OBJECTIVE: The aim was to investigate the causal relationships of inflammatory cytokines and serum metabolites in cerebral small vessel disease (CSVD).
METHODS: Bidirectional Mendelian randomization was first conducted to screen inflammatory cytokines and serum metabolites that were associated with imaging features of CSVD, including white matter hyperintensities, recent small subcortical infarcts, cortical cerebral microinfarcts, cerebral microbleeds, lacunes and enlarged perivascular spaces. Sensitivity analyses were performed to evaluate the robustness and pleiotropy of these results. Subsequently, inflammatory cytokines and serum metabolites that were associated with CSVD were subjected to functional enrichment. Finally, mediation analysis was employed to investigate whether inflammatory cytokines or serum metabolites acted as an intermediary for the other in their causal relationship with CSVD.
RESULTS: Of the inflammatory cytokines, five were risk factors (e.g., tumour-necrosis-factor-related apoptosis-inducing ligand) and five (e.g., fibroblast growth factor 19) were protective factors for CSVD. Eleven serum metabolites that increased CSVD risk and 13 metabolites that decreased CSVD risk were also identified. The majority of these markers of CSVD susceptibility were lipid metabolites. Natural killer cell receptor sub-type 2B4 was determined to act as a mediating factor of an unidentified metabolite for the enlargement of perivascular spaces.
CONCLUSIONS: Several inflammatory cytokines and serum metabolites had causal relationships with imaging features of CSVD. A natural killer cell receptor mediated in part the promotional effect of a metabolite on perivascular space enlargement.

UNASSIGNED: Uveitis refers to a group inflammation affecting the uvea, retina, retinal blood vessels as well as vitreous body, which is one of the common causes of blindness. There is growing evidence linking different types of immune cells to uveitis, although it remains uncertain if these associations imply causal relationships. Recent advancements in high-density genetic markers like SNPs or CNVs for genotyping, along with the progress in genome-wide association studies (GWAS) technologies, have improved our understanding of the immunological mechanisms involved in ocular diseases. Therefore, our objective was to investigate the potential causal link between immune cells and uveitis using a Mendelian randomization study.
UNASSIGNED: The exposure and outcome GWAS data for this study were sourced from an open-access database (https://gwas.mrcieu.ac.uk/). Two-sample MR analysis was utilized to evaluate the causal relationship between 731 immune cell features and uveitis. Various MR methods were employed to reduce bias and obtain dependable estimates of the causal link between the immune cell variables and the outcomes. Instrumental variable selection criteria were carefully chosen to enhance the accuracy and efficacy of the causal relationship between different immune cell types and the risk of uveitis.
UNASSIGNED: Using two-sample MR, IVW modeling showed that GAD had significant effect on immunophenotypes. CD3 levels on CD45RA- CD4+ T cells (OR = 1.087, 95%CI = 1.029 ~ 1.147, p = 0.003) and CD3 levels on CM CD4+ T cells (OR = 1.086, 95%CI = 1.033 ~ 1.141, p = 0.001) were found to be elevated in cases of uveitis. HLA DR levels in CD14- CD16+ monocyte cells (OR = 0.735, 95% CI = 0.635 ~ 0.850, p < 0.001) and HLA DR levels in NK cells (OR = 0.910, 95% CI = 0.851 ~ 0.972, p = 0.005) were observed to be reduced in individuals with uveitis. Furthermore, Two cells were identified to be significantly associated with uveitis risk: HLA DR on in NK cells (OR = 0.938, 95%CI = 0.899 ~ 0.979, p = 0.003), HLA DR on CD14- CD16+ monocytes (OR = 0.924, 95%CI = 0.878 ~ 0.972, p = 0.002).
UNASSIGNED: This study highlights the intricate relationship between immune cells and generalized anxiety disorder using genetic methods, offering valuable insights for future clinical investigations.

UNASSIGNED: Constipation is affected by a number of risk variables, including cardiovascular disease and growth factors. However, the impacts of gut flora on constipation incidence has not been shown. This work, Single-Variable Mendelian Randomization (SVMR) was utilized to estimate the causal relationship between the Eubacterium genus or Rumphococcus, and constipation.
UNASSIGNED: Data for constipation, Eubacterium genus and Rumphococcus were taken from the Integrated Epidemiology Unit (IEU) open GWAS database. Including 218,792 constipation samples, and there were 16,380,466 Single Nucleotide Polymorphisms (SNPs) for constipation. The ids of Eubacterium genus and Rumphococcus were sourced from MiBioGen database. The sample count for the Eubacterium genus was 17,380, with 656 SNPs. In addition, the sample size for Rumphococcus was 15,339, with 545 SNPs. The SVMR was performed to assess the risk of Eubacterium genus and Rumphococcus in constipation using weighted median, MR Egger, simple mode, inverse variance weighted (IVW), and weighted mode. Finally, we did a sensitivity analysis that included a heterogeneity, horizontal pleiotropy, and Leave-One-Out (LOO) test to examine the viability of the MR data.
UNASSIGNED: The SVMR revealed that the Eubacterium genus and Rumphococcus were causally connected to constipation, with Rumphococcus (P = 0.042, OR = 1.074) as a hazardous factor and Eubacterium genus (P = 0.004, OR = 0.909) as a safety factor. Sensitivity tests then revealed the absence of variability between the constipation and the exposure factors (Eubacterium genus and Rumphococcus). Additionally, there were no other confounding factors and the examined SNPs could only influence constipation through the aforementioned exposure factors, respectively. As a result, the MR results were fairly robust.
UNASSIGNED: Our investigation verified the causal links between the Eubacterium genus or Rumphococcus, and constipation, with greater Rumphococcus expression increasing the likelihood of constipation and the opposite being true for the Eubacterium genus.

BACKGROUND: Despite numerous studies investigating the association between androgenetic alopecia (AGA) and serum uric acid (SUA), the causal relationship between AGA and SUA remains unknown.
METHODS: We utilized bidirectional Mendelian randomization (MR) to explore the causality between AGA and SUA. Our study chose single nucleotide polymorphisms associated with genome-wide significance (p < 5×10-8) for the exposure and showing low linkage disequilibrium (R2 < 0.001) as IVs. Various MR methods were employed to evaluate causality, including inverse-variance weighted (IVW), Weighted Median, MR-Egger, Weighted Mode and Simple Mode. Sensitivity analyses were performed to test the robustness of the results.
RESULTS: Using the IVW method, we did not find a significant causal relationship between AGA and SUA (OR = 1.00, 95% CI 0.99-1.01; p = 0.451). Similarly, the IVW method did not reveal evidence of causality between SUA and AGA (OR = 0.97, 95% CI = 0.91-1.03; p = 0.301). The results from other methods were consistent with those of the IVW approach.
CONCLUSIONS: The study did not identify a causal relationship between AGA and SUA. Future research should involve larger cohorts and advanced methods to validate the findings and explore the complex interactions between AGA and SUA levels in different populations.

UNASSIGNED: The association between psychiatric disorders and dentofacial deformities has attracted widespread attention. However, their relationship is currently unclear and controversial.
UNASSIGNED: A two-sample bidirectional MR analysis was performed to study the causal relationship between dentofacial deformity and eight psychiatric disorders, including major depressive disorder, panic disorder, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, Alzheimer\'s disease, autism spectrum disorder, and neuroticism. Inverse variance weighted, weighted median, MR-Egger regression, weighted mode four methods, and further sensitivity analyses were conducted.
UNASSIGNED: The major depressive disorder affected dentofacial deformity, with an OR = 1.387 (95% CI = 1.181-1.629, P = 6.77×10-5). No other psychiatric disorders were found to be associated with dentofacial deformity. In turn, dentofacial deformity were associated with neuroticism, with an OR = 1.050 (95% CI = 1.008-1.093, P = 0.018). And there was no evidence that dentofacial deformity would increase the risk of other psychiatric disorders.
UNASSIGNED: Major depressive disorder might elevate the risk of dentofacial deformities, and dentofacial deformity conditions would increase the risk of the incidence of neuroticism.

BACKGROUND: Observational studies consistently indicate an association between early-life body mass index (BMI) and several cardiovascular diseases (CVDs). However, the causal relationship remains uncertain. The primary objective of this study was to assess the causal relationship between early-life BMI and six types of CVDs using the Mendelian Randomization (MR) approach.
METHODS: The dataset for this study was derived from large-scale, summary-level Genome-Wide Association Studies. Specifically, the following datasets we used, early-life BMI (n = 61 111, age = 2-10), heart failure (HF) dataset (n = 977 323), atrial fibrillation (AF) dataset (n = 1 030 836), coronary artery disease (CAD) dataset (n = 184 305), peripheral artery disease (PAD) dataset (n = 243 060), deep venous thrombosis (DVT) dataset (n = 1 500 861) and myocardial infarction (MI) dataset (n = 638 000). Multiple MR methods were utilized to evaluate the causal relationship between exposure and outcomes, accompanied by sensitivity analysis.
RESULTS: Early-life BMI positively correlates with the risk of developing the six distinct CVDs included in this study. Specifically, elevated BMI during childhood is associated with a 31.9% risk for HF (Odds ratio [OR] = 1.319, 95% CI [1.160 to 1.499], p = 2.33 × 10-5), an 18.3% risk for AF (R = 1.183, 95% CI [1.088 to 1.287], p = 8.22 × 10-5), an 14.8% risk for CAD (OR = 1.148, 95% CI [1.028 to 1.283], p = 1.47 × 10-2), a 40.5% risk for PAD (OR = 1.405, 95% CI [1.233 to 1.600], p = 3.10 × 10-7) and 12.0% risk for MI (OR = 1.120, 95% CI [1.017 to 1.234], p = 2.18 × 10-2). Interestingly, the risk for deep venous thrombosis only increased by 0.5% (OR = 1.005, 95% CI [1.001 to 1.008], p = 2.13 × 10-3).
CONCLUSIONS: Genetically inferred early-life BMI is significantly associated with six distinct CVDs. This indicates that elevated early-life BMI is a significant risk factor for multiple cardiovascular disorders.

UNASSIGNED: Alterations gastrointestinal diseases (GDs) were reported in individuals with obstructive sleep apnea (OSA), however, the genetic background between OSA and GDs is still unclear.
UNASSIGNED: This investigation employed Mendelian randomization (MR) analyses to evaluate the causal effect between OSA and 19 types of GDs (gastroesophageal reflux disease (GERD), ulcerative colitis, celiac disease, Crohn\'s disease, chronic gastritis, irritable bowel syndrome, primary biliary cholangitis, diverticular disease, gastroduodenal ulcer, acute pancreatitis, non-alcoholic fatty liver disease, primary sclerosing cholangitis, cirrhosis, calculus of bile duct, calculus of gallbladder, pancreatic cancer, gastric cancer, colorectal cancer, and esophageal cancer). The inverse-variance weighted (IVW) method was used to evaluate the main effects model of causality.
UNASSIGNED: This MR study suggests that OSA may play a causal role inflammation-related GDs (GERD, PIVW=5.94×10-9; gastroduodenal ulcer, PIVW=1×10-4; chronic gastritis, PIVW=0.0214; ulcerative colitis, PIVW=0.0296), and gallstones (calculi of the gallbladder, PIVW=0.0429; calculi of the bile duct, PIVW=0.0068). After accounting for obesity, type 2 diabetes, smoking, and alcohol consumption, the multivariate MR (MVMR) analysis identified that OSA is an independent risk factor for GERD, gastroduodenal ulcer, and calculus of the bile duct. The reverse MVMR analysis showed a causal effect of GERD on OSA. Besides, we did not find that the predisposition to OSA was associated with 4 cancers.
UNASSIGNED: This MR analysis provides compelling evidence of an independent causal relationship between genetically predicted OSA and an elevated risk of inflammation-related GDs. Besides, no causal association was observed between OSA and cancers. Further studies should be carried out to verify our findings.

UNASSIGNED: Benign prostatic hyperplasia (BPH) is a common disease occurring in elderly and middle-aged men, and cardiovascular diseases (CVDs) are one of the major causes of death worldwide. Many observational studies examined have found a strong association between BPH and CVDs, but the causal relationship between them is unclear. The aim of this study was to determine the causal relationship between BPH and CVDs, specifically five diseases: stroke, coronary heart disease (CHD), heart failure, myocardial infarction (MI), and atrial fibrillation (AF).
UNASSIGNED: In this study, we obtained single nucleotide polymorphisms (SNPs) of patients with BPH from the UK Biobank database and patients with CVDs from the UK Biobank, the HERMES Consortium, and the FinnGen Genome Database, each used as a genetic tool for a Mendelian randomization (MR) study. We used conventional MR analysis to assess potential causal direction between BPH and CVDs, as well as MR-Egger, MR-PRESSO, model-based estimation (MBE) and weighted median methods for sensitivity analysis.
UNASSIGNED: Using a bidirectional two-sample MR study, we found that BPH patients had an increased risk of developing CHD (ConMix OR = 1.152, 95% CI: 1.011-1.235, p = 0.035) and MI (ConMix OR = 1.107.95% CI: 1.022-1.164, p = 0.013), but a decreased risk of stroke (ConMix OR = 0.872, 95% CI: 0.797-0.926, p = 0.002). The reverse study was not statistically significant and further research may be needed.
UNASSIGNED: Our study suggests a potential causal relationship between BPH and CVDs. BPH appears to be a risk factor for CHD and MI, but it may be protective against stroke. There was no evidence of a causal association in the reverse study, and a larger sample size was needed in follow-up to further explore the potential association.

Existing research indicates that different types of meat have varying effects on health and aging, but the specific causal relationships remain unclear. This study aimed to explore the causal relationship between different types of meat intake and aging-related phenotypes. This study employed Mendelian randomization (MR) to select genetic variants associated with meat intake from large genomic databases, ensuring the independence and pleiotropy-free nature of these instrumental variables (IVs), and calculated the F-statistic to evaluate the strength of the IVs. The validity of causal estimates was assessed through sensitivity analyses and various MR methods (MR-Egger, weighted median, inverse-variance weighted (IVW), simple mode, and weighted mode), with the MR-Egger regression intercept used to test for pleiotropy bias and Cochran\'s Q test employed to evaluate the heterogeneity of the results. The findings reveal a positive causal relationship between meat consumers and DNA methylation PhenoAge acceleration, suggesting that increased meat intake may accelerate the biological aging process. Specifically, lamb intake is found to have a positive causal effect on mitochondrial DNA copy number, while processed meat consumption shows a negative causal effect on telomere length. No significant causal relationships were observed for other types of meat intake. This study highlights the significant impact that processing and cooking methods have on meat\'s role in health and aging, enhancing our understanding of how specific types of meat and their preparation affect the aging process, providing a theoretical basis for dietary strategies aimed at delaying aging and enhancing quality of life.

OBJECTIVE: Oxidative stress is strongly associated with atopic dermatitis (AD), and increased antioxidant intake could potentially reduce the risk of or alleviate its symptoms. However, the argument is disputed. Therefore, we conducted a Mendelian randomization (MR) analysis to explore the causal relationship between dietary antioxidant vitamin intake and AD.
METHODS: We applied MR analysis to examine the causative association between dietary antioxidant vitamin intake (vitamin C, vitamin E, carotene, and retinol) and AD. The genome-wide association study (GWAS) summary data for antioxidant vitamins intake and AD were obtained from the IEU OpenGWAS database and the UK biobank. Our study consisted of two major parts, MR analysis to detect the causal relationship between exposure and outcome, and sensitivity analysis as supplemental evidence to verify the robustness of the results.
RESULTS: The results revealed a suggestive causal relationship between vitamin E intake and AD (p = 0.038, OR 95% CI = 0.745-0.992). However, there was no causal relationship between the other three vitamins (vitamin C, carotene, and retinol) and AD (p = 0.507, OR 95% CI = 0.826-1.099) (p = 0.890, OR 95% CI = 0.864-1.184) (p = 0.492, OR 95% CI = 0.893-1.264). None of the single nucleotide polymorphisms (SNPs) were detected as heterogeneous and pleiotropy in the sensitivity analysis (p > 0.05).
CONCLUSIONS: The analysis suggested that dietary intake of vitamin E may potentially lower the risk of AD. Conversely, intake of vitamin C, retinol, and carotene is not causally related to AD. Although vitamin E intake could be protective against AD, intake of dietary antioxidant vitamins to prevent or treat AD is not necessary.