COPD and T2DM: a Mendelian randomization study
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PROVIDER: S-EPMC10883379 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:PurposeThe associations of adiponectin with type 2 diabetes mellitus (T2DM), glucose homeostasis (including β-cell function index (HOMA-β), insulin resistance (HOMA-IR), fasting insulin (FI) and fasting glucose (FG)) have reported in epidemiological studies. However, the previous observational studies are prone to biases, such as reverse causation and residual confounding factors. Herein, a Mendelian Randomization (MR) study was conducted to determine whether causal effects exist among them.Materials and and methodsTwo-sample MR analyses and multiple sensitivity analyses were performed using the summary data from the ADIPOGen consortium, MAGIC Consortium, and a meta-analysis of GWAS with a considerable sample of T2DM (62,892 cases and 596,424 controls of European ancestry). We got eight valid genetic variants to predict the causal effect among adiponectin and T2DM and glucose homeostasis after excluding the probable invalid or pleiotropic variants.ResultsAdiponectin was not associated with T2DM (odds ratio (OR) = 1.004; 95% confidence interval (CI): 0.740, 1.363) when using MR Egger after removing the invalid SNPs, and the results were consistent when using the other four methods. Similar results existed among adiponectin and HOMA-β, HOMA-IR, FI, FG.ConclusionOur MR study revealed that adiponectin had no causal effect on T2DM and glucose homeostasis and that the associations among them in observational studies may be due to confounding factors.
| S-EPMC7250315 | biostudies-literature
Project description:Observational studies have demonstrated an association between elevated homocysteine (Hcy) level and risk of multiple myeloma (MM). However, it remains unclear whether this relationship is causal. We conducted a Mendelian randomization (MR) study to evaluate whether genetically increased Hcy level influences the risk of MM. We used the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism as an instrumental variable, which affects the plasma Hcy levels. Estimate of its effect on plasma Hcy level was based on a recent genome-wide meta-analysis of 44,147 individuals, while estimate of its effect on MM risk was obtained through meta-analysis of case-control studies with 2,092 cases and 4,954 controls. By combining these two estimates, we found that per one standard-deviation (SD) increase in natural log-transformed plasma Hcy levels conferred a 2.67-fold increase in risk for MM (95% confidence interval (CI): 1.12-6.38; P = 2.7 × 10(-2)). Our study suggests that elevated Hcy levels are causally associated with an increased risk of developing MM. Whether Hcy-lowering therapy can prevent MM merits further investigation in long-term randomized controlled trials (RCTs).
| S-EPMC4850434 | biostudies-other
Project description:Diabetic dyslipidemia is a common condition in patients with Type 2 diabetes mellitus (T2DM). However, with the increasing application of statins which mainly decrease low-density lipoprotein cholesterol (LDL-C) levels, clinical trials and meta-analysis showed a clearly increase of the incidence of new-onset DMs, partly due to genetic factors. To determine whether a causal relationship exists between LDL-C and T2DM, we conducted a two-sample Mendelian Randomization (MR) analysis using genetic variations as instrumental variables (IVs). Initially, 29 SNPs significantly related to LDL-C (P≤ 5.0×10-8) were selected as based on results from the study of Henry et al, which processed loci data influencing lipids identified by the Global Lipids Genetics Consortium (GLGC) from 188,577 individuals of European ancestry. While 6 SNPs related to T2DM (P value < 5×10-2) were deleted, with the remaining 23 SNPs without LD eventually being deemed as IVs. The combined effect of all these 23 SNPs on T2DM, as generated with use of the penalized robust inverse-variance weighted (IVW) method (Beta value 0.24, 95%CI 0.087~0.393, P-value=0.002) demonstrated that elevated LDL-C levels significantly increased the risk of T2DM. The relationship between LDL-C and Type 1 diabetes mellitus (T1DM) with this analysis producing negative pooled results (Beta value -0.202, 95%CI -2.888~2.484, P-value=0.883).
| S-EPMC7041740 | biostudies-literature
Project description:A large number of clinical studies have shown that interleukin-18 (IL-18) plasma levels are positively correlated with the pathogenesis and development of type 2 diabetes mellitus (T2DM), but it remains unclear whether IL-18 causes T2DM, primarily due to the influence of reverse causality and residual confounding factors. Genome-wide association studies have led to the discovery of numerous common variants associated with IL-18 and T2DM and opened unprecedented opportunities for investigating possible associations between genetic traits and diseases. In this study, we employed a two-sample Mendelian randomization (MR) method to analyze the causal relationships between IL-18 plasma levels and T2DM using IL18-related SNPs as genetic instrumental variables (IVs). We first selected eight SNPs that were significantly associated with IL-18 but independent of T2DM. We then used these SNPs as IVs to evaluate their effects on T2DM using the inverse-variance weighted (IVW) method. Finally, we conducted sensitivity analysis and MR-Egger regression analysis to evaluate the heterogeneity and pleiotropic effects of each variant. The results based on the IVW method demonstrate that high IL-18 plasma levels significantly increase the risk of T2DM, and no heterogeneity or pleiotropic effects appeared after the sensitivity and MR-Egger analyses.
| S-EPMC6459887 | biostudies-literature
Project description:BackgroundIn epidemiological studies, it has been proven that the occurrence of type 2 diabetes mellitus (T2DM) is related to an increased risk of infectious diseases. However, it is still unclear whether the relationship is casual.MethodsWe employed a two-sample Mendelian randomization (MR) to clarify the causal effect of T2DM on high-frequency infectious diseases: sepsis, skin and soft tissue infections (SSTIs), urinary tract infections (UTIs), pneumonia, and genito-urinary infection (GUI) in pregnancy. And then, we analyzed the genome-wide association study (GWAS) meta-analysis of European-descent individuals and conducted T2DM-related single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) that were associated with genome-wide significance (p < 5 × 10-8). MR estimates were obtained using the inverse variance-weighted (IVW), the MR-Egger regression, the simple mode (SM), weighted median, and weighted mode.ResultsThe UK Biobank (UKB) cohort (n > 500,000) provided data for GWASs on infectious diseases. MR analysis showed little evidence of a causal relationship of T2DM with five mentioned infections' (sepsis, SSTI, UTI, pneumonia, and GUI in pregnancy) susceptibility [odds ratio (OR) = 0.99999, p = 0.916; OR = 0.99986, p = 0.233; OR = 0.99973, p = 0.224; OR = 0.99997, p = 0.686; OR, 1.00002, p = 0.766]. Sensitivity analysis showed similar results, indicating the robustness of causality. There were no heterogeneity and pleiotropic bias.ConclusionT2DM would not be causally associated with high-frequency infectious diseases (including sepsis, SSTI, UTI, pneumonia, and GUI in pregnancy).
| S-EPMC8435717 | biostudies-literature
Project description:BackgroundObservational studies show an association between reduced lung function and impaired cognition. Cognitive dysfunction influences important health outcomes and is a precursor to dementia, but treatments options are currently very limited. Attention has therefore focused on identifying modifiable risk factors to prevent cognitive decline and preserve cognition. Our objective was to determine if lung function or risk of COPD causes reduced cognitive function using Mendelian randomization (MR).MethodsSingle nucleotide polymorphisms from genome wide association studies of lung function and COPD were used as exposures. We examined their effect on general cognitive function in a sample of 132,452 individuals. We then performed multivariable MR (MVMR), examining the effect of lung function before and after conditioning for covariates.ResultsWe found only weak evidence that reduced lung function (Beta - 0.002 (SE 0.02), p-value 0.86) or increased liability to COPD (- 0.008 (0.008), p-value 0.35) causes lower cognitive function. MVMR found both reduced FEV1 and FVC do cause lower cognitive function, but that after conditioning for height (- 0.03 (0.03), p-value 0.29 and - 0.01 (0.03) p-value 0.62, for FEV1 and FVC respectively) and educational attainment (- 0.03 (0.03) p-value 0.33 and - 0.01 (0.02), p-value 0.35) the evidence became weak.ConclusionWe did not find evidence that reduced lung function or COPD causes reduced cognitive function. Previous observational studies are probably affected by residual confounding. Research efforts should focus on shared risk factors for reduced lung function and cognition, rather than lung function alone as a modifiable risk factor.
| S-EPMC8296721 | biostudies-literature
Project description:Chronic obstructive pulmonary disease (COPD) has been associated with alterations in the brain cortical structure. Nonetheless, the causality between COPD and brain cortical structure has not been determined. In the present study, we used Mendelian randomization (MR) analysis to explore the causal effects of genetic predicated COPD on brain cortical structure, namely cortical surface area (SA) and cortical thickness (TH). Genetic association summary data for COPD were obtained from the FinnGen consortium (N = 358,369; Ncase = 20,066). PRISm summary genetic data were retrieved from a case-control GWAS conducted in the UK Biobank (N = 296,282). Lung function indices, including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC, were extracted from a meta-analysis of the UK Biobank and SpiroMeta consortium (N = 400,102). Brain cortical structure data were obtained from the ENIGMA consortium (N = 51,665). Inverse-variance weighted (IVW) method was used as the primary analysis, and a series of sensitivity tests were exploited to evaluate the heterogeneity and pleiotropy of our results. The results identified potential causal effects of COPD on several brain cortical specifications, including pars orbitalis, cuneus and inferior parietal gyrus. Furthermore, genetic predicated lung function index (FEV1, FVC and FEV1/FVC), as well as PRISm, also has causal effects on brain cortical structure. According to our results, a total of 15 functional specifications were influenced by lung function index and PRISm. These findings contribute to understanding the causal effects of COPD and lung function to brain cortical structure.
| S-EPMC11251327 | biostudies-literature
Project description:The goal of the study was to identify genes whose aberrant expression can contribute to diabetic retinopathy. We determined differential response in gene expression to high glucose in lymphoblastoid cell lines derived from matched type 1 diabetic individuals with and without retinopathy. Those genes exhibiting the largest difference in glucose response between diabetic subjects with and without retinopathy were assessed for association to diabetic retinopathy utilizing genotype data from a meta-genome-wide association study. All genetic variants associated with gene expression (expression QTLs; eQTLs) of the glucose response genes were tested for association with diabetic retinopathy. We detected an enrichment of the glucose response gene eQTLs among small association p-values for diabetic retinopathy. Among these, we identified FLCN as a susceptibility gene for diabetic retinopathy. Expression of FLCN in response to glucose is greater in individuals with diabetic retinopathy compared to diabetic individuals without retinopathy. Three large, independent cohorts of diabetic individuals revealed an enhanced association of FLCN eQTL to diabetic retinopathy. Mendelian randomization confirmed a direct positive effect of increased FLCN expression on retinopathy in diabetic individuals. Together, our studies integrating genetic association and gene expression implicate FLCN as a disease gene in diabetic retinopathy.
2020-03-10 | GSE146615 | GEO
Project description:Background and aimsSmoking increases the risk of severe COVID-19, but whether lung function or chronic obstructive pulmonary disease (COPD) mediate the underlying associations is unclear. We conducted the largest Mendelian randomization study to date, to our knowledge, to address these questions.DesignMendelian randomization study using summary statistics from genome-wide association studies (GWAS), FinnGen and UK Biobank. The main analysis was the inverse variance weighted method, and we included a range of sensitivity analyses to assess the robustness of the findings.SettingGWAS which included international consortia, FinnGen and UK Biobank.ParticipantsThe sample size ranged from 193 638 to 2 586 691.MeasurementsGenetic determinants of life-time smoking index, lung function [e.g. forced expiratory volume in 1 sec (FEV1 )], chronic obstructive pulmonary disease (COPD) and different severities of COID-19.ResultsSmoking increased the risk of COVID-19 compared with population controls for overall COVID-19 [odds ratio (OR) = 1.19 per standard deviation (SD) of life-time smoking index, 95% confidence interval (CI) = 1.11-1.27], hospitalized COVID-19 (OR = 1.67, 95% CI = 1.42-1.97) or severe COVID-19 (OR = 1.48, 95% CI = 1.10-1.98), with directionally consistent effects from sensitivity analyses. Lung function and COPD liability did not appear to mediate these associations.ConclusionThere is genetic evidence that smoking probably increases the risk of severe COVID-19 and possibly also milder forms of COVID-19. Decreased lung function and increased risk of chronic obstructive pulmonary disease do not seem to mediate the effect of smoking on COVID-19 risk.
| S-EPMC9111410 | biostudies-literature
Project description:Metabolic disorders are an important feature of chronic lung disease. Patients diagnosed with chronic obstructive pulmonary disease (COPD) have been found to experience metabolic disorders. Nonetheless, evidence on the causal role of circulating metabolites in promoting or preventing COPD is still lacking. Conducting a methodical examination on the causal connection between blood metabolites and COPD can aid in identifying fresh objectives for the screening and prevention of COPD. Therefore, we performed a two-sample Mendelian randomization (MR) analysis to evaluate the causal association between COPD and 486 blood metabolites.We used two-sample MR techniques and genome-wide association study (GWAS) data to evaluate the correlation between COPD and 486 serum metabolites. To evaluate the causal impact of serum metabolites on the risk of COPD, we predominantly employed inverse variance weighting (IVW) methodology. The MR-Egger regression test was employed to assess multiple validity, while the presence of heterogeneity was examined using the Cochran's Q test. To ensure the reliability of the findings, a leave-one-out analysis was conducted. The Bonferroni correction is used to adjust for multiple comparisons, ensuring rigorous validation of our results.After filtering by IVW and sensitivity analysis, we identified 10 known metabolites including fructose, margarate (17:0), guanosine, 2-stearoylglycerophosphocholine, hexadecanedioate, lactate, 5-oxoproline, paraxanthine, phenyllactate (PLA) and N-acetylglycine. Of these, fructose, margarate (17:0), guanosine, 2-stearoylglycerophosphocholine and hexadecanedioate are risk metabolites, and additionally, lactate, 5-oxoproline, paraxanthine phenyllactate(PLA) and N-acetylglycine are protective metabolites. In addition, the study identified five currently unknown chemical structures. Cochran's Q-test showed no significant heterogeneity, and MR Egger's intercept analysis confirmed the absence of horizontal multidirectionality. Leave-one-out analysis also proved the reliability of the MR analysis.We identified seven COPD-related risks and eight protective human serum metabolites. By combining genomics and metabolism, it provides new insights into the underlying mechanisms of COPD, with important implications for COPD screening and prevention.
| S-EPMC11873255 | biostudies-literature