Search

Background Despite studies confirming that patients with inflammatory bowel disease (IBD) present with dyslipidaemia, the associations between IBD and the serum lipid profile have not been determined. The present study aimed to investigate the causal relationship between the serum lipid profile and IBD risk and elucidate the nature of the interactions between them.Methods Two-sample Mendelian randomisation (MR) analysis was performed to investigate the causal links between total cholesterol (TC), total triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A (Apo A), apolipoprotein B (Apo B) and lipoprotein (a) (Lp(a)) and IBD. The study was carried out using the R TwoSampleMR and Mendelian randomisation packages.Results All MR methods, including the weighted median, weighted mode, inverse-variance weighted model, MR-PRESSO, contamination mixture and MR Egger, supported a null causal relationship between TG, TC, HDL-C, LDL-C, Apo A, Apo B and Lp(a) and between IBD, Crohn’s disease and ulcerative colitis. Null causal effects of lipid indices on IBD were validated through independent genome-wide association studies (GWAS), indicating that the findings are robust.Conclusion Our findings suggest that none of the seven lipid indices may be a potential risk factor for the onset of IBD. However, additional research is needed since our MR analyses cannot assess the potential non-linear causal relationship between serum lipids and IBD.

As a key adipokine, leptin has been extensively investigated for its potential role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, concordant conclusions have not been attained. In this study, we investigated the relationship between leptin and COPD using an integrative analysis that combined a Mendelian randomization (MR) study with transcriptomic data analysis. Here, the MR analysis was performed on the online platform MR-Base, and the bioinformatics analyses were performed with the aid of R Bioconductor packages. No evidence was found by the integrative analysis to support the association of the two attributes. All methods detected a null causal effect of leptin on COPD in the MR analysis. In particular, when the genetically predicted leptin level increased one unit, the risk of developing COPD was estimated as 0.999 (p = 0.943), 0.920 (p = 0.516), 1.002 (p = 0.885), and 1.002 (p = 0.906) by the Inverse Variance Weighted (IVW), MR-Egger, weighted median, and weighted mode method, respectively. Furthermore, no leptin-associated genes except one were identified as being differentially expressed between COPD and control in bioinformatics analysis. The observed association between leptin and COPD in previous observational studies may be attributable to unmeasured confounding effects or reverse causation.

Abstract Lung cancer, a major contributor to cancer-related fatalities worldwide, involves a complex pathogenesis. Cathepsins, lysosomal cysteine proteases, play roles in various physiological and pathological processes, including tumorigenesis. Observational studies have suggested an association between cathepsins and lung cancer. However, the causal link between the cathepsin family and lung cancer remains undetermined. This study employed Mendelian randomization analyses to investigate this causal association. The univariable Mendelian randomization analysis results indicate that elevated cathepsin H levels increase the overall risk of lung cancer, adenocarcinoma, and lung cancer among smokers. Conversely, reverse Mendelian randomization analyses suggest that squamous carcinoma may lead to increased cathepsin B levels. A multivariable analysis using nine cathepsins as covariates reveals that elevated cathepsin H levels lead to an increased overall risk of lung cancer, adenocarcinoma, and lung cancer in smokers. In conclusion, cathepsin H may serve as a marker for lung cancer, potentially inspiring directions in lung cancer diagnosis and treatment.

AimThis study aimed to examine the association of liver enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl-transferase (GGT), with type 2 diabetes (T2D) risk, particularly their dose-response relationship.MethodsThis cross-sectional study enrolled participants aged >20 years old who underwent physical examination at our local hospital from November 2022 to May 2023. A generalized additive model (GAM) was fit to assess the dose-response relationship between liver enzymes and T2D risk. Furthermore, data from the UK Biobank (n=217,533) and National Health and Nutrition Examination Survey (NHANES 2011-2018; n= 15,528) were analyzed to evaluate whether the dose-response relationship between liver enzymes and T2D differed by population differences.ResultsA total of 14,100 participants were included (1,155 individuals with T2D and 12,945 individuals without diabetes) in the analysis. GAM revealed a non-linear relationship between liver enzymes and T2D risk (Pnon-linear < 0.001). Specifically, T2D risk increased with increasing ALT and GGT levels (range, 50 IU/L. Elevated AST within a certain range (range, 35 IU/L) became a risk factor for T2D. The UK Biobank and NHANES data analysis also showed a similar non-linear pattern between liver enzymes and T2D incidence.ConclusionLiver enzymes were non–linearly associated with T2D risk in different populations, including China, the UK, and the US. Elevated ALT and GGT levels, within a certain range, could increase T2D risk. More attention should be given to liver enzyme levels for early lifestyle intervention and early T2D prevention. Further studies are necessary to explore the mechanism of the non-linear association between liver enzymes and T2D risk.

Epidemiological studies have shown that the levels of serum adipokine such as leptin and resistin are associated with the risk of developing systemic lupus erythematosus (SLE). Nevertheless, whether either leptin or resistin has causal impacts on the risk of SLE is still unknown. In this study, two-sample univariable MR analyses and multivariable MR analysis were performed to explore the causal relationships between adipokines and SLE. Additionally, the potential causal effects of SLE on major adipokines were evaluated using reverse MR analyses. The results of inverse-variance weighted (IVW), weighted median, weighted mode and MR‒Egger methods concordantly supported that major adipokines have no causal effects on the risk of SLE. In the multivariable MR IVW analysis with leptin and resistin as covariates, neither leptin (odds ratio (OR) = 3.093, P = 0.067) nor resistin (OR = 0.477, P = 0.311) was identified as an independent risk factor for SLE, which is in line with the univariable MR results. In conclusion, our analyses revealed no evidence to support that these three major adipokines are risk factors for SLE.

BackgroundObservational studies have demonstrated an association between white blood cells (WBC) subtypes and type 2 diabetes (T2D) risk. However, it is unknown whether this relationship is causal. We used Mendelian randomization (MR) to investigate the causal effect of WBC subtypes on T2D and glycemic traits.MethodsThe summary data for neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts were extracted from a recent genome-wide association study (n = 173,480). The DIAGRAM and MAGIC consortia offered summary data pertaining to T2D and glycemic characteristics, including fasting glucose (FG) (n = 133,010), glycosylated hemoglobin (HbA1c) (n = 46,368), and homeostatic model assessment-estimated insulin resistance (HOMA-IR) (n = 37,037). A series of MR analyses (univariable MR, multivariable MR, and reverse MR) were used to investigate the causal association of different WBC subtypes with T2D and glycemic traits.ResultsUsing the inverse-variance weighted method, we found one standard deviation increases in genetically determined neutrophil [odd ratio (OR): 1.086, 95% confidence interval (CI): 0.877-1.345], lymphocyte [0.878 (0.766-1.006)], monocyte [1.010 (0.906-1.127)], eosinophil [0.995 (0.867-1.142)], and basophil [0.960 (0.763-1.207)] were not causally associated with T2D risk. These findings were consistent with the results of three pleiotropy robust methods (MR-Egger, weighted median, and mode-based estimator) and multivariable MR analyses. Reverse MR analysis provided no evidence for the reverse causation of T2D on WBC subtypes. The null causal effects of WBC subtypes on FG, HbA1c, and HOMA-IR were also identified.ConclusionsWBCs play no causal role in the development of insulin resistance and T2D. The observed association between these factors may be explained by residual confounding.

Lung adenocarcinoma (LUAD) has a poor prognosis. Circadian genes such as TIMELESS have been associated with several pathologies, including cancer. The expression of TIMELESS and the relationship between TIMELESS, infiltration of tumors and prognosis in LUAD requires further investigation. In this study, we investigated the expression of TIMELESS and its association with survival across several types of human cancer using data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression Program. Noncoding RNAs (ncRNAs) regulating overexpression of TIMELESS in lung adenocarcinoma (LUAD) were explored with expression, correlation, and survival analyses. Immune cell infiltration and biomarkers were analyzed between different TIMELESS expression levels. The relationship between TIMELESS expression and immunophenoscores, which were used to predict response to immunotherapy, was evaluated. TIMELESS was identified as a potential oncogene in LUAD. NcRNA analysis showed MIR4435-2HG/hsa-miR-1-3p may interact with TIMELESS in a competitive endogenous RNA network in LUAD tumor tissues. Most immune cells were significantly decreased in TCGA LUAD tumor tissues with high TIMELESS expression except for CD4+T cells and Th2 cells. TIMELESS expression in LUAD tumor tissues was significantly negatively correlated with neutrophil biomarkers, dendritic cell biomarkers (HLA-DPB1, HLA-DQB1, HLA-DRA, HLA-DPA1, CD1C) and an immunophenoscore that predicted outcomes associated with the use of immune checkpoint inhibitors. These findings imply that ncRNAs-mediated TIMELESS overexpression in LUAD tumor tissues correlated with poor prognosis, reduced immune cell infiltration in the tumor microenvironment, and poor response to immune checkpoint inhibitors.

ABSTRACTObservational studies have been conducted to investigate the correlation between adiponectin and diabetic retinopathy (DR), but no consistent relationship has been established. In this study, we employed an integrative analysis that combined Mendelian randomization (MR) and bioinformatics analyses to comprehensively explore the association between DR and adiponectin, aiming to provide a unified answer of their relationship. Using the inverse-variance weighted (IVW) method, the odd ratio (OR) of developing DR per 1 mg/dL increment in genetically predicted log-transformed adiponectin concentration was estimated to be 0.949 (P = 0.557). Other robust MR methods produced consistent results, confirming the absence of a causal effect of adiponectin on DR. Additionally, the expression levels of the six adiponectin-related genes showed no significant differences among normal controls, individuals with diabetes but without DR, and those with DR Furthermore, the biological pathways enriched by these genes were not strongly relevant to DR. At both the individual gene and pathway levels, there were no overlaps between the adiponectin-related genes and the differentially expressed genes, indicating a lack of association between adiponectin and DR based on gene expression profiles. In summary, the integrative analysis, which combined MR and bioinformatics data mining, yielded compelling evidence supporting the notion that adiponectin is not a risk factor for DR.

As breast cancer is a multistage progression disease resulting from a genetic sequence of mutations, understanding the genes whose expression values increase or decrease monotonically across pathologic stages can provide insightful clues about how breast cancer initiates and advances. Utilizing variational autoencoder (VAE) networks in conjunction with traditional statistical testing, we successfully ascertain long non-coding RNAs (lncRNAs) that exhibit monotonically differential expression values in breast cancer. Subsequently, we validate that the identified lncRNAs really present monotonically changed patterns. The proposed procedure identified 248 monotonically decreasing expressed and 115 increasing expressed lncRNAs. They correspond to a total of 65 and 33 genes respectively, which possess unique known gene symbols. Some of them are associated with breast cancer, as suggested by previous studies. Furthermore, enriched pathways by the target mRNAs of these identified lncRNAs include the Wnt signaling pathway, human papillomavirus (HPV) infection, and Rap 1 signaling pathway, which have been shown to play crucial roles in the initiation and development of breast cancer. Additionally, we trained a VAE model using the entire dataset. To assess the effectiveness of the identified lncRNAs, a microarray dataset was employed as the test set. The results obtained from this evaluation were deemed satisfactory. In conclusion, further experimental validation of these lncRNAs with a large-sized study is warranted, and the proposed procedure is highly recommended.

AimsAlanine aminotransferase (ALT) is positively related to diabetes risk in observational studies, whereas Mendelian randomization supports a linear causal association. In contrast, the relationship between ALT and diabetic nephropathy, and diabetic retinopathy is counter-intuitive in observational studies. Furthermore, no MR study has examined their causal association. The study aimed to investigate whether genetically determined ALT has a causal effect on diabetic nephropathy and diabetic retinopathy.MethodsGenetic instruments associated with ALT (P < 5×10-8) were obtained from a recent genome-wide association study (GWAS) that included 437,267 individuals of European ancestry. Summary data of diabetic microvascular complications were derived from the FinnGen study (3,283 cases and 181,704 controls for diabetic nephropathy, and 14,584 cases and 176,010 controls for diabetic retinopathy, both were of European ancestry). Effect estimation and pleiotropy testing were performed using inverse variance weighted (IVW), MR-Egger regression, weighted median, and mode-based estimator methods. We additionally performed sensitivity analysis excluding proxy single nucleotide polymorphisms (SNPs) or lowering the GWAS significance threshold (P < 5×10-7) to test the robustness of the results.ResultsBased on IVW, a 2-fold increase in genetically determined ALT level was positively associated with diabetic nephropathy (odd ratio, [95% confidence interval], 1.73 [1.26-2.37], P = 0.001) and diabetic retinopathy (1.29 [1.08-1.54], P = 0.005), but a null causal association in three pleiotropy robust methods, namely, MR-Egger, weighted median and mode-based estimator. We obtained similar results in the sensitivity analysis of excluding proxy SNPs or lowering the GWAS significance threshold.ConclusionsWith caution, we concluded that ALT plays no linear causal role in developing both diabetic nephropathy and diabetic retinopathy. Further investigations are required to test the hypothesis of a non-linear causal association.

AimThe association between gamma-glutamyl transferase (GGT) and type 2 diabetes mellitus (T2DM) is controversial. In this study, we investigated the association between GGT and the risk of T2DM using real-world data, Mendelian randomization (MR) analysis, and literature mining.MethodsA cross-sectional study enrolled 3,048 participants (>40 years) from a community in Northeastern China was conducted. A generalized additive model was used to examine the relation between GGT and T2DM. A two-sample MR was performed to investigate the causal effect of GGT (61,089 individuals, mostly of European ancestry) on T2DM (29,193 cases and 182,573 controls of European ancestry).ResultsGGT was related to glucose metabolism indicators, such as fasting plasma glucose and glycosylated hemoglobin (P < 0.05). The odds ratios (ORs) [95% confidence interval (95% CI), P] for T2DM across the GGT categories (14–16, 17–20, 21–25, 26–35, ≥36) were 1.14 [(0.88-1.47), P = 0.330], 1.55 [(1.22-1.98), P < 0.001], 1.87 [(1.47-2.28), P < 0.001], 1.97 [(1.55-2.52), P < 0.001], and 2.29 [(1.78-2.94), P < 0.001] versus GGT ≤ 13 category after adjusting for potential confounding factors. A generalized additive model identified a non-linear correlation between GGT and T2DM and indicated that the risk of T2DM almost levelled out when GGT exceeded 34 IU/L. The MR analysis showed that the odds of having T2DM for a one-time increase in genetically determined GGT was 0.998 [(0.995-1.002), P = 0.34].ConclusionsOur analysis of observational study suggested that GGT, its increment, within a certain range, is indicative of the development of T2DM. However, MR analysis provided no evidence that GGT is a linear causal factor of T2DM. Further investigation is required to determine if GGT exerts a non-linear causal effect on T2DM.

The question of whether or not intermittent fasting diets improve the clinical indicators of glycolipid metabolism remains unclear. This study systematically reviewed the relevant clinical trials to evaluate the effects of intermittent fasting diet on glucose and lipid metabolism and insulin sensitivity in patients with metabolic syndrome. To evaluate the effect of intermittent fasting diet intervention on patients with disorders of glucose and lipid metabolism, random-effect or fixed-effect meta-analysis models were used to calculate the average difference before and after intermittent fasting diet intervention and the corresponding 95% confidence intervals (CIs). After intermittent fasting diet intervention, in terms of glucose metabolism, fasting blood glucose reduced by 0.15 mmol/L (95% CI: −0.23; −0.06), glycosylated hemoglobin reduced by 0.08 (95% CIs: −0.25; −0.10), insulin plasma levels reduced by 13.25 uUI (95% CIs: −16.69; −9.82), and HOMA-IR decreased by 0.31 on an average (95% CIs: −0.44; −0.19). In addition, BMI decreased by 0.8 kg/m2 (95% CIs: −1.32; −0.28), body weight reduced by 1.87 kg (95% CIs: −2.67; −1.07), and the waist circumference decreased by 2.08 cm (95% CIs: −3.06; −1.10). Analysis of lipid metabolism showed that intermittent fasting diet intervention effectively reduced the total cholesterol level by 0.32 mmol/L (95% CIs: −0.60; −0.05), low-density lipoprotein level by 0.22 mmol/L (95% CIs: −0.37; −0.07), and triglyceride level by 0.04 mmol/L (95% CIs: −0.15; −0.07). Intermittent fasting diets have certain therapeutic effects on blood glucose and lipids in patients with metabolic syndrome and significantly improve insulin resistance. It may be considered as an auxiliary treatment to prevent the occurrence and development of chronic diseases.