Primary Method Of Analysis Research Articles

Analyzing the causal role of blood cells in aging: a Mendelian randomization study.

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.

The Causal Role of Thyroid Hormones in Bipolar Disorders: A Two-Sample Mendelian Randomization Study.

Bipolar disorder is a complex psychiatric condition with distinctions between clinical subtypes including Type 1 and 2 disorders. Several studies have proposed that thyroid hormones may be involved in the aetiology of bipolar disorders. This study employed a two-sample Mendelian randomization (MR) approach to investigate the causal relationships between six thyroid hormone metrics (TSH, FT4, FT3, TT3, FT3/FT4 and TT3/FT4) and bipolar disorder and Type 1 and 2 disorders, separately. Genome-wide association (GWAS) data from the ThyroidOmics Consortium (up to 271,040 individuals of European ancestry) were used for thyroid function metrics. Bipolar disorder GWAS data included 41,917 cases and 371,549 controls (25,060 Type 1 and 6,781 Type 2 cases). We applied inverse variance weighted (IVW) methods for primary MR analysis, with MR Egger, weighted median and weighted mode for sensitivity. Additional tests assessed horizontal pleiotropy and heterogeneity. Higher FT4 levels showed a protective causal effect against bipolar disorder (OR: 0.92, 95% CI: 0.86-0.97, p = 4.58 × 10-3) and a suggestive effect on Type 1 disorders (OR: 0.92, 95% CI: 0.86-0.99, p = 3.21 × 10-2). Elevated FT3 (OR: 1.18, 95% CI: 1.03-1.35, p = 1.55 × 10-2) and FT3/FT4 ratio (OR: 1.97, 95% CI: 1.02-3.82, p = 4.46 × 10-2) had suggestive harmful effects on Type 1 disorders. Sensitivity analyses showed consistent effects, with no significant horizontal pleiotropy or heterogeneity. These findings highlight the protective role of FT4 and the potentially harmful effect of elevated FT3 in Type 1 bipolar disorder, highlighting the need for further research on thyroid hormone levels as a potential treatment strategy for Type 1 bipolar disorder.

Preliminary Study of Air Pollution and Adverse Pregnancy Outcomes: A Mendelian Randomization Study

The chief aim of this research is to investigate the causality of air pollutants and adverse pregnancy outcomes. Two-sample Mendelian randomization was conducted, employing genetic variants connected with air pollution as instrumental variables. Sixteen adverse pregnancy outcomes were extracted as the main outcome measures from the genome-wide association study (GWAS). The inverse-variance weighted (IVW) method was conducted as the primary analysis method. This study found that there were causal association between NO2 and pre-eclampsia (weighted median: OR = 1.30, 95% CI = [1.03–1.64], p = 0.029) and between PM2.5 and placental abruption (IVW: OR = 10.94, 95% CI = [1.28–93.45], p = 0.029). There were potential causal relationships between NO2 and gestational hypertension (IVW: OR = 1.14, 95% CI = [0.99–1.30], p = 0.060); NO2 and placental abruption (IVW: OR = 1.97, 95% CI = [0.90–4.28], p = 0.089); NOx and fetal growth restriction (IVW: OR = 0.06, 95% CI = [0.99–1.12], p = 0.089); PM2.5 and slow fetal growth and fetal malnutrition (MR–Egger: OR = 54,240.95, 95% CI = [2.08–1,411,757,729.46], p = 0.059); PM10 and hyperemesis gravidarum (MR–Egger: OR = 0.12, 95% CI = [0.02–0.97], p = 0.086); PM10 and preterm birth (weighted median: OR = 1.60, 95% CI = [0.95–2.70], p = 0.075); and PM10 and spontaneous abortion (weighted median: OR = 1.60, 95% CI = [0.95–2.70], p = 0.075). There was no pleiotropy, but there was some heterogeneity. In conclusion, air pollution has a causal effect on several adverse pregnancy outcomes.

Exploring the association between skin microbiota and inflammatory skin diseases: a two-sample Mendelian randomization analysis.

Dysbiosis in the skin microbiome is closely associated with various inflammatory skin diseases. However, current research on the causal relationship between the skin microbiome and inflammatory skin diseases lacks comprehensive and detailed investigation. We used a two-sample Mendelian randomization (MR) approach to explore associations between the skin microbiome and seven inflammatory skin diseases, including acne, atopic dermatitis, erysipelas, vitiligo, psoriasis, rosacea, and urticaria. The GWAS summary data for the skin microbiome was derived from 647 participants in two German population-based cohorts, and for the inflammatory skin diseases, they were sourced from the FinnGen consortium. Our primary MR analysis method was the inverse variance weighted (IVW) method, complemented by alternatives like MR-Egger regression, weighted median estimation, and constrained maximum likelihood. Sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, and MR-PRESSO outlier detection, were conducted to validate and stabilize our findings. We identified significant causal relationships between the skin microbiome and seven inflammatory skin diseases: acne, atopic dermatitis, erysipelas, vitiligo, psoriasis, rosacea, and urticaria, with 7, 6, 9, 1, 7, 4, and 7 respective causal relationships for each disease. These relationships comprise 20 protective and 14 risk causal relationships. We applied the false discovery rate correction to these results. Sensitivity analysis revealed no significant pleiotropy or heterogeneity. Our study revealed both beneficial and detrimental causal relationships between diverse skin microbiota and inflammatory skin diseases. Additionally, the ecological niche of the skin microbiome was crucial to its functional impact. This research provided new insights into how skin microbiota impacted skin diseases and the development of therapeutic strategies.

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.

The role of mitochondrial DNA copy number in autoimmune disease: a bidirectional two sample mendelian randomization study.

Mitochondrial DNA (mtDNA) plays an important role in autoimmune diseases (AD), yet the relationship between mitochondria and autoimmune disease is controversial. This study employed bidirectional Mendelian randomization (MR) to explore the causal relationship between mtDNA copy number and 13 ADs (including ankylosing spondylitis [AS], Crohn's disease [CD], juvenile rheumatoid arthritis [JRA], polymyalgia rheumatica [PMR], psoriasis [PSO], rheumatoid arthritis [RA], Sjogren's syndrome [SS], systemic lupus erythematosus [SLE], thyrotoxicosis, type 1 diabetes mellitus [T1DM], ulcerative colitis [UC], and vitiligo). A two-sample MR analysis was performed to assess the causal relationship between mtDNA copy number and AD. Genome-wide association study (GWAS) for mtDNA copy number were obtained from the UK Biobank (UKBB), while those associated with AD were sourced from the FinnGen Biobank. Inverse variance weighting (IVW) was the primary analysis method, complemented by three sensitivity analyses (MR-Egger, weighted median, weighted mode) to validate the results. IVW MR analysis identified significant associations between mtDNA copy number and CD (OR=2.51, 95% CI 1.56-4.22, P<0.001), JRA (OR=1.87, 95% CI 1.17-7.65, P=0.022), RA (OR=1.71, 95%CI 1.18-2.47, P=0.004), thyrotoxicosis (OR=0.51, 95% CI0.27-0.96, P=0.038), and T1DM (OR=0.51, 95% CI 0.27-0.96, P=0.038). Sensitivity analyses indicated no horizontal pleiotropy. Our study revealed a potential causal relationship between mtDNA copy number and ADs, indicating that these markers may be relevant in exploring new therapeutic approaches.

Association Between Arterial Stiffness Index and Age-Related Diseases: A Mendelian Randomization Study.

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.

Assessing the causal relationship between non-small cell lung cancer and sepsis: a Mendelian randomization study

BackgroundA Two-sample Mendelian randomization (MR) Analysis was used to assess the causal relationship between non-small cell lung cancer (NSCLC) and sepsis.MethodSingle nucleotide polymorphisms (SNPs) closely associated with NSCLC were utilized as instrumental variables (IVs) in this study. The Inverse Variance Weighted (IVW) method was used as the primary method for MR analysis, supplemented by the Weighted median, Weighted model, and MR-Egger regression method. Sensitivity analysis was conducted to improve result robustness, and data from various sources were validated and integrated. Bonferroni tests were applied to adjust for multiple comparisons.ResultsAfter Bonferroni tests correcting the combined results, MR analysis revealed a significant association between genetically predicted NSCLC and an increased susceptibility to sepsis (odds ratios [OR]: 1.140, 95% confidence interval [CI]: 1.085–1.199, P = 2.61 × 10− 7). The combined results demonstrated that NSCLC is associated with a heightened risk of sepsis in patients under 75 years of age (OR: 1.085, 95%CI: 1.037–1.353, P = 3.84 × 10− 4). Furthermore, lung adenocarcinoma (LUAD) was found to be potentially associated with an increased susceptibility to sepsis (OR: 1.040, 95% CI: 1.009–1.073, P = 1.16 × 10− 2). These results withstood multiple sensitivity analyses, demonstrating their robustness.ConclusionThis study confirms that NSCLC can significantly increase susceptibility to sepsis at the genetic level, providing valuable insights for the early identification of individuals at risk for sepsis.

Systematic evaluation of the correlation between serum metabolites and tinnitus

Objective: We performed a Mendelian randomisation (MR) analysis to explore the relationship between serum metabolites and tinnitus. Methods: In this study, 486 serum metabolites were considered as exposure factors, and single nucleotide polymorphisms (SNP) significantly associated with them were used as instrumental variables (IV). The serum metabolite data were obtained from a public database (http://metabolomips.org/gwas/index.php), while the genome-wide association study (GWAS) summary association statistics for tinnitus were obtained from a Finnish database (https://r10.finngen.fi/pheno/H8_TINNITUS). The inverse variance weighting (IVW) method was employed as the primary determination method for MR analysis, with corrections for multiple comparisons made using the false discovery rate (FDR). Sensitivity tests were conducted using the MR-Egger regression, Mendelian random polymorphism residuals and outliers (MR-PRESSO) methods. The identified serum metabolites were subjected to chained disequilibrium regression analysis (LDSC) and metabolic pathway analysis. Reverse MR analysis was performed to investigate the possibility of reverse causality. Analyses were performed in R software (version 4.3.1). Results: A total of 17 serum metabolites (including 10 known and 7 unknown metabolites) associated with tinnitus were identified. The known metabolites included protective metabolites such as acetylcarnitine, hydroxyisovaleryl carnitine, glycine, monounsaturated glycerol ester, and glycine-L-valine, and hazardous metabolites such as allantoin, glycerylphosphorylcholine 1-eicosatrienoate, myo-inositol, 15-methylpalmitate, and pseudouridine; the strongest causally protective metabolites were acetylcarnitine, the followed by hydroxyisopentanoyl carnitine and glycine; the hazardous metabolite with the strongest causal effect was pseudouridine, followed by inositol and 15-methylpalmitate; and only hydroxyisopentanoyl carnitine (PFDR=0.04) and glycerol monooleate (PFDR=0.04) reached significance values after FDR correction. The findings were free of heterogeneity, pleiotropy and reverse causal associations. The metabolic pathways were mainly enriched in pathways such as ascorbic acid and aldolac metabolism. Conclusions: The study suggests a causal relationship between serum metabolites and tinnitus risk. Serum metabolite levels may influence tinnitus-related metabolic pathways.

Investigating the relationship between blood metabolites and diabetic retinopathy using two-sample mendelian randomization and in vivo validation

We addressed fundamental questions about the influence of metabolites on the development of Diabetic retinopathy (DR), and explored the related pathological mechanism. Genome-wide association study (GWAS) database data for metabolites and DR were used to perform Mendelian randomization (MR) studies. The inverse variance weighting (IVW) was chosen as the primary analysis method. Sensitivity analysis was conducted using MR-PRESSO, leave-one-out and Cochran’s Q test. Confounding factors were eliminated to ensure robustness. We also conducted metabolic pathway analysis. In vivo experimental validation was conducted using Sprague Dawley rats. The serum metabolites of the DR group rats and normal group rats were examined to evaluate the MR results. The screen identified eighteen metabolites associated with DR risk, twelve of which were known components. Seven metabolites were positively correlated with DR risk, while five could reduce it. Eight metabolites associated with proliferative DR (PDR) risk were identified, four of which are known components. Three of these were positively associated with PDR risk and one metabolite reduced PDR risk. Additionally, two possible metabolic pathways involved in the biological mechanism of DR were identified. The ELISA results showed that the serum levels of isoleucine and 4-HPA were significantly increased in DR rats, while the level of inosine was decreased. This study offers novel insights into the biological mechanisms underlying DR. Metabolites that are causally linked to DR may serve as promising biomarkers and therapeutic targets.

Causal associations between type 2 diabetes mellitus, glycemic traits, dietary habits and the risk of pressure ulcers: univariable, bidirectional and multivariable Mendelian randomization.

Previous research has established a connection between Type 2 Diabetes Mellitus (T2DM), glycemic traits, dietary habits, and the risk of Pressure Ulcers (PUs). The aim of our study is to disentangle any potential causal relationship between T2DM, glycemic traits, and dietary factors, and the risk of PUs. The exposure and outcome datasets were sourced from the IEU Open GWAS project, the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), and the FinnGen biobank, respectively. The primary MR analysis method employed was the inverse variance-weighted method. Furthermore, we employed multivariable MR (MVMR) adjusting for BMI. Then, we investigated the possibility of a reverse association between glycemic traits and PUs through bidirectional MR. Finally, Heterogeneity and pleiotropic analysis were conducted to ensure the accuracy and robustness of the results. The findings revealed that T2DM (OR = 1.282, 95% CI: 1.138-1.445, p < 0.001) and Fasting Glucose (FG; OR = 2.111, 95% CI: 1.080-4.129, p = 0.029) were associated with an increased risk of PUs, while salad/raw vegetable intake (OR: 0.014; 95% CI: 0.001-0.278; p = 0.005) was identified as a protective element. However, no other dietary elements demonstrated a statistically significant causality with PUs. In addition, in the reverse direction, there were positive correlation between genetic susceptibility to PUs and an increase in FG (OR: 1.007, 95% CI: 1.000-1.013, p = 0.048) and Fasting Insulin (FI; OR: 1.012, 95% CI: 1.003-1.022, p = 0.011). MVMR results indicated that the causal effect of T2DM on PUs was independent of BMI (OR: 1.260, 95% CI: 1.112-1.427, p < 0.001). These results remained robust when considering weak instrument bias, pleiotropy, and heterogeneity. This study establishes a causal link between genetically predicted T2DM, FG and an increased risk of PUs. Conversely, Salad/raw vegetable intake is significantly inversely associated with PUs. Simultaneously, we identified two downstream effector factor (FG and FI) that were associated with PUs. These findings may have clinical implications for both prevention and treatment.

Periodontitis and Hepatocellular Carcinoma: A Two-Sample Mendelian Randomisation Study

Introduction and AimsObservational studies have reported conflicting associations between periodontitis (PD) and hepatocellular carcinoma (HCC). To overcome these limitations, we performed a two-sample Mendelian randomization (MR) analysis to investigate the potential association between PD and HCC. MethodsWe used summary data from genome-wide association studies (GWASs) of European ancestry, integrating data from chronic/acute periodontitis (CP/AP) samples (n1 = 34,615; n2 = 277,036; n3 = 410,811) and HCC samples (n1 = 456,348; n2 = 475,638). The inverse variance-weighted (IVW) approach represents our primary analysis method, supplemented by MR-Egger regression, weighted median, weighted-mode, and simple-mode methods. Pleiotropy and heterogeneity tests were also performed. ResultsIVW analysis suggested that PD had no effect on HCC (Group 1: odds ratio [OR] = 0.912, 95% confidence interval [CI] = 0.690-1.204, P = .514; Group 2: OR = 1.038, 95% CI = 0.895-1.203, P = .623; Group 3: OR = 0.966, 95% CI = 0.851-1.096, P = .591; Group 4: OR = 1.103, 95% CI = 0.576-2.113, P = .768; Group 5: OR = 1.257, 95% CI = 0.511-1.037, P = .540; Group 6: OR = 0.728, 95% CI = 0.511-1.037, P = .079). Four complementary analyses further support this conclusion. Both the IVW and MR-Egger results indicate that the instrumental variables in each group did not exhibit significant pleiotropy. MR-Egger regression analysis showed no evidence of pleiotropic effects. ConclusionOur MR analysis suggests that PD does not significantly impact the risk of developing HCC. These results provide a new perspective on the relationship between these 2 conditions. Clinical RelevanceThis MR study suggests no significant genetic causal relationship between PD and HCC, providing a new perspective. It indicates that clinicians may not need to over-intervene in periodontal disease to prevent liver cancer, thereby avoiding unnecessary psychological burden on patients.

Inflammatory cytokines and their potential role in kidney stone disease: a Mendelian randomization study.

Previous studies have reported a complex relationship between inflammatory cytokines and kidney stone disease (KSD). The purpose of this paper is to investigate the potential causal impact of inflammatory cytokines on KSD by Mendelian randomization (MR) analysis. In our study, a thorough two-sample Mendelian randomization (MR) analysis was performed by us to determine the potential causal relationship between inflammatory cytokines and kidney stone disease. Utilizing GWAS summary data of inflammatory cytokines and KSD, we performed the first two-sample MR analysis. Genetic variants in GWASs related to inflammatory cytokines were employed as instrumental variables (IVs). The data on cytokines were derived from 14,824 participants and analyzed by utilizing the Olink Target-96 Inflammation Panel. GWAS summary data related to KSD (9713 cases and 366,693 controls) were obtained from the FinnGen consortium. The primary MR analysis method was Inverse variance weighted. Reverse MR analysis, Cochran's Q test, MR Egger, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were used to assess the stability of the results. 91 cytokines were enrolled in the MR analysis after strict quality control of IV. The IVW analysis revealed 2 cytokines as risk factors for KSD: Cystatin D (OR 1.06, 95% CI 1.01-1.11), Fibroblast growth factor 5 (OR 1.06, 95% CI 1.00-1.12), suggesting they are positively associated with the occurrence of kidney stones. We also found 3 protective associations between cytokines and KSD: Artemin (OR 0.86, 95% CI 0.78-0.96), T-cell surface glycoprotein CD6 isoform (OR 0.92, 95% CI 0.88-0.98), STAM-binding protein (OR 0.83, 95% CI 0.69-0.99). There was no horizontal pleiotropy or significant heterogeneity in our MR analysis, as determined by the p-value results of our MR Egger's intercept test, Cochrane Q-test, and MR-PRESSO, which were all > 0.05. Our study explored a variety of inflammatory cytokines related to KSD through MR analysis, which validated several previous findings and provided some new potential biomarkers for KSD. However, the findings require further investigation to validate their exact functions in the pathogenesis and evolution of KSD.

Causal relationship between circulating immune cells and gastric cancer: a bidirectional Mendelian randomization analysis using UK Biobank and FinnGen datasets.

The role of immune cells in cancer pathogenesis remains controversial due to conflicting reports, potentially arising from various confounding factors. Emerging evidence suggests that cancer can also influence immune cell populations and functions, making it challenging to investigate their causal relationship. Traditional observational studies often fail to eliminate all confounding factors and are prone to reverse causality. Therefore, we employ Mendelian randomization (MR) to determine the causal relationship between immune cells and cancer, as this method can identify causal relationships independent of confounding factors and avoid reverse causality. Genome-wide association study (GWAS) summary statistics on immune traits, encompassing 310 immune cell phenotypes, were obtained from 3,757 European individuals, with peripheral blood immune cells tested using flow cytometry. GWAS summary statistics for gastric cancer were derived from 476,116 European individuals across two large-scale biobanks: the UK Biobank and FinnGen. Gastric cancer was identified by the International Classification of Diseases, 9th Revision (ICD-9), and 10th Revision (ICD-10) codes. Significant single nucleotide polymorphisms (SNPs) for immune traits were extracted at a threshold of P<1×10-5, while a threshold of P<5×10-8 was used for gastric cancer GWAS data. Linkage imbalance-based clumping was performed to obtain independent SNPs, and those with F<10 were excluded to mitigate weak instrument bias. Phenoscanner V2 was used to exclude SNPs directly associated with potential confounders or outcomes. Two-sample MR was conducted using five MR methods, with inverse-variance-weighted (IVW) as the primary analysis method. A false discovery rate (FDR) correction was used to reduce the likelihood of type 1 errors. In addition, we conducted MR-Egger intercept tests and Cochran's Q tests. The numbers of CD4-CD8- T cells and IgD-CD27- B cells were positively correlated with the development of gastric cancer, with odds ratios (ORs) of 1.15 [95% confidence interval (CI), 1.07-1.24; P<0.001; PFDR=0.041; IVW method] and 1.07 (95% CI, 1.03-1.11; P=0.001; PFDR=0.187; IVW method), respectively. However, the percentage of IgD+CD24- B cells in lymphocytes were negatively associated with the development of gastric cancer (OR =0.90; 95% CI, 0.84-0.96; P=0.002; PFDR=0.187; IVW method). MR analysis of the above three immune cell phenotypes showed no significant heterogeneity or horizontal pleiotropy. In the reverse MR analysis, gastric cancer was not causally associated with any of the immune cell phenotypes. Circulating CD4-CD8- T cells and IgD-CD27- B cells are positively correlated with the development of gastric cancer, while the percentage of IgD+CD24- B cells in lymphocytes are negatively correlated. These findings provide insight into the relationship between immune cells and gastric cancer pathogenesis and may serve as a basis for the development of immunotherapies for gastric cancer.

Causal relationship between Lipdome and Chronic Obstructive Pulmonary Disease and Asthma: Mendelian randomization

Genetic risk significantly influence susceptibility and heterogeneity of chronic obstructive pulmonary disease (COPD) and asthma, and increasing evidence suggests their close association with lipdome. However, their causal relationship remains unclear. In this study, we conducted a two-sample MR (Mendelian randomization) analysis using publicly available large-scale genome-wide association studies (GWAS) data to evaluate the causal impact of lipdome on COPD and asthma. The inverse variance weighted (IVW) method served as the primary analysis method, and multiple sensitivity and heterogeneity tests were performed to assess the reliability of the results. Finally, a Meta-analysis was conducted on lipdome with significant causal relationships to validate the robustness of the results. Our findings suggest that Sterol ester (27:1/18:2), Phosphatidylcholine (15:0_18:2), (16:0_18:2), (16:0_20:2), (17:0_18:2), (18:1_18:1), (18:1_18:2), (18:1_20:2), Triacylglycerol (54:3), and (56:4) levels are protective factors for COPD, while levels of Phosphatidylcholine (16:0_22:5), (18:0_20:4), and (O-16:0_20:4) are risk factors for COPD. Meta-analysis of lipids causally related to COPD also indicates significant results. Phosphatidylcholine (16:0_20:4), (16:0_22:5), and (18:0_20:4) levels are risk factors for asthma, while Phosphatidylcholine (18:1_18:2), (18:1_20:2), and Sphingomyelin (d38:1) levels are protective factors for asthma. However, the lack of statistical significance in the Meta-analysis may be due to heterogeneity in research methods and data statistics. This study indicates that 4 lipdome species have significant correlations with COPD and asthma. Phosphatidylcholine (18:1_18:2) and (18:1_20:2) are protective factors, while Phosphatidylcholine (16:0_22:5) and (18:0_20:4) are risk factors. Additionally, due to differences in molecular subtypes, phosphatidylcholine, sterol ester, and triacylglycerol exhibit differential effects on the diseases.

Causal relationship between thyroid function and multiple sclerosis: A bidirectional Mendelian randomization study.

An association between thyroid function and multiple sclerosis (MS) has been reported in several observational studies, but the causal relationship between them is still unclear. Thus, this study used a bidirectional Mendelian randomization (MR) to investigate the associations between thyroid function and MS. Bidirectional MR was used to explore the causal relationship between thyroid function (thyroid-stimulating hormone [TSH], free thyroxine [FT4], hyperthyroidism, and hypothyroidism) and MS. Genome-wide association study (GWAS) data of thyroid function and MS were obtained from the ThyroidOmics Consortium and the FinnGen Consortium, respectively. Inverse-variance weighted method (IVW) was the primary analysis method to assess causality with Weighted median, MR-Egger regression, weighted mode, and simple mode as auxiliary methods. Sensitivity analyses were performed using heterogeneity tests, horizontal pleiotropy tests and leave-one-out method. There was a positive causal relationship between TSH and MS (IVW: OR = 1.202, 95% CI: 1.040-1.389, P = .013), and no strong evidence was found for an effect of FT4 (IVW: OR = 1.286, 95% CI: 0.990-1.671, P = .059), hypothyroidism (IVW: OR = 1.247, 95% CI: 0.961-1.617, P = .096), and hyperthyroidism (IVW: OR = 0.966, 95% CI: 0.907-1.030, P = .291) on the risk of MS. In the reverse MR results, there was no causal relationship between MS and TSH (IVW: β = -0.009, P = .184), FT4 (IVW: β = -0.011, P = .286), hypothyroidism (IVW: OR = 0.992, 95% CI: 0.944-1.042, P = .745), and hyperthyroidism (IVW: OR = 1.026, 95% CI: 0.943-1.117, P = .549). Cochran's Q test, MR-Egger intercept test, MR-PRESSO global test, and Leave-one-out did not observe horizontal pleiotropy and heterogeneity. In conclusion, MR analysis supported a positive causal relationship between TSH and MS.

Causal Relationships between Lymphocyte Subsets and Risk of Coronary Artery Disease: A Two-Sample Mendelian Randomization Study.

Currently, the causal relationship between lymphocyte subsets and coronary artery disease (CAD) remains unclear. Therefore, we utilized Mendelian randomization (MR) to assess the association between lymphocyte subsets and CAD. We performed a two-sample MR analysis using publicly available genome-wide association studies (GWAS) datasets. The primary method of analysis to comprehensively evaluate causal effects was the inverse variance-weighted (IVW) method. The four additional MR approaches were MR-Egger, weighted median, simple mode, and weighted mode. Sensitivity analysis incorporated Cochran's Q and MR-Egger intercept tests to identify residual heterogeneity and potential horizontal pleiotropy, respectively. The MR-PRESSO distortion test was applied to identify potential pleiotropic outliers. Leave-one-out analysis confirmed that no single single-nucleotide polymorphism (SNP) significantly affected the MR estimate. We conducted reverse MR analysis to investigate the impact of variables correlated with outcomes in forward MR analysis. The IVW method revealed a significant positive association between B cell count and CAD (odds ratio (OR) = 1.08 (95% CI: 1.04, 1.11), p = 2.67 × 10-5). A similar association was observed between B cell count and myocardial infarction (MI) (OR = 1.07 (95% CI: 1.03, 1.11), p = 5.69 × 10-4). Sensitivity analyses detected no outliers, heterogeneity, or pleiotropy. The reverse MR analysis was conducted to investigate the impact of CAD and MI on B cell count, and the IVW results showed no statistical significance. Our study suggests that a higher absolute B cell count is linked to an increased risk of CAD and MI.

Non-linear associations between cardiovascular metabolic indices and metabolic-associated fatty liver disease: A cross-sectional study in the US population (2017-2020).

The cardiometabolic index (CMI) is an emerging and effective indicator for predicting the presence of metabolic-associated fatty liver disease (MAFLD). This study aims to investigate the relationship between CMI and MAFLD using data from NHANES 2017-2020. In this cross-sectional study, a total of 3,749 subjects were included. The study conducted a thorough analysis of CMI with three multivariate logistic regression models, subgroup analyses, and restricted cubic splines (RCS) were utilized. Using multifactorial logistic regression as the primary method of analysis, we found that a higher CMI was also significantly associated with an increased risk of MAFLD (OR = 1.45, 95% CI (1.05-2.01)). This result was further visualized by the RCS curve: There was a non-linear positive correlation between CMI and MAFLD incidence (the turning point is CMI = 0.4554). These findings were strongly reinforced by subsequent subgroup and sensitivity analyses. There is a robust positive relationship between the CMI and the risk of MAFLD, providing valuable clinical benefits for early detection and screening of MAFLD. It is important to highlight the presence of a non-linear association between CMI and MAFLD, with an inflection point identified at CMI = 0.4554.

Can Omega-3 prevent the accidence of stroke: a mendelian randomization study

BackgroundThe lipid-lowering effects of Omega-3 fatty acids have been widely reported, yet their impact on ischemic stroke remains controversial. Reports on the protective effects of unsaturated fatty acids, such as Omega-6 and Omega-7, as well as saturated fatty acids in cardiovascular diseases, including hypertension and ischemic stroke, are less frequent.ObjectivesThis study aims to identify fatty acids associated with blood pressure and ischemic stroke through Mendelian randomization. Besides, it seeks to determine whether specific fatty acids can prevent ischemic stroke by managing blood pressure and revealing the specific mechanisms of this action.MethodsThis research involved downloading relevant data from websites and extracting SNPs that met the standard criteria as instrumental variables. Simultaneously, the ‘MR-PRESSO’ package and ‘Mendelian Randomization’ package were used to eliminate confounding SNPs that could bias the study results. Then, inverse variance weighting and the weighted median were employed as primary analysis methods, accompanied by sensitivity analysis to assess the validity of the causal relationships. Initially, multivariable Mendelian randomization was used to identify fatty acids linked to blood pressure and the incidence of ischemic stroke. The causal link between certain fatty acids and the initiation of ischemic stroke was then investigated using bidirectional and mediator Mendelian randomization techniques. Stepwise Regression and the Product of Coefficients Method in mediator Mendelian randomization were utilized to ascertain whether specific fatty acids reduce ischemic stroke risk by lowering blood pressure.ResultsMultivariable Mendelian randomization analysis indicated a potential inverse correlation between Omega-3 intake and both blood pressure and ischemic stroke. Consequently, Omega-3 was selected as the exposure, with blood pressure and ischemic stroke-related data as outcomes, for further bidirectional and mediation Mendelian Randomization analyses. Bidirectional Mendelian Randomization revealed that Omega-3 significantly influences DBP (P = 1.01e-04) and IS (P = 0.016). It also showed that DBP and SBP significantly affect LAS, SVS, CES, IS, and LS. Mediator Mendelian Randomization identified five established mediating pathways: Omega-3-Diastolic blood pressure-Small vessel stroke, Omega-3-Diastolic blood pressure-Cardioembolic stroke, Omega-3-Diastolic blood pressure-Lacunar stroke, Omega-3-Diastolic blood pressure-Large artery atherosclerosis stroke, and Omega-3-Diastolic blood pressure-Ischemic stroke. Of these, four pathways are complete mediation, and one pathway is partial mediation.ConclusionsThe findings suggest that Omega-3 may indirectly reduce the incidence of ischemic stroke by lowering blood pressure. Thus, blood pressure modulation might be one of the mechanisms through which Omega-3 prevents ischemic stroke. In summary, incorporating an increased intake of Omega-3 in the diet can serve as one of the dietary intervention strategies for patients with hypertension. Additionally, it can act as an adjunctive therapy for the prevention of ischemic strokes and their complications.

Serum folate levels and risk of metabolic dysfunction-associated steatotic liver disease: results from a cross-sectional study and Mendelian randomization analysis.

Evidence from observational studies on the association between folate and metabolic dysfunction-associated steatotic liver disease (MASLD) is conflicting. This study aimed to investigate the association between serum folate concentration and MASLD and further assess the causal relationship using Mendelian randomization (MR) analysis. To investigate the causal relationship between serum folate and MASLD, we conducted a cross-sectional study that selected 1,117 participants from the 2017-2020 National Health and Nutrition Examination Survey (NHANES). The association between serum folate level and the risk of MASLD was evaluated under a multivariate logistic regression model. In addition, we conducted a two-sample MR study using genetic data from a large genome-wide association study (GWAS) to compare serum folate level (37,465 individuals) and MASLD (primary analysis: 8,434 cases/770,180 controls; Secondary analysis:1,483 cases/17,781 controls) were performed to infer causal relationships between them. Inverse variance weighted (IVW) was used as the primary method of MR Analysis. The results from the NHANES database showed that Tertile 3 group (Tertile 3: ≥ 48.6 nmol/L) had a significantly lower risk (OR = 0.58, 95% CI: 0.38-0.88, p = 0.010) of MASLD than Tertile 1 group (Tertile 1: < 22.3 nmol/L) after complete adjustments. However, in the IVW of MR analysis, there was no causal relationship between serum folate level and MASLD risk in the primary analysis (OR = 0.75, 95% CI: 0.55-1.02, p = 0.065) and secondary analysis (OR = 0.83, 95% CI: 0.39-1.74, p = 0.618). In observational analyses, we observed an inverse association between higher serum folate concentrations and a reduced risk of MASLD. Our MR study generated similar results, but the association failed to reach the significance threshold of p < 0.05, suggesting that our MR study does not support a causal relationship between serum folate levels and MASLD risk. Additional research involving a larger number of cases would contribute to enhancing the confirmation of our preliminary findings.