Two-sample Mendelian Randomization Analysis Research Articles

Estimated GFR Decline is Causally Associated with Acute Pulmonary Embolism: A Nested Case-Control and Mendelian Randomization Study.

Renal dysfunction is highly prevalent among patients with pulmonary embolism (PE). This study combined population-based study and Mendelian randomization to observe the relationship between renal function and PE. A nested case-control study were performed using data of PE patients and controls were from two nationwide cohorts, the China pUlmonary thromboembolism REgistry Study (CURES) and China Health and Retirement Longitudinal Survey (CHARLS). Baseline characteristics were balanced using propensity score matching and inverse probability of treatment weighting. Restricted cubic spline models were applied for the relationship between estimated glomerular filtration rate (eGFR) decline and the risk of PE. Bidirectional two-sample Mendelian randomization (MR) analyses were performed using Genome-wide association study summary statistics for eGFR involving 1,201,909 individuals and for PE from the FinnGen consortium. The nested case-control study including 17,547 participants (6,322 PE patients) found that eGFR distribution was significantly different between PE patients and controls (P<0.001), PE patients had a higher proportion of eGFR<60 mL/min/1·73 m2. eGFR below 88 mL/min/1·73 m2 was associated with a steep elevation in PE risk. MR analyses indicated a potential causal effect of eGFR decline on PE (OR=4·26, 95%CI 2·07-8·79), with no evidence of horizontal pleiotropy and reverse causality. Our findings support the hypothesis that renal function decline contributes to an elevated PE risk. Together with the high prevalence of chronic kidney diseases globally, there arises the necessity for monitoring and modulation of renal function in effective PE prevention.

Breast cancer and neoplasms of the thyroid gland: a bidirectional two-sample Mendelian randomization study.

With the rising incidence of breast cancer (BC) and neoplasms of the thyroid gland, a potential link between the two has drawn increasing attention. However, the causal relationship remains unclear due to various confounding factors. This study aims to investigate the causality between BC and thyroid tumors using Mendelian Randomization (MR) analysis. We conducted a bidirectional two-sample MR analysis, utilizing breast cancer-associated single nucleotide polymorphisms (SNPs) from the Breast Cancer Association Consortium (BCAC) and thyroid tumor-related SNPs from the FinnGen (https://www.finngen.fi/) database. First, we performed univariable MR (UVMR) to assess the causal relationship between BC and both malignant and benign thyroid tumors, followed by reverse causality analysis. To account for potential confounders, we applied multivariable MR (MVMR). The inverse-variance weighted (IVW) method was primarily used, with secondary analyses performed using the weighted median and MR-Egger regression approaches. UVMR analysis revealed a significant positive causal relationship between BC and malignant thyroid tumors (odds ratio [OR] and 95% confidence interval [CI]: 1.291, 1.143-1.458, P = 3.90×10-5). No causal relationship was found between BC and benign thyroid tumors. The MVMR analysis, adjusting for confounding factors such as smoking, drinking, and body mass index (BMI), confirmed the robustness of the results. This study provides genetic evidence supporting a causal relationship between BC and malignant thyroid tumors. These findings highlight the importance of thyroid cancer screening in BC patients. However, further MR studies or randomized controlled trials (RCTs) are necessary to assess small effects accurately.

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

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

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.

Association between dietary fat intake and the risk of Alzheimer's disease: Mendelian randomisation study.

Observational studies have shown a controversial relationship between dietary fat intake and Alzheimer's disease, and the causal effects are unclear. To assess the causal effects of total fat, saturated fat and polyunsaturated fat (PUF) intakes on the risk of Alzheimer's disease. A two-sample Mendelian randomisation analysis was performed using genome-wide association study summary statistics on different types of fat intake from UK Biobank (n = 51 413) and on late-onset Alzheimer's disease (LOAD; 4282 cases, n = 307 112) and all forms of Alzheimer's disease (6281 cases, n = 309 154) from the FinnGen consortium. In addition, a multivariable Mendelian randomisation (MVMR) analysis was conducted to estimate the effects independent of carbohydrate and protein intakes. Genetically predicted per standard deviation increase in the total fat and saturated fat intakes were associated with 44 and 38% higher risks of LOAD (total fat: odds ratio = 1.44, 95% CI 1.03-2.02; saturated fat: odds ratio = 1.38, 95% CI 1.002-1.90; P = 0.049). The associations remained significant in the MVMR analysis (total fat: odds ratio = 3.31, 95% CI 1.74-6.29; saturated fat: odds ratio = 2.04, 95% CI 1.16-3.59). Total fat and saturated fat intakes were associated with a higher risk of all forms of Alzheimer's disease in the MVMR analysis (total fat: odds ratio = 2.09, 95% CI 1.22-3.57; saturated fat: odds ratio = 1.60, 95% CI 1.01-2.52). The PUF intake was not associated with LOAD or all forms of Alzheimer's disease. This study indicated that total dietary fat intake, especially saturated fat, contributed to the risk of Alzheimer's disease, and the effects were independent of other nutrients. These findings informed prevention strategies and management for Alzheimer's disease directly towards reducing dietary saturated fat intake.

The impact of sleep problems on cerebral aneurysm risk is mediated by hypertension: a mediated Mendelian randomization study.

Cerebral aneurysm (CA) is a common vascular disease. The risk factors of CA include hypertension, smoking, and a family history of genetic predisposition. Although sleep-related problems have been found to have a strong association with cardiovascular disease, there is a lack of research regarding the causal relationship with cerebral aneurysms. In this study, we investigated the causal relationship between four sleep-related problems, including snoring, insomnia, narcolepsy, and napping during the day, and CA using a two-sample Mendelian randomization (MR) analysis. Moreover, the potential confounders before sleep problems and CA were further analyzed by multivariate MR (MVMR). The causal relationship between insomnia and CA was obtained analytically by means of sixMR analyses. There was a strong causal effect relationship between insomnia and CA, which suggests this as a potential risk factor [odds ratio (OR) = 8.35, 95% confidence interval (CI) = 2.422-28.791, p = 7.772e-04]. On this basis, hypertension was identified as a mediator between insomnia and CA by MVMR, with a mediating effect of 52.538% (OR = 3.05, 95% CI = 1.549-4.55, p = 0.015). The causal relationship between insomnia and CA was predicted using genetic variance data, and insomnia was found to be a potential risk factor. Furthermore, hypertension is a mediator between insomnia and CA. Therefore, focusing on sleep problems and improving sleep quality may be an active and effective strategy to prevent CA.

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

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

Association between gut microbiota and diabetic nephropathy: a two-sample mendelian randomization study

BackgroundObservational studies have demonstrated the alterations of gut microbiota composition in diabetic nephropathy (DN), however, the correlation between gut microbiota and DN remains unclear.MethodsA two-sample Mendelian randomization (MR) analysis was designed to estimate the association between gut microbiota and DN. The summary statistics of gut microbiota from phylum level to genus level were obtained from a large-scale, genome-wide association study involving 18,340 individuals, and the data at the species level was derived from the study of TwinsUK Registry, including 1126 twin pairs. The summary statistics of DN were originated from the latest release data of FinnGen (R7, 299623 participants). The MR estimation was calculated using inverse variance weighted, weighted median, MR-Egger regression, and MR-PRESSO. Heterogeneity was assessed using Cochrane’s Q test.ResultsInverse variance weighted results indicated that the order Bacteroidetes and its corresponding class and phylum [odds ratio (OR), 1.58; 95% confidence interval (CI), 1.15–2.17], the family Verrucomicrobiaceae and its corresponding class and order (OR, 1.46; 95% CI, 1.14–1.87), the genera Akkermansia (OR, 1.46; 95% CI, 1.14–1.87) and Catenibacterium (OR, 1.33; 95% CI, 1.07–1.66) might be associated with a higher risk of DN; whereas the genera Coprococcus2 (OR, 0.68; 95% CI, 0.51–0.91) and Eubacterium_coprostanoligenes_group (OR, 0.69; 95% CI, 0.52–0.92) might play protective roles in DN.ConclusionsThis MR study suggested that several gut bacteria were potentially associated with DN, further studies are required to validate these findings.

The causal effects of inflammatory bowel disease on skin carcinoma: A two-sample Mendelian randomization study.

Observational studies have indicated that inflammatory bowel disease (IBD) patients have higher incidence of skin carcinoma (SC), including melanoma skin carcinoma (MSC) and nonmelanoma skin carcinoma (NMSC) than healthy people. However, whether there is a causal relationship between the 2 is unclear. The purpose of this study was to evaluate the causality of IBD on SC using the Mendelian randomization (MR) analysis. We performed a two-sample MR analysis using publicly available genome-wide association study data. Eligible instrumental variables were selected based on the 3 core assumptions of MR analysis. The inverse-variance weighted (IVW) approach served as the primary analytical method. Supplementary analyses were conducted using MR-Egger regression, the weighted median, the weighted mode, and MR pleiotropy residual sum and outlier methods. Genetically predicted IBD (IVW odds ratio [OR] = 1.07, 95% confidence interval [CI]: 1.02-1.13, P = .011) and ulcerative colitis (UC; IVW OR = 1.09, 95% CI: 1.03-1.16, P = .003) were associated with an increased risk of MSC. Results of complementary methods were consistent with those of the IVW method with the exception of the weighted mode. In addition, Crohn disease (CD; IVW OR = 1.04, 95% CI: 0.99-1.08, P = .128) did not have a causal effect on MSC. Moreover, IBD (IVW OR = 1.03, 95% CI: 1.00-1.07, P = .034) and CD (IVW OR = 1.03, 95% CI: 1.00-1.06, P = .045) were associated with an increased risk of NMSC. However, UC (IVW OR = 1.00, 95% CI: 0.97-1.04, P = .803) was not significantly associated with an increased risk of NMSC. Our study revealed genetically predicted associations between IBD and the risks of MSC and NMSC in European populations. Furthermore, UC was associated with an increased risk of MSC, while CD was associated with a higher risk of NMSC. However, the potential influence of immunosuppressive agents or biologics cannot be excluded.

Mendelian randomization reveals that abnormal lipid metabolism mediates the causal relationship between body mass index and keratoconus

Previous studies suggest that a high body mass index (BMI) may be a risk factor for keratoconus (KC), but the causal relationship remains unclear. This study used Mendelian randomization (MR) to investigate this connection and explore the mediating role of circulating serum metabolites and inflammatory factors in this association. Two-sample MR analysis was conducted to assess the relationship between BMI and KC. The study employed a two-step MR approach to evaluate the mediating roles of 91 inflammatory markers and 249 serum metabolites in the BMI-KC relationship. Inverse variance weighting (IVW) was the primary method, and multiple sensitivity analyses were performed to ensure robustness. IVW analysis revealed a positive causal relationship between BMI and KC (OR IVW = 1.811, 95% CI 1.005–3.262, P = 0.048). Although IL-12β and IL-4 were causally associated with KC, they did not mediate the BMI-KC relationship. Five serum metabolites were identified as potential mediators, with HDL cholesterol and triglyceride ratios showing significance. This study clarified the causal relationship between high BMI and KC, suggesting that high BMI may induce KC through lipid metabolism abnormalities. These findings underscore the importance of managing BMI for KC prevention.

Can depression lead to chronic constipation, or does chronic constipation worsen depression? NHANES 2005–2010 and bidirectional mendelian randomization analyses

BackgroundDepression and chronic constipation often co-occur, but the reciprocal influence between the two remains unclear. The purpose of this study is to explore the potential association between depression and chronic constipation.MethodsThis study initially utilized data from National Health and Nutrition Examination Survey (NHANES) 2005–2010 to explore the correlation between depression scores and chronic constipation, assessing the non-linear relationship between the two. Subsequently, we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal relationship between depression and major depression with chronic constipation. The Inverse Variance Weighting (IVW) method served as the primary reference, supplemented by sensitivity tests. Finally, a reverse MR analysis was performed to assess the presence of any reverse causation. The STROBE-MR checklist for the reporting of MR studies was used in this study.ResultsIn the NHANES analysis, survey-weighted logistic regression revealed a significantly positive correlation between depression scores and chronic constipation (OR = 1.04, 95% CI = 1.02–1.07, p = 0.002), even after adjusting for the included covariates. The nonlinear analysis using Restricted Cubic Splines (RCS) enhanced the robustness of the association (P-non-liner = 0.01). The MR analysis also confirmed the causal relationship between depression (OR = 11.43, 95% CI = 1.85–70.67, p = 0.008) and major depression (OR = 1.12, 95% CI = 1.03–1.22, p = 0.007) with chronic constipation, passing rigorous sensitivity tests. No evidence of reverse causation was observed in the reverse MR analysis (P > 0.05).ConclusionsDepression is positively correlated with the risk of chronic constipation. Therefore, enhancing attention to chronic constipation in patients with depression may be effective in clinical practice.

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.

Relationship between hearing impairment and dementia and cognitive function: a Mendelian randomization study

BackgroundThere is a substantial body of observational research indicating an association between hearing impairment and dementia, yet the causal relationship and underlying mechanisms remain uncertain. This study aims to investigate the causal relationship between hearing impairment and its subtypes with dementia and cognitive function using two-sample Mendelian randomization (MR) analysis.MethodsWe performed two-sample MR analysis to examine the causal effects of hearing impairment and its subtypes, including conductive and sensorineural hearing loss (CSHL), conductive hearing loss (CHL), sensorineural hearing loss (SHL), and sudden sensorineural hearing loss (SIHL), on six dementia phenotypes (overall dementia, Alzheimer’s disease [AD], Lewy body dementia [DLB], frontotemporal dementia [FTD], Parkinson’s disease dementia, and vascular dementia) and four cognitive functions. Additionally, multivariable MR (MVMR) analysis was employed to investigate potential mediating mechanisms.ResultsGenetically determined CSHL was associated with an elevated risk of DLB (odds ratio [OR] 1.69; 95% CI 1.08 to 2.63; P = 0.021) and FTD (OR 1.66; 1.04 to 2.67; P = 0.035), but not AD (P = 0.958). Genetic predisposition to CHL was found to link with increased risks of AD (OR 1.07; 1.01 to 1.14; P = 0.031). Genetically determined SHL was causally associated with an elevated risk of semantic dementia (OR 3.81; 1.09 to 13.37; P = 0.037). Genetically predicted CHL and SIHL were both causally associated with lower general cognitive performance (β -0.015 and − 0.043; P = 0.007 and 0.013) and fluid intelligence score (β -0.045 and − 0.095; P = 0.037 and 0.040). In MVMR analysis, the causal relationship between hearing impairment and dementia was mediated by loneliness, depressed mood, and brain cortical volume, particularly the medial temporal lobe, but not by aging or ischemic stroke.ConclusionOverall, the study provides evidence supporting a causal relationship between hearing impairment and increased risks of different types of dementia (including AD, FTD, and DLB), as well as poorer general cognitive function. These findings underscore the importance of addressing hearing impairment as a modifiable risk factor for dementia.

A genetically informed study reveals modifiable pathways in skin cancer

BackgroundIdentifying modifiable risk factors is essential for the prevention of skin cancer; however, establishing causality can be challenging in conventional epidemiological studies. This study aimed to determine the causal associations of potentially modifiable risk factors with skin cancer using Mendelian randomization (MR).MethodsGenetic instruments for 53 risk factors, including socioeconomic status, dietary and lifestyle factors, anthropometric measures, medication use, and comorbidities, were identified from previous genome-wide association studies. Two-sample MR analyses were performed using summary statistics for three major types of skin cancer: melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Findings were verified using multiple MR methods under different assumptions and replication datasets.ResultsGenetic liability to sunburn occasions, actinic keratosis, and prior skin cancers was associated with a higher risk of all three types of skin cancer, whereas genetic liability to vitiligo was associated with a lower risk. For specific skin cancer types, genetically predicted higher nevus counts and occupational class were associated with an increased risk of melanoma. Genetic liability to rheumatoid arthritis, type 2 diabetes, and increased physical activity were associated with a lower risk of BCC. Genetically predicated body mass index showed a negative association with BCC, and a positive association with SCC.ConclusionsOur study reaffirmed several previously established risk factors and identified novel potential risk factors for skin cancer. Further work is needed to unravel the biological pathways in different skin cancer types and translate our findings to inform public health policies.

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

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

Causal links between circulatory inflammatory cytokines and risk of digestive polyps: a Mendelian randomization analysis.

There is a high morbidity of polyps in the digestive tract, and certain subtypes of polyps are thought to induce cancer progression and often recur, which may be associated with chronic inflammation. Mendelian randomization (MR) can help identify potential causative relationships and inform early treatment action. We performed a bidirectional two-sample MR analysis implementing the results from genome-wide association studies for 41 serum cytokines from 8,293 Finnish individuals, and three types of polyps from European ancestry, respectively, including gastric polyp (6,155 cases vs. 341,871 controls), colonic polyp (22,049 cases vs. 332,368 controls) and gallbladder polyp (458 cases vs. 340,083 controls). Inverse-variance weighted (IVW), weight median (WM), and MR-Egger methods were used for calculating causal estimates. Furthermore, Bayesian model averaging MR (MR-BMA) method was employed to detect the dominant causal circulatory cytokines with adjustment for pleiotropy effects. Our univariable MR using inverse-variance weight method identified causal associations of IL-2ra (OR: 0.892, 95%CI: 0.828-0.961, p = 0.003), MIG (OR: 1.124, 95%CI: 1.046-1.207, p = 0.001) and IL-18 (OR: 0.912, 95%CI: 0.852-0.977, p = 0.008) with gastric polyp, MIP1b (OR: 0.956, 95%CI: 0.927-0.987, p = 0.005) and IL-6 (OR: 0.931, 95%CI: 0.870-0.995, p = 0.035) with colonic polyp and IL-9 (OR: 0.523, 95%CI: 0.345-0.794, p = 0.0007) with gallbladder polyp. Finally, our MR-BMA analysis prioritized MIG (MIP = 0.332, MACE = 0.022; PP: 0.264, MSCE = 0.059), IL-18 (MIP = 0.302, MACE = -0.020; PP: 0.243, MSCE = -0.059) and IL-2ra (MIP: 0.129; MACE: -0.005; PP: 0.112, MSCE: -0.031) for gastric polyp, and MIP1b (MIP = 0.752, MACE = -0.033; PP: 0.665, MSCE = -0.044) and IL-6 (MIP: 0.196; MACE: -0.012; PP: 0.140, MSCE: -0.064) for colonic polyp, and IL-9 (MIP = 0.936, MACE = -0.446; PP: 0.781, MSCE = -0.478) for gallbladder polyp as the top-ranked protective factors. Our research advances the current understanding of the function of certain inflammatory biomarker pathways in the genesis and malignant mutation of polyps in the digestive tract. Deeper substantiation is necessary to assess the potential of these cytokines as pharmacological or lifestyle targets for digestive polyps prevention.

The levels of amino acid metabolites in serum induce the pathogenesis of atopic dermatitis by mediating the inflammatory protein S100A12

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting tens of millions of people globally. The causal relationship between metabolites and AD pathology has not yet been formally indicated, and the mediating mechanism by which metabolites affect AD has not yet been explored. This study aimed to determine the genetic relationship between metabolites and AD and to determine the pathways through which amino acid metabolites affect AD. Meta-analysis integrates the results of multiple GWAS analyses using METAL software. Using bidirectional two-sample Mendelian randomization (MR), we analyzed the causal relationships between metabolites and AD. The principal MR test of causal effects was conducted using inverse-variance weighted regression, and we used reverse MR analysis to exclude reverse causality. We also performed the MR-PRESSO test to detect and correct for possible pleiotropic effects, and used the Cochran Q test to assess heterogeneity. Two-step MR was utilized to analyze the mediating factors between amino acid metabolites and the onset of AD. The correlation between mediating factors (inflammatory protein S100A12) and immune cell infiltration was analyzed using the edgeR and GSVA software packages. Using single-cell sequencing data from skin tissues of patients with AD, we studied the regulatory role of the S100A12 gene in immune cells. Multiple drug databases and macromolecular docking were used to search for S100A12-targeting drugs. Bidirectional two-sample MR analyses indicated that twenty-two metabolites and one inflammatory protein (S100A12) were significantly associated with AD pathogenesis. S100A12 is a mediator of amino acid metabolites (N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine) that are genetically associated with AD. S100A12 was positively correlated with the infiltration of multiple immune cell types in lesional AD skin. The amino acid metabolites N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine influence AD pathogenesis by mediating S100A12 expression.

Plasma proteome-wide analysis of cerebral small vessel disease identifies novel biomarkers and disease pathways.

Cerebral small vessel disease (SVD), as defined by neuroimaging characteristics such as white matter hyperintensities (WMHs), cerebral microhemorrhages (CMHs), and lacunar infarcts, is highly prevalent and has been associated with dementia risk and other clinical sequelae. Although conditions such as hypertension are known to contribute to SVD, little is known about the diverse set of subclinical biological processes and molecular mediators that may also influence the development and progression of SVD. To better understand the mechanisms underlying SVD and to identify novel SVD biomarkers, we used a large-scale proteomic platform to relate 4,877 plasma proteins to MRI-defined SVD characteristics within 1,508 participants of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Our proteome-wide analysis of older adults (mean age: 76) identified 13 WMH-associated plasma proteins involved in synaptic function, endothelial integrity, and angiogenesis, two of which remained associated with late-life WMH volume when measured nearly 20 years earlier, during midlife. We replicated the relationship between 9 candidate proteins and WMH volume in one or more external cohorts; we found that 11 of the 13 proteins were associated with risk for future dementia; and we leveraged publicly available proteomic data from brain tissue to demonstrate that a subset of WMH-associated proteins was differentially expressed in the context of cerebral atherosclerosis, pathologically-defined Alzheimer's disease, and cognitive decline. Bidirectional two-sample Mendelian randomization analyses examined the causal relationships between candidate proteins and WMH volume, while pathway and network analyses identified discrete biological processes (lipid/cholesterol metabolism, NF-kB signaling, hemostasis) associated with distinct forms of SVD. Finally, we synthesized these findings to identify two plasma proteins, oligodendrocyte myelin glycoprotein (OMG) and neuronal pentraxin receptor (NPTXR), as top candidate biomarkers for elevated WMH volume and its clinical manifestations.

Effect of inflammatory factors on myocardial infarction

BackgroundCohort studies have increasingly shown associations between inflammatory markers and myocardial infarction (MI); however, the specific causal relationships between inflammatory markers and the development of MI remain unclear.Methods and resultsBy utilizing publicly accessible genome-wide association studies, we performed a two-sample Mendelian randomization (MR) analysis to explore the causal associations between inflammatory markers and myocardial infarction (MI). A random-effects inverse-variance weighted method was used to calculate effect estimates. The study included a total of 395,795 European participants for MI analysis and various sample sizes for inflammatory factors, ranging from 3,301 to 563,946 participants.Neutrophil count was found to increase the risk of MI (odds ratio [OR] = 1.08; 95% confidence interval [CI], 1.00–1.17; p = 0.04). C-reactive protein levels correlated positively with MI. No associations were observed with IL-1 beta, IL-6, IL-18, procalcitonin, TNF-α, total white cell count, or neutrophil percentage of white cells. Neutrophil count and C-reactive protein were inversely associated with lactate dehydrogenase: neutrophil cell count (OR 0.95; 95% CI, 0.93–0.98; p < 0.01) and C-reactive protein (OR 0.96; 95% CI, 0.92–1.00; p = 0.02). No associations of MI with myoglobin, troponin I, and creatine kinase-MB levels were found.ConclusionsThis two-sample MR analysis revealed a causal positive association of MI with neutrophil count, C-reactive protein level, and the myocardial injury marker lactate dehydrogenase. These results indicate that monitoring C-reactive protein and neutrophil counts may be useful in management of MI patients.

Gut microbiota causally impacts adrenal function: a two-sample mendelian randomization study

Some studies have reported that the gut microbiota can influence adrenal-related hormone levels. However, the causal effects of the gut microbiota on adrenal function remain unknown. Therefore, we employed a two-sample Mendelian randomization (MR) study to systematically investigate the impact of gut microbiota on the function of different regions of the adrenal gland. The summary statistics for gut microbiota and adrenal-related hormones used in the two-sample MR analysis were derived from publicly available genome-wide association studies (GWAS). In the MR analysis, inverse variance weighting (IVW) was used as the primary method, with MR-Egger, weighted median, and cML-MA serving as supplementary methods for causal inference. Sensitivity analyses such as the MR-Egger intercept test, Cochran’s Q test, and leave-one-out analysis were used to assess pleiotropy and heterogeneity. We identified 27 causal relationships between 23 gut microbiota and adrenal function using the IVW method. Among these, Sellimonas enhanced the function of the adrenal cortex reticularis zone (beta = 0.008, 95% CI: 0.002–0.013, P = 0.0057). The cML-MA method supported our estimate (beta = 0.009, 95% CI: 0.004–0.013, P = 2 × 10− 4). Parasutterella, Sutterella, and Anaerofilum affect the functioning of different regions of the adrenal gland. Notably, pleiotropy was not observed. Our findings revealed that the gut microbiota is causally associated with adrenal function. This enhances our understanding of the gut-microbiota-brain axis and provides assistance in the early diagnosis and treatment of adrenal-related diseases in clinical practice.