the risk of diabetic neuropathy. Upon adjusting for multiple comparisons, higher levels of phosphatidylcholine (16:0_20:2) (OR = 0.82, 95%CI: 0.73-0.91; P < 0.001, FDR = 0.033) and phosphatidylcholine (16:1_18:1) (OR = 0.77, 95%CI: 0.67-0.88; P < 0.001, FDR = 0.019) are associated with a decreased risk of diabetic neuropathy. Further multivariable MR (MVMR) analysis demonstrated the effect of genetically predicted phosphatidylcholine (16:1_18:1) remained after adjusting for body mass index (BMI) and glycated hemoglobin (HbA1c). Sensitivity assessments have confirmed the robustness of these findings, revealing no evidence of heterogeneity or pleiotropy. Conclusion: Our research linked certain lipid species with diabetic neuropathy risk, suggesting that targeting lipids could be a therapeutic strategy in clinical trials addressing this condition. [ABSTRACT FROM AUTHOR]

Objective: The impact of lipid-lowering medications on chronic kidney disease (CKD) remains a subject of debate. This Mendelian randomization (MR) study aims to elucidate the potential effects of lipid-lowering drug targets on CKD development. Methods: We extracted 11 genetic variants encoding targets of lipid-lowering drugs from published genome-wide association study (GWAS) summary statistics, encompassing LDLR, HMGCR, PCSK9, NPC1L1, APOB, ABCG5/ABCG8, LPL, APOC3, ANGPTL3, and PPARA. A Mendelian randomization analysis was conducted targeting these drug-related genes. CKD risk was designated as the primary outcome, while estimated glomerular filtration rate (eGFR) and blood urea nitrogen (BUN) were assessed as secondary outcomes. Additionally, mediation analysis was performed utilizing 731 immune cell phenotypes to identify potential mediators. Results: The meta-analysis revealed a significant association between ANGPTL3 inhibitors and a reduced risk of CKD (OR [95% CI] = 0.85 [0.75-0.96]). Conversely, LDLR agonists were significantly linked to an increased risk of CKD (OR [95% CI] = 1.11 [1.02-1.22]). Regarding secondary outcomes, lipid-lowering drugs did not significantly affect eGFR and BUN levels. Mediation analysis indicated that the reduction in CKD risk by ANGPTL3 inhibitors was mediated through modulation of the immune cell phenotype, specifically HLA-DR on CD14+ CD16+ monocytes (Mediated proportion: 4.69%; Mediated effect: -0.00899). Conclusion: Through drug-targeted MR analysis, we identified a causal relationship between lipid-lowering drug targets and CKD. ANGPTL3 and LDLR may represent promising candidate drug targets for CKD treatment. [ABSTRACT FROM AUTHOR]

Objective: The main objective of this study was to explore and identify new genetic targets in small-cell lung cancer (SCLC) through transcriptomics analysis and Mendelian randomization (MR) analysis, which will help in the subsequent development of new therapeutic interventions. Methods: In this study, we extracted the SCLC dataset from the Gene Expression Omnibus (GEO) database, processed the data, and screened out differentially expressed genes (DEGs) using R software. Based on expression quantitative trait loci data and the genome-wide association study data of SCLC, MR analysis was used to screen the genes closely related to SCLC disease, which intersect with DEGs to obtain co-expressed genes (CEGs), and the biological functions and pathways of CEGs were further explored by enrichment analysis. In addition, the CIBERSORT algorithm was applied to assess the level of immune cell infiltration in SCLC and to analyze the correlation between CEGs and immune cells. Meanwhile, we performed a survival analysis on these five CEGs using an independent cohort of SCLC patients. Finally, the results for the target genes were validated. Results: In this study, 857 DEGs were identified, including 443 up-regulated and 414 down-regulated genes, and 5 CEGs (PSAT1, PSRC1, COLEC12, PLLP, HP) that were significantly associated with SCLC were identified through further intersecting. The results of enrichment analyses indicated that CEGs play important roles in several key functions and pathways. Immune-cell-related analysis revealed the unique distribution of immune cell infiltration in SCLC and the mechanism of immune cell regulation by CEGs. Survival analysis results indicated that PSRC1 was significantly correlated with the overall survival of SCLC, and the survival rate of the high-expression group was markedly lower than that of the low-expression group. Finally, the consistency of the results between the validation group analyses and MR analysis confirmed that the results of this study is reliable. Conclusion: The CEGs and their associated functions and pathways screened in this study may be potential targets of therapeutic intervention in SCLC by targeting specific molecular pathways. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionThis study aims to explore the relationship between autoimmune rheumatic diseases (ARDs) and the risk of iridocyclitis (IC) using Mendelian randomization (MR) analysis.Data of ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), juvenile idiopathic arthritis (JIA), Behcet’s disease (BD), and iridocyclitis were obtained from genome-wide association studies with large sample sizes. The instrumental variable utilized in this study for each exposure was the single nucleotide polymorphism. The inverse-variance weighted (IVW) method, which included random effects, was used to analyze causal effects. In addition, sensitivity analyses were conducted using the weighted median and MR-Egger methods. The presence of pleiotropic effects was identified and addressed through MR pleiotropic effects residual and outlier tests, as well as MR-Egger modeling.We found a causal effect of AS (IVW, OR = 2.74 × 1029, 95% CI 6.39 × 107 − 1.18 × 1051, p = 0.008) on IC. Conversely, we also found a causal effect of IC on AS (IVW OR = 1.01, 95% CI 1.00 − 1.01, p < 0.001). Besides, sensitivity analysis showed no evidence of pleiotropy and heterogeneity. However, no causal relationship between SLE, JIA, BD, and IC was detected.Bilateral causal relationships of IC and AS were identified, which could offer evidence for clinical use and lay the groundwork for detecting potential mechanism behind them. [ABSTRACT FROM AUTHOR]

Objective: Previous observational studies suggest a potential link between gut microbiota, metabolites, and diabetic nephropathy. However, the exact causal relationship among these factors remains unclear. Method: We conducted a two-sample bidirectional Mendelian randomization study using summary statistics from the IEU OpenGWAS Project database to investigate gut microbiota, metabolites, and diabetic nephropathy. A range of methods, including inverse variance weighting, MR-Egger, weighted median, and simple median, were applied to examine causal associations. Sensitivity analyses were performed to assess the robustness of the results. Additionally, reverse Mendelian randomization analysis was conducted, treating significant gut microbiota as the outcome, to evaluate effects and perform sensitivity testing. This comprehensive approach provided an in-depth assessment of the interactions among gut microbiota, metabolites, and diabetic nephropathy. Result: The Inverse Variance Weighted estimates revealed that the abundance of Lachnospiraceae, Parasutterella , and Eubacterium exhibited negative causal effects on diabetic nephropathy, while Coprococcus, Sutterella, Faecalibacterium prausnitzii , and Bacteroides vulgatus showed protective causal effects against the condition. However, reverse Mendelian randomization analysis did not identify any significant associations between diabetic nephropathy and the identified gut microbiota. Furthermore, the estimates indicated that Cholesterol, Pyridoxate, Hexanoylcarnitine, X-12007, Octanoylcarnitine, 10-nonadecenoate (19:1n9), X-12734, and the average number of double bonds in a fatty acid chain had negative causal effects on diabetic nephropathy. In contrast, Methionine, Glycodeoxycholate, X-06351, 1-stearoylglycerol (1-monostearin), 5-dodecenoate (12:1n7), X-13859, 2-hydroxyglutarate, Glycoproteins, Phospholipids in IDL, and the concentration of small HDL particles demonstrated protective causal effects. Notably, sensitivity analyses did not detect any heterogeneity or horizontal pleiotropy, ensuring the robustness of the findings. Conclusion: Modulating gut microbiota diversity and composition offers a promising strategy for improving the incidence and prognosis of diabetic nephropathy. This highlights the need for future clinical trials focusing on microbiome-based interventions, potentially utilizing microbiome-dependent metabolites. Such approaches could transform the treatment and management of diabetic nephropathy and its associated risk factors, paving the way for more effective therapeutic strategies to combat this debilitating condition. [ABSTRACT FROM AUTHOR]

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition that can be accompanied by alterations in immune markers. However, the intricate nature of the association between ADHD and immune markers remains insufficiently elucidated. To explore the currently ambiguous causal relationship between ADHD and the immune system, we performed a bidirectional Mendelian randomization (MR) analysis of immune cell traits and ADHD under the randomized inverse variance weighting (IVW) method based on genome-wide association study (GWAS) summary data. We found ADHD increased the level of 3 immune cell traits including myeloid dendritic cells (β = 0.28, P = 0.008), monocyte (β = 0.25, P = 0.024) and granulocyte (β = 0.2, P = 0.042). We also identified 1 trait which belongs to B cell panel was a risk factor (odds ratio (OR) = 1.07, P = 0.001) for ADHD onset. Other 5 traits including CD14+ monocyte (OR = 0.98, P = 0.002), immature myeloid-derived suppressor cells (MDSC) (OR = 0.98, P = 0.003), monocyte MDSC (OR = 0.95, P = 0.005), CD33br HLA DR+ (OR = 0.97, P = 0.021) and basophil (OR = 0.96, P = 0.022) were protective factors for ADHD. Here we identified a range of causal relationships extending from ADHD to immune cell traits, underscoring the complex interaction patterns between ADHD and the immune system. Enhanced interventions for protective and risk factors may be beneficial in the prevention and treatment of ADHD. • Attention-deficit/hyperactivity disorder (ADHD) and immune function have the potential for interaction. • ADHD increase levels of specific immune cells, and different immune cells are also risky or protective factors for ADHD. • It is imperative to monitor alterations in immune function among ADHD patients throughout the course of treatment. • B cells are probably implicated in the development of ADHD and may have potential to be a biotherapeutic target. [ABSTRACT FROM AUTHOR]

Previous observational studies have reported inconsistent associations between nut consumption and cardiovascular diseases (CVD). This study aims to identify the causal relationship between different types of nuts consumption and CVD, and to quantify the potential mediating effects of cardiometabolic factors. We utilized Genome-Wide Association Study (GWAS) data to assess the causal effects of nut consumption on CVD using two-sample Mendelian randomization (MR) and a two-step MR analysis. The inverse variance weighted (IVW) method indicated that processed (salted or roasted) peanuts were potentially and positively associated with ischaemic heart disease (IHD) (OR 1.4866; 95%CI 1.0491-2.1065). No causal relationships were found between nuts consumption and other CVD outcomes, including atrial fibrillation, angina, coronary atherosclerosis, coronary heart disease, IHD, myocardial infarction, subarachnoid hemorrhage, intracerebral haemorrhage and stroke. Both MR-Egger and median-based methods yielded similar results to IVW. Furthermore, in the two-step MR analysis, fasting insulin, low-density lipoprotein cholesterol and fasting blood glucose were identified as mediators in the potential causal relationship between processed peanuts and IHD, explaining 16.98%, 6.38% and 4.91% of the mediation, respectively. In total, these mediators accounted for 28.27% of the association between salted or roasted peanuts and IHD. [ABSTRACT FROM AUTHOR]

Background: The association of changes in metabolic syndrome (MetS) with cognitive function remains unclear. We explored this association using prospective and Mendelian randomization (MR) studies. Methods: MetS components including high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), waist circumference (WC), fasting plasma glucose (FPG), and triglycerides were measured at baseline and two follow-ups, constructing a MetS index. Immediate, delayed memory recall, and cognitive function along with its dimensions were assessed by immediate 10-word recall test (IWRT) and delayed 10-word recall test (DWRT), and mini-mental state examination (MMSE), respectively, at baseline and follow-ups. Linear mixed-effect model was used. Additionally, the genome-wide association study (GWAS) of MetS was conducted and one-sample MR was performed to assess the causality between MetS and cognitive function. Results: Elevated MetS index was associated with decreasing annual change rates (decrease) in DWRT and MMSE scores, and with decreases in attention, calculation and recall dimensions. HDL-C was positively associated with an increase in DWRT scores, while SBP and FPG were negatively associated. HDL-C showed a positive association, whereas WC was negatively associated with increases in MMSE scores, including attention, calculation and recall dimensions. Interaction analysis indicated that the association of MetS index on cognitive decline was predominantly observed in low family income group. The GWAS of MetS identified some genetic variants. MR results showed a non-significant causality between MetS and decrease in DWRT, IWRT, nor MMSE scores. Conclusion: Our study indicated a significant association of MetS and its components with declines in memory and cognitive function, especially in delayed memory recall. [ABSTRACT FROM AUTHOR]

Objectives: Observational studies suggested a potential correlation between dietary intake and amyotrophic lateral sclerosis (ALS), but conflicting findings exist and causality remains unclear. Here, we performed a Mendelian randomization (MR) analysis to evaluate the causal impact of relative intake of (i) carbohydrate, (ii) fat, and (iii) protein on ALS risk. Methods: The genome-wide association summary statistics of three dietary macronutrient intake traits and ALS were obtained. Initially, forward and reverse univariable MR (UVMR) analysis were conducted using the inverse variance weighted (IVW) method as the primary approach, supplemented by MR-Egger, weighted median, and maximum likelihood. Subsequently, multivariable MR (MVMR) analysis was performed to assess the independent causal effects of each dietary. Additionally, diverse sensitivity tests were conducted to evaluate the reliability of the MR analyses. Results: The forward UVMR analysis conducted by IVW indicated that relative carbohydrate intake significantly increased ALS risk. Furthermore, results from three other MR methods paralleled those from IVW. However, the other two dietary intake traits did not have a causative impact on ALS risk. The reverse UVMR analysis indicated that ALS did not causatively influence the three dietary intake traits. The MVMR analysis showed that after adjusting for the effects of the other two dietary intake traits, relative carbohydrate intake independently and significantly increased ALS risk. Sensitivity tests indicated no significant heterogeneity or horizontal pleiotropy. Discussion: MR analysis supported relative carbohydrate independently increasing ALS risk. Nevertheless, further validation of this finding in future large cohorts is required. [ABSTRACT FROM AUTHOR]

Obese adults are often reported to have smaller brain volumes than their non-obese peers. Whether this represents evidence of accelerations in obesity-driven atrophy or is instead a legacy of developmental differences established earlier in the lifespan remains unclear. This study investigated whether early-life differences in adiposity explain differences in numerous adult brain traits commonly attributed to mid-life obesity. We used a two-sample life course Mendelian randomization study in 37 501 adults recruited to UK Biobank (UKB) imaging centres from 2014, with secondary analyses in 6996 children assessed in the Adolescent Brain Cognitive Development Study (ABCD) recruited from 2018. Exposures were genetic variants for childhood (266 variants) and adult (470 variants) adiposity derived from a genome-wide association study (GWAS) of 407 741 UKB participants. Primary outcomes were: adult total brain volume; grey matter volume, thickness and surface area; white matter volume and hyperintensities; and hippocampus, amygdala and thalamus volumes at mean age 55 in the UKB. Secondary outcomes were equivalent childhood measures collected at mean age 10 in ABCD. In the UKB, individuals who were genetically predicted to have had higher levels of adiposity in childhood were found to have multiple smaller adult brain volumes relative to intracranial volume [e.g. z -score difference in normalized brain volume per category increase in adiposity—95% confidence interval (CI) = −0.20 (−0.28, −0.12); P = 4 × 10−6]. These effect sizes remained essentially unchanged after accounting for birthweight or current adult obesity in multivariable models, whereas most observed adult effects attenuated towards null [e.g. adult z -score (95% CI) for total volume = 0.06 (−0.05, 0.17); P = 0.3]. Observational analyses in ABCD showed a similar pattern of changes already present in those with a high body mass index by age 10 [ z -score (95% CI) = −0.10 (−0.13, −0.07); P = 8 × 10−13], with follow-up genetic risk score analyses providing some evidence for a causal effect already at this early age. Sensitivity analyses revealed that many of these effects were likely due to the persistence of larger head sizes established in those who gained excess weight in childhood [childhood z -score (95% CI) for intracranial volume = 0.14 (0.05, 0.23); P = 0.002], rather than smaller brain sizes per se. Our data suggest that the persistence of early-life developmental differences across the life course may underlie numerous neuroimaging traits commonly attributed to obesity-related atrophy in later life. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a significant health burden. There is an essential need for novel biomarkers and therapeutic targets to improve diagnosis and management. Mendelian randomization (MR) was applied to explore causal links between SLE and various biomarkers like immune cells, metabolites, and inflammatory cytokines using multiple databases. Initially, biomarkers significantly associated with SLE were identified. Bidirectional MR helped clarify these relationships, and a two-step mediation MR examined their effects on SLE risk. Intersection analysis was used to identify biomarkers with consistent effects across datasets. Four biomarkers were identified as having significant associations with SLE risk: 1-palmitoyl-2-arachidonoyl-GPI levels [odds ratio (OR), 1.379; 95% confidence interval (CI), 1.180 to 1.613; FDR, 0.046], IL-17A levels (OR, 2.197; 95% CI, 1.412 to 3.418; FDR, 0.044), N-acetyl-aspartyl-glutamate (NAAG) levels (OR, 0.882; 95% CI, 0.831 to 0.936; FDR, 0.030), and ribitol levels (OR, 0.743; 95% CI, 0.644 to 0.857; FDR, 0.012). Bidirectional MR showed an inverse effect of NAAG on IL-17A levels (OR, 0.978; 95% CI, 0.962 to 0.994; p = 0.006). Mediation analysis indicated that NAAG influenced SLE risk both directly (beta = − 0.108) and indirectly through IL-17A (beta = − 0.018), highlighting the potential mediating role of IL-17A. After expanding the significance criteria to p < 0.05, intersection analysis across multiple datasets revealed 29 biomarkers with consistent beta directions, including 19 potential risk factors (beta > 0) and 10 protective factors (beta < 0) for SLE. This research has revealed significant genetic associations with SLE and demonstrated that IL-17A mediates the relationship between NAAG levels and SLE risk, highlighting potential new targets for personalized therapeutic interventions. Key Points • This study employs MR to identify significant genetic associations between various biomarkers and SLE, providing novel insights into potential biomarkers and therapeutic targets. • Four key biomarkers were identified as significantly associated with SLE risk: 1-palmitoyl-2-arachidonoyl-GPI, IL-17A, N-acetyl-aspartyl-glutamate (NAAG), and ribitol. • The findings suggest that NAAG levels have a protective effect against SLE, partly mediated through IL-17A, indicating a complex interplay between these biomarkers in the pathogenesis of SLE. • Intersectional analysis across multiple datasets revealed 29 biomarkers with consistent effects on SLE risk, highlighting new directions for future research and potential personalized therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Falls are a major public health concern. Daily vitamin D supplementation is a proposed fall prevention strategy; however, safety concerns have arisen from some clinical trials showing increased fall risk when using higher vitamin D dosing methods. The relationship between vitamin D and falls may be influenced by factors, such as inflammation, which can alter the balance of essential nutrients like vitamin D and retinol, potentially affecting motor function. We use a genetic epidemiological approach to explore the association of inflammation, vitamin D, and fall risk. Methods: We included 307,082 UK Biobank participants and conducted observational and Mendelian randomization (MR) analyses to investigate associations between 25-hydroxyvitamin D [25(OH)D] and fall risk, with analyses including restriction to participants who had fallen and had inflammation as defined by CRP ≥ 5 mg/L. Results: In the observational analysis, CRP was associated with a higher (per 5 mg/L CRP increase OR = 1.06, 95% CI 1.05–1.07) and 25(OH)D with a lower odds of falls. The association between 25(OH)D concentrations and fall risk was non-linear (p < 0.001), reflecting a plateauing of the association at higher concentrations. There was an interaction between 25(OH)D and CRP on their association with the odds of falls (p = 0.009). In participants with CRP ≥ 5 mg/L, the association was U-shaped, and the fall risk was elevated for both 25(OH)D < 25 nmol/L and ≥ 100 nmol/L (p < 0.004). The association between high 25(OH)D and falls was most pronounced for participants with CRP ≥ 20 mg/L (≥ 100 nmol/L vs. 50–74.99 nmol/L: OR = 2.40, 95% CI, 1.50–3.86). Genetically predicted higher 25(OH)D was not associated with fall risk in the overall population, but a suggestive association with fall risk was seen in participants who had fallen and had CRP > 20 mg/L (926 cases; OR = 1.20, 95% CI, 1.00–1.44). Conclusions: Our study suggests that inflammation might modify the vitamin D and fall risk relationship. Both low and high 25(OH)D levels are associated with more falls in individuals with chronic inflammation, with supporting evidence seen in both observational and MR analyses. This may provide insight into the increased fall risk following high-dose vitamin D supplementation in clinical trials, warranting further research. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusion Previous studies have linked sleep quality to temporomandibular joint disorders (TMD), suggesting a role for snoring in this association. However, the directionality of this relationship remains a subject of debate. This investigation aimed to elucidate the connections between snoring and TMD.This research employed a two‐sample Mendelian randomization (MR) approach, leveraging publicly available large‐scale genome‐wide association study (GWAS) data on snoring and TMD. We utilised a suite of analytical methods, including the inverse variance weighted (IVW) method, maximum likelihood estimation, adjusted profile score, weighted median, MR–Egger regression, and a series of sensitivity analyses, to rigorously assess the existence of relationships.Our findings indicate that a greater genetic predisposition to snoring is significantly associated with a reduced risk of TMD (IVW method; odds ratio [OR] = 0.156, 95% confidence interval [CI] = 0.028–0.843, p = 0.0309). Conversely, the analysis did not support a potential influence of TMD on snoring susceptibility (IVW method; 95% CI = 0.990 to 1.002, p = 0.1926). Additionally, our sensitivity analyses did not reveal any significant pleiotropy that could bias these findings.This MR study provides limited but novel genetic evidence supporting a potential causal link between snoring and a decreased risk of developing TMD. On the other hand, it does not substantiate an effect of TMD on the likelihood of snoring. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer is among the most lethal malignancies, characterized by a poor prognosis and limited modifiable factors. Emerging evidence indicates that serum mineral levels may influence the likelihood of developing pancreatic cancer. However, the causal relationship between serum minerals and pancreatic cancer remains unclear and warrants further investigation. Methods: This Mendelian randomization (MR) study was conducted to explore the causal effects of serum mineral levels on pancreatic cancer risk. Genetic variants associated with serum mineral levels, including calcium, iron, magnesium, zinc, selenium, and copper, were selected as instrumental variables (IVs) from large-scale genome-wide association study (GWAS) data. Multiple methods, including inverse variance weighting (IVW), MR-Egger, weighted median, weight methods, were employed to perform MR analysis. The effect sizes from the MR analysis, using two independent GWAS summary datasets related to pancreatic cancer, were combined through meta-analysis. The Cochrane Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out test were conducted for sensitivity tests. Results: Our MR analysis demonstrated a significant causal effect of genetically predicted serum calcium levels on increased pancreatic cancer risk [OR = 1.64, 95% CI 1.05–2.57, P = 0.029 (discovery cohort); OR = 1.52, 95% CI 1.07–2.15, P = 0.019 (validation cohort)], while no significant associations were found for other serum minerals (P > 0.05). Additional meta-analysis reinforces and substantiates this conclusion (pooled OR = 1.56, 95% CI 1.19–2.06, P = 0.001). No evidence of pleiotropy or heterogeneity was detected across multiple sensitivity tests (P > 0.05). Conclusion: This study provides new evidence supporting the causal role of certain serum minerals, particularly calcium, in the development of pancreatic cancer. These findings may help inform future research into preventive strategies or therapies aimed at modulating mineral levels in patients at high risk of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Growing evidence suggests that depression affects gastroesophageal reflux disease (GERD). But, the relationship between depression and GERD is unclear. To examine the relationship between depression and the risk of GERD, as well as the mediating role of risk factors. Methods: We found genetic variants associated with GERD (N = 78,707) and depression (N = 500,199 (excluding 23 and Me) from the largest genome-wide association study and we applied two-sample Mendelian randomization (MR) to find out if they are related. We further used two-step MR to find the mediating factors. Results: The results found a causal link between depression and GERD, inverse-variance weighted (IVW), risk OR 2.149 (95% CI, 1.910 to 2.418; P <0.001). F-statistics for all instrumental variables (IVs) were greater than 10. Multivariate MR maintained the significance of the depression-GERD link even after adjusting for body mass index (BMI), waist-to-hip ratio (WHR), and educational attainment (EA). Mediation analysis revealed that increased depression is associated with lower EA (OR = 0.94; 95% CI, 0.89 to 0.99; P = 0.03), while EA itself significantly impacts GERD risk (OR = 0.25; 95% CI, 0.18 to 0.34; P = 8.24 × 10-9). Ultimately, EA mediates the effect of depression on GERD (OR = 1.09; 95% CI, 1.01 to 1.18; P = 0.04), accounting for 11.4% of the mediated effect. Conclusions: Depression is associated with an increased risk of developing GERD, with some of the effects mediated by EA. This result may provide important information for the prevention and intervention of depression and GERD. [ABSTRACT FROM AUTHOR]

Previous observational studies have indicated associations between various immune cells and diabetic nephropathy (DN). However, the causality remains unclear. We aimed to further evaluate the causal association between immune cells and DN using bidirectional two-sample Mendelian randomization (MR) analysis. The DN data were retrieved from the IEU OpenGWAS Project database, while the data for 731 immune cells were sourced from GWAS summary statistics by Orru ̀ et al. The investigation into the causal relationship between immune cells and DN employed the inverse variance weighted (IVW), weighted median (WME), and MR-Egger methods. The stability and reliability of the findings underwent evaluation through Cochran’s Q test, MR-Egger intercept’s P-value, MR-PRESSO, and Leave-One-Out (LOO) method. The IVW estimates suggested a positive causal effect of CD25 on IgD-CD38dim B cell, CD25 on naive-mature B cell, CD127 on granulocyte, SSC-A on HLA DR + Natural Killer, HLA DR on plasmacytoid Dendritic Cell, and HLA DR on Dendritic Cell on DN. Conversely, the abundance of Myeloid Dendritic Cell, CD62L- Dendritic Cell %Dendritic Cell, CD86+ myeloid Dendritic Cell %Dendritic Cell, CD14- CD16-, CX3CR1 on CD14- CD16-, and SSC-A on CD4+ T cell had negative causal effects on DN. However, after correcting the P value for significant causality results using the FDR method, it was concluded that only Myeloid Dendritic Cells had a causal relationship with DN (FDR-p = 0.041), while the other immune cells showed no significant association with DN, so their relationship was suggestive. The results were stable with no observed horizontal pleiotropy and heterogeneity. Reverse MR analysis indicated no causal relationship between DN and the increased risk of positively identified immune cells. This study provides an initial insight into the genetic perspective of the causal relationship between immune cells and DN. It establishes a crucial theoretical foundation for future endeavors in precision medicine and individualized treatment. [ABSTRACT FROM AUTHOR]

Previous observational studies have shown that immune cells play an important role in IgA nephropathy. However, the specific causal relationship between the two is inconsistent. We used a two-sample mendelian randomization(MR) analysis to investigate the causal association between 731 immune cell signatures and IgA nephropathy in this study. Based on published GWAS data, immune cells were characterized by four immune types absolute cell (AC) counts, median fluorescence intensity (MFI), morphological parameters (MP), relative cell (RC) counts. Meanwhile, heterogeneity test, horizontal pleiotropy and sensitivity test were used to evaluate the robustness and reliability of the results. An important causal association was achieved for 14 RC traits/IgA nephropathy, 3 AC traits/IgA nephropathy, 10 MFI traits/IgA nephropathy, and 1 MP trait/IgA nephropathy. However, after false discovery rate (FDR) correction, only one immunophenotype was found to be protective against IgA nephropathy. The OR of herpesvirus entry mediator (HVEM) on terminally differentiated CD4+ T cell (maturation stages of T-cell panel) on IgA nephropathy risk was estimated to be 0.727 (95%CI: 0.624-0.847, p = 4.20e − 05, PFDR = 0.023) according to inverse variance weighting (IVW) method, and the weighted-median method yielded similar results (OR = 0.743, 95% CI: 0.596-0.927, p = 0.008). Although not statistically significant, the association was consistent with MR-Egger, simple mode and weighted mode. Our study further confirmed that immune cells play a complex and important role in the pathogenesis of IgA nephropathy, providing evidence for clinical research. [ABSTRACT FROM AUTHOR]

BACKGROUND: There is an association between thyroid dysfunction and cerebral infarction (CI), but the causality cannot be determined. A two‐sample two‐way Mendelian randomization (MR) study was conducted to assess the causal relationship between thyroid function and CI. METHODS: We selected single‐nucleotide polymorphisms (SNPs) associated with five phenotypes, including CI from the UK Biobank (n = 361,194), hyperthyroidism from the IEU Open GWAS database (n = 484,598), hypothyroidism from the IEU Open GWAS database (n = 473,703), normal thyroid‐stimulating hormone (TSH) (n = 271,040), and normal free thyroxine (FT4) (n = 119,120) from the Thyroidomics Consortium database. For the forward MR analysis, the exposures were hyperthyroidism, hypothyroidism, TSH, and FT4. The inverse variance weighted (IVW) method, weighted median (WM), and MR‐Egger revealed the causality with CI. For the reverse MR analysis, CI was regarded as the exposure, and four thyroid function phenotypes were the outcomes. The sensitivity and heterogeneity test was assessed using Cochran's Q test, MR‐Egger regression, and leave‐one‐out analysis. RESULTS: The MR analysis indicated that genetic susceptibility to hyperthyroidism increased the risk of CI (IVW‐OR = 1.070; 95% CI: 1.015–1.128; p = 0.003). In reverse MR, genetic susceptibility to RA is not associated with hyperthyroidism (IVW‐OR = 1.001; 95% CI: 1.000–1.001; p = 0.144). Any positive or reverse causal relationship between hypothyroidism, FT4, and TSH with CI could not be established. Sensitivity and heterogeneity test consolidated our findings. CONCLUSION: The causality between CI and hyperthyroidism demonstrated patients with hyperthyroidism have a risk of genetic variants for CI. In the future, further studies are needed to fully explore their mechanisms of action. [ABSTRACT FROM AUTHOR]

Background & Aims: Sex hormones and sex hormone-binding globulin (SHBG) have been confirmed to involve in the pathophysiology of functional gastrointestinal disorders (FGIDs), including irritable bowel syndrome (IBS) and functional dyspepsia (FD). However, causal associations have not yet been investigated. Utilizing data from Genome-wide association studies, we conducted bidirectional two-sample mendelian randomization (MR) analyses to assess the causal relationships between sex hormones, SHBG and FGIDs. Methods: Data for sex hormones including testosterone and estradiol, and SHBG were collected from the UK Biobank and FinnGen study. Relevant single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs). Inverse variance weighted (IVW) analysis were performed to assess the causal relationships., supplemented with MR-Egger, weighted median, and weighted mode approaches. Additionally, we used Cochran's Q test to evaluate the heterogeneity of genetic variants and implemented leave-one-out analysis to assess the impact of individual SNPs on the causal estimates. Several sensitivity analyses were conducted to assess the robustness of the results. Results: Significant negative causal relationship was found between genetically predicted testosterone and the risk of IBS (OR=0.90, 95%CI: 0.83-0.97; p=0.007). SHBG demonstrated an inverse correlation with the risk of IBS (OR=0.82, 95%CI: 0.68-0.98; p=0.035) and FD (OR=0.83, 95%CI: 0.69-0.99; p=0.048). However, no statistically significant association was found between testosterone and FD, while estradiol also showed no causal association with FGIDs. Conclusions: Our study revealed a negative causal relationship between testosterone and IBS risk, and SHBG appears to be inversely associated with FD. This provided new ideas for the prevention and control of IBS, and future research is warranted to elucidate the underlying mechanisms driving these associations and their potential clinical implications. [ABSTRACT FROM AUTHOR]

Introduction: Growth hormone (GH) is crucial for immune system development and regulation, potentially benefiting COVID-19 outcomes. However, there are limited studies on the role of GH treatment in COVID-19 in children with short stature. Methods: We conducted a survey study to evaluate the association between GH treatment and COVID-19 risk in short stature children aged 7 to 18 years. Two groups were defined: GH Treated and GH Untreated. The primary endpoint was the proportion of children with COVID-19 histories. Secondary endpoints included the presence, severity, and duration of COVID-19 symptoms. Exploratory endpoints included the frequency of common colds after GH treatment. We further performed two-sample Mendelian randomization (MR) analyses to explore the causal relationship between GH levels and COVID-19 susceptibility, hospitalization, and severity using genome-wide association study summary-level data. Results: Of the 201 children, 113 (56.2%) reported COVID-19 history, and 149 (74.1%) used GH. The mean age was 11.02 ± 2.10 years. GH treatment was associated with a somewhat lower proportion of COVID-19 history (− 9.77%, 95% confidence interval [CI] − 26.41% to 6.87%; P = 0.289), and the odds ratio (OR) is 0.58 (95% CI 0.29 to 1.14, P = 0.120) after adjusting for confounders. Among the 113 children with COVID-19 histories, the highest body temperature was significantly lower in the GH Treated group (P = 0.040). In the MR analyses, for one unit increase in GH level, the OR was 0.95 (95% CI 0.92 to 0.99, P = 0.022) for COVID-19 susceptibility, 0.86 (95% CI 0.77 to 0.96, P = 0.007) for COVID-19 hospitalization, and 0.95 (95% CI 0.84 to 1.07, P = 0.392) for COVID-19 severity. Conclusion: GH treatment was associated with somewhat decreased COVID-19 susceptibility but was not statistically significant. Higher GH levels were causally associated with a significantly lower rate of COVID-19 susceptibility and hospitalization. [ABSTRACT FROM AUTHOR]

Purpose: Novel, effective, and safe preventive therapy targets for AF are still needed. Circulating proteins with causal genetic evidence are promising candidates. We aimed to systematically screen circulating proteins for AF drug targets and determine their safety and efficacy using genetic methods. Methods: The protein quantitative trait loci (pQTL) of up to 1949 circulating proteins were retrieved from nine large genome-proteome-wide association studies. Two-sample Mendelian Randomization (MR) and colocalization analyses were used to estimate the causal effects of proteins on the risk of AF. Furthermore, phenome-wide MR was conducted to depict side effects and the drug-target databases were searched for drug validation and repurposing. Results: Systematic MR screen identified 30 proteins as promising AF drug targets. Genetically predicted 12 proteins increased AF risk (TES, CFL2, MTHFD1, RAB1A, DUSP13, SRL, ANXA4, NEO1, FKBP7, SPON1, LPA, MANBA); 18 proteins decreased AF risk (PMVK, UBE2F, SYT11, CHMP3, PFKM, FBP1, TNFSF12, CTSZ, QSOX2, ALAD, EFEMP1, FLRT2, LRIG1, OLA1, SH3BGRL3, IL6R, B3GNT8, FCGR2A). DUSP13 and TNFSF12 possess strong colocalization evidence. For the proteins that were identified, extended phe-MR analysis was conducted to assess their side-effect profiles, while drug-target databases provided information on their approved or investigated indications. Conclusion: We identified 30 circulating proteins as potential preventive targets for AF. [ABSTRACT FROM AUTHOR]

Mendelian randomization (MR) is a statistical method that uses genetic variants as instrumental variables to estimate the causal effect of exposure on an outcome in the presence of unmeasured confounding. In this review, we argue that it is crucial to acknowledge the instrumental variable assumptions in MR analysis. We describe widely used MR methods, using an example from obesity-related metabolic disorders. We describe situations in which instrumental variable assumptions are violated and explain how to evaluate these violations and employ robust methods for accommodating such violations.

Miao Hu, Yi Deng, Yujie Bai, Jiayan Zhang, Xiahong Shen, Lei Shen, Ling Zhou Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of ChinaCorrespondence: Ling Zhou, Email zl66060@163.comBackground: Renal failure related death caused by diabetic kidney disease (DKD) is an inevitable outcome for most patients. This study aimed to identify the critical genes involved in the onset and progression of DKD and to explore potential therapeutic targets of DKD.Methods: We conducted a batch of protein quantitative trait loci (pQTL) Mendelian randomization analysis to obtain a group of proteins with causal relationships with DKD and then identified key proteins through colocalization analysis to determine correlations between variant proteins and disease outcomes. Subsequently, the specific mechanisms of key regulatory genes involved in disease progression were analyzed through transcriptome and single-cell analysis. Finally, we validated the mRNA expression of five key genes in the DKD mice model using reverse transcription quantitative PCR (RT-qPCR).Results: Five characteristic genes, known as protein kinase B beta (AKT2), interleukin-2 receptor beta (IL2RB), neurexin 3(NRXN3), slit homolog 3(SLIT3), and TATA box binding protein like protein 1 (TBPL1), demonstrated causal relationships with DKD. These key genes are associated with the infiltration of immune cells, and they are related to the regulatory genes associated with immunity. In addition, we also conducted gene enrichment analysis to explore the complex network of potential signaling pathways that may regulate these key genes. Finally, we identified the effectiveness and reliability of these selected key genes through RT-qPCR in the DKD mice model.Conclusion: Our results indicated that the AKT2, IL2RB, NRXN3, SLIT3, and TBPL1 genes are closely related to DKD, which may be useful in the diagnosis and therapy of DKD.Keywords: Mendelian randomization analysis, diabetic kidney disease, clinical correlated genes, biomarker, immune cell infiltration

Qingqing Li,&ast; Jing Yin,&ast; Qibin Lin, Jilong He, Xiu Shi, Hanxiang Nie Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hanxiang Nie, Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuchang District, Wuhan, 430060, People’s Republic of China, Email nhxiang@whu.edu.cnBackground: Lung transplantation is the only effective therapeutic option for patients with end-stage lung disease. However, ischemia/reperfusion injury (IRI) during transplantation is a leading cause of primary graft dysfunction (PGD). Ferroptosis, a form of iron-dependent cell death driven by lipid peroxidation, has been implicated in IRI across various organs. This study aims to explore the role of ferroptosis in lung transplantation-related ischemia/reperfusion injury and to identify its potential molecular mechanisms through bioinformatics analysis.Methods: Transcriptome data from lung transplant patients were obtained from the Gene Expression Omnibus (GEO) database. Ferroptosis-related differentially expressed genes (FRGs) were identified by analyzing gene expression profiles before and after reperfusion. Weighted gene co-expression network analysis (WGCNA) was used to identify module genes, and overlapping genes were further analyzed using two machine learning algorithms. The CIBERSORT algorithm was applied to assess immune cell infiltration, while Mendelian randomization (MR) analysis was used to investigate causal relationships between candidate genes and PGD. Finally, Consensus clustering based on FRGs was performed to identify subtypes.Results: We identified four candidate genes associated with ferroptosis during lung reperfusion: tumor necrosis factor alpha-induced protein 3 (TNFAIP3), C-X-C motif chemokine ligand 2 (CXCL2), neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L), and sestrin 2 (SESN2). These genes were closely associated with immune cell infiltration. MR analysis suggested that SESN2 might play a protective role against PGD. Additionally, consensus clustering revealed distinct immune infiltration patterns across subtypes, providing insights for personalized therapeutic approaches to lung ischemia/reperfusion injury (LIRI).Conclusion: This study highlights TNFAIP3, CXCL2, NEDD4L, and SESN2 as candidate genes associated with ferroptosis during LIRI, with SESN2 potentially protecting against PGD. These findings offer promising therapeutic targets for preventing LIRI and improving outcomes in lung transplantation.Keywords: lung ischemia/reperfusion injury, ferroptosis, biomarkers, immune cell infiltration