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Frontiers in Microbiology 2024Previous studies have highlighted a robust correlation between gut microbiota/immune cells and ischemic stroke (IS). However, the precise nature of their causal...
BACKGROUND
Previous studies have highlighted a robust correlation between gut microbiota/immune cells and ischemic stroke (IS). However, the precise nature of their causal relationship remains uncertain. To address this gap, our study aims to meticulously investigate the causal association between gut microbiota/immune cells and the likelihood of developing IS, employing a two-sample Mendelian randomization (MR) analysis.
METHODS
Our comprehensive analysis utilized summary statistics from genome-wide association studies (GWAS) on gut microbiota, immune cells, and IS. The primary MR method employed was the inverse variance-weighted (IVW) approach. To address potential pleiotropy and identify outlier genetic variants, we incorporated the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) technique, along with MR-Egger regression. Heterogeneity was assessed using Cochran's Q-test. Additionally, leave-one-out analysis was conducted to pinpoint any individual genetic variant influencing the observed causal associations. Finally, a reverse MR analysis was performed to explore the potential of reverse causation.
RESULTS
Our investigation revealed four gut microbial taxa and 16 immune cells with a significant causal relationship with IS ( < 0.05). Notably, two bacterial features and five immunophenotypes were strongly associated with a lower IS risk: genus. (OR: 0.907, 95% CI: 0.836-0.983, = 0.018), genus. (OR: 0.918, 95% CI: 0.853-0.983, = 0.988), Activated & resting Treg % CD4++ (OR: 0.977, 95% CI: 0.956-0.998, = 0.028). Additionally, significant associations between IS risk and two bacterial features along with eleven immunophenotypes were observed: genus. (OR: 1.106, 95% CI: 1.043-1.172, < 0.001), genus. (OR: 1.119, 95% CI: 1.034-1.210, = 0.005), CD127 on granulocyte (OR: 1.039, 95% CI: 1.009-1.070, = 0.011). Our analyses did not reveal heterogeneity based on the Cochrane's Q-test ( > 0.05) nor indicate instances of horizontal pleiotropy according to MR-Egger and MR-PRESSO analyses ( > 0.05). Furthermore, the robustness of our MR results was confirmed through leave-one-out analysis.
CONCLUSION
Our study provides further evidence supporting the potential association between gut microbiota and immune cells in relation to IS, shedding light on the underlying mechanisms that may contribute to this condition. These findings lay a solid foundation for future investigations into targeted prevention strategies.
PubMed: 38894965
DOI: 10.3389/fmicb.2024.1402718 -
Iranian Journal of Public Health Feb 2024Ischemic stroke (IS) is the leading cause of disability and mortality worldwide. Low-density lipoprotein cholesterol (LDL-C) levels hadno potential risk on ischemic...
BACKGROUND
Ischemic stroke (IS) is the leading cause of disability and mortality worldwide. Low-density lipoprotein cholesterol (LDL-C) levels hadno potential risk on ischemic stroke. However, higher LDL-C levels were closely related to IS. Based on two antagonistic viewpoints, a Mendelian randomization (MR) study was designed to evaluate the causal effects of LDL-C levels on IS.
METHODS
Datasets of LDL-C levels and ischemic stroke were acquired from genome-wide association studies (GWAS). Weighted median method was conducted for main analysis, and MR-Egger and inverse-variance weighted (IVW) methods were performed for auxiliary analyses. Heterogeneity and pleiotropic tests were utilized to confirm the reliability of this study.
RESULTS
A total of 359 single nucleotide polymorphisms (SNPs) were associated with LDL-C levels ( < 5 × 10) and 337 SNPs were available in ischemic stroke with eliminating outliers. LDL-C levels were significantly associated with ischemic stroke (OR = 1.104, 95%CI = 1.019 - 1.195, = 1.52 × 10). MR-Egger and IVW showed directionally similar estimates (MR-Egger: OR = 1.120, 95%CI = 1.040 - 1.207, = 3.12 × 10; IVW: OR = 1.120, 95%CI = 1.064 - 1.178, = 1.17 × 10).
CONCLUSION
LDL-C levels had causal effects on IS, providing insights into the design of future interventions to reduce the burden of ischemic stroke.
PubMed: 38894840
DOI: 10.18502/ijph.v53i2.14924 -
Journal of Clinical Medicine May 2024: To determine whether a sitting position with the femoral heads centered into the acetabulum is more effective than the usual sitting position in preventing migration...
UNLABELLED
: To determine whether a sitting position with the femoral heads centered into the acetabulum is more effective than the usual sitting position in preventing migration percentage progression in non-ambulatory children with bilateral cerebral palsy. : This was a multicenter, randomized controlled trial.
INCLUSION CRITERIA
spastic or dyskinetic cerebral palsy, Gross Motor Function Classification System level IV-V, age 1-6 years, migration percentage <41%, and informed consent.
EXCLUSION CRITERIA
contractures affecting the hip, anterior luxation, previous hip surgery, and lumbar scoliosis. The treatment group sat with their hips significantly abducted to reduce the head into the acetabulum in a customized system for at least five hours/day for two years. Controls sat with the pelvis and lower limbs aligned but the hips less abducted in an adaptive seating system. The primary outcome was migration percentage (MP) progression. Health-related quality of life and family satisfaction were among the secondary outcomes. The study was approved by the local ethics board and conducted in accordance with CONSORT reporting guidelines.
CLINICALTRIALS
gov ID: NCT04603625.
RESULTS
Overall median MP progression was 1.6 after the first year and 2.5 after the second year. No significant differences were observed between the groups. MP exceeded 40% and 50% in 1.8% and 0% of the experimental group and 5.4% and 3.6% of controls in years 1 and 2, respectively. Both groups expressed satisfaction with the postural system and stable health-related quality of life. : MP remained stable over the two-year period in both groups. Considering outliers which progressed over 50%, a more protective trend of the hip-centering sitting approach emerged, but this needs to be confirmed in a final, larger dataset.
PubMed: 38892841
DOI: 10.3390/jcm13113129 -
European Journal of Medical Research Jun 2024Nowadays, there has been limited Mendelian randomization (MR) research focusing on the causal relationship between estradiol and vaginitis. Therefore, this study...
OBJECTIVE
Nowadays, there has been limited Mendelian randomization (MR) research focusing on the causal relationship between estradiol and vaginitis. Therefore, this study conducted a two-way MR study to clarify the causal effect and related influencing factors between them.
METHODS
All genetic datasets were obtained using publicly available summary statistics based on individuals of European ancestry from the IEU GWAS database. MR analysis was performed using MR-Egger, weighted median (WM) and inverse variance weighted (IVW) methods to assess the causal relationship between exposure and outcome and to validate the findings by comprehensively evaluating the effects of pleiotropic effects and outliers.
RESULTS
MR analysis revealed no significant causal relationship between estradiol and vaginitis risk. There was a negative correlation between estradiol and age at menarche (IVW, OR: 0.9996, 95% CI: 0.9992-1.0000, P = 0.0295; WM, OR: 0.9995, 95% CI: 0.9993-0.9998, P = 0.0003), and there was a positive correlation between age at menarche and vaginitis (IVW, OR: 1.5108, 95% CI: 1.1474-2.0930, P = 0.0043; MR-Egger, OR: 2.5575, 95% CI: 1.7664-9.6580, P = 0.0013). Estradiol was negatively correlated with age at menopause (IVW, OR: 0.9872, 95% CI: 0.9786-0.9959, P = 0.0041). However, there was no causal relationship between age at menopause and vaginitis (P > 0.05). In addition, HPV E7 Type 16, HPV E7 Type 18, and Lactobacillus had no direct causal effects on estradiol and vaginitis (P > 0.05). Sensitivity analyses revealed no heterogeneity and horizontal pleiotropy.
CONCLUSION
When estrogen levels drop, it will lead to a later age of menarche, and a later age of menarche may increase the risk of vaginitis, highlighting that the longer the female reproductive tract receives estrogen stimulation, the stronger the defense ability is formed, and the prevalence of vaginitis is reduced. In conclusion, this study indirectly supports an association between reduced level of estrogen or short time of estrogen stimulation and increased risk of vaginitis.
Topics: Humans; Female; Mendelian Randomization Analysis; Estradiol; Vaginitis; Menarche; Inflammation
PubMed: 38890725
DOI: 10.1186/s40001-024-01914-4 -
Diabetology & Metabolic Syndrome Jun 2024The aim of this study was to investigate whether a causal relationship exists between serum uric acid (SUA) and diabetic microvascular complications using a two-sample...
BACKGROUND
The aim of this study was to investigate whether a causal relationship exists between serum uric acid (SUA) and diabetic microvascular complications using a two-sample Mendelian randomization (MR) method.
METHODS
We used the MR approach, utilizing genome-wide association study (GWAS) summary statistics, to estimate the causal effect of SUA on diabetic microvascular complications in European individuals. The summary statistical data of SUA were obtained from the open database (IEU OPEN GWAS PROJECT) (p < 5 × 10), and data on diabetic microvascular complications (diabetic nephropathy, diabetic neuropathy, diabetic retinopathy) were obtained from the FinnGen consortium. F-statistics were calculated to assess the correlation between instrumental variables (IVs) and SUA, and single nucleotide polymorphisms (SNPs) associated with confounders or outcomes were excluded by consulting the PhenoScanner database. Inverse variance weighting (IVW) was used for primary estimation, and MR‒Egger, weighted median (WM), and Mendelian randomization pleiotropy residuals sum and outliers (MR-PRESSO) were used for additional assessment. Heterogeneity was assessed using the Cochran's Q test, and polytropy was assessed using the MR‒Egger intercept.
RESULTS
MR analysis revealed a causal relationship between a genetically predicted increase in SUA and diabetic nephropathy [OR = 1.32, 95%(CI) = 1.07-1.63, p = 0.008]. The results were consistent with those after MR-PRESSO [OR = 1.30, 95%(CI) = 1.07-1.58, p = 0.008]. There was a causal relationship between type 2 diabetes mellitus (T2DM) and renal complication IVW [OR = 1.27, 95%(CI) = 1.00-1.62, p = 0.049]. These results were consistent with those after MR-PRESSO [OR = 1.27, 95%(CI) = 1.00-1.62, p = 0.050]. There was no significant causal relationship between the genetically predicted increase in SUA and diabetic retinopathy [OR 1.09, 95%(CI) = 0.94-1.26, p = 0.249] or diabetic neuropathy [OR = 1.08, 95%(CI) = 0.84-1.40, p = 0.549].
CONCLUSIONS
This MR analysis suggests a causal relationship between genetically predicted uric acid increases and diabetic microvascular complications. A significant causal relationship exists between SUA and diabetic nephropathy but not between SUA and diabetic retinopathy or diabetic neuropathy.
PubMed: 38890685
DOI: 10.1186/s13098-024-01377-x -
Heredity Jun 2024Forest tree populations harbour high genetic diversity thanks to large effective population sizes and strong gene flow, allowing them to diversify through adaptation to...
Forest tree populations harbour high genetic diversity thanks to large effective population sizes and strong gene flow, allowing them to diversify through adaptation to local environmental pressures within dispersal distance. Many tree populations also experienced historical demographic fluctuations, including spatial population contraction or expansions at various temporal scales, which may constrain their ability to adapt to environmental variations. Our aim is to investigate how recent contraction and expansion events interfere with local adaptation, by studying patterns of adaptive divergence between closely related stands undergoing environmentally contrasted conditions, and having or not recently expanded. To investigate genome-wide signatures of local adaptation while accounting for demography, we analysed divergence in a European beech population by testing pairwise differentiation among four tree stands at ~35k Single Nucleotide Polymorphisms from ~9k genomic regions. We applied three divergence outlier search methods resting on different assumptions and targeting either single SNPs or contiguous genomic regions, while accounting for the effect of population size variations on genetic divergence. We found 27 signals of selective signatures in 19 target regions. Putatively adaptive divergence involved all stand pairs. We retrieved signals both when comparing old-growth stands and recently colonised areas and when comparing stands within the old-growth area. Therefore, adaptive divergence processes have taken place both over short time spans, under strong environmental contrasts, and over short ecological gradients, in populations that have been stable in the long term. This suggests that standing genetic variation supports local, microgeographic divergence processes, which can maintain genetic diversity at the landscape level.
PubMed: 38890557
DOI: 10.1038/s41437-024-00696-z -
Frontiers in Cardiovascular Medicine 2024The risk of atrial fibrillation (AF) is increased in individuals with gastroesophageal reflux disease (GERD), according to observational research. The causal...
BACKGROUND
The risk of atrial fibrillation (AF) is increased in individuals with gastroesophageal reflux disease (GERD), according to observational research. The causal significance of this association is still unclear. This study sought to assess GERD's role as a potential contributing factor in AF.
METHODS
With the use of a two-sample Mendelian randomization (MR) technique, we assessed the causal relationship between GERD and AF. The association of genetic variants with GERD was examined using data from a recent genome-wide association study (GWAS) that included 602,604 people. Data on the association between genetic variations and AF was obtained from a second GWAS with 1,030,836 participants. The effect sizes were examined based on the inverse-variance weighted method. Additional statistical techniques, including MR-Egger, simple mode, weighted mode, MR Pleiotropy Residual Sum, outlier, and weighted median were used in the sensitivity analysis.
RESULTS
MR analyses in inverse-variance weighted models, using 76 single nucleotide polymorphisms (SNPs) as markers, revealed a relationship between genetically predicted GERD and a greater AF incidence [odds ratio (OR): 1.165, 95% CI 1.102-1.231; = 7.637 × 10]. According to MR-Egger, there was no evidence of gene pleiotropy that could be found (intercept = 0.003, = 0.581). The findings of the sensitivity study, which used several MR methods, were found to be reliable.
CONCLUSION
The MR analysis revealed a correlation between GERD and increased AF incidence, supporting the idea that treating patients with GERD as early as possible might reduce their chance of developing AF.
PubMed: 38887451
DOI: 10.3389/fcvm.2024.1393383 -
Frontiers in Immunology 2024The pathogenesis of vitiligo remains elusive. Emerging evidence suggests that vitiligo is an immune-mediated disorder, in which a plethora of immune cells play pivotal...
BACKGROUND
The pathogenesis of vitiligo remains elusive. Emerging evidence suggests that vitiligo is an immune-mediated disorder, in which a plethora of immune cells play pivotal roles. However, the association between circulating immune cells and vitiligo continues to be enigmatic.
MATERIALS AND METHODS
We extracted single nucleotide polymorphisms (SNPs) associated with immune circulating cells at a genome-wide significance level from the BLOOD CELL CONSORTIUM's genome-wide association study (GWAS) dataset. Summary data for 385,801 cases of vitiligo were obtained from a large-scale Finnish genome-wide association study (ncases=292, ncontrols=385,509). The inverse variance weighted (IVW) method was employed as the primary analytical approach for Mendelian randomization (MR) analysis. Additionally, heterogeneity was assessed using Cochran's Q value, and horizontal pleiotropy was evaluated using MR-Egger Mendelian Randomization Pleiotropy RESidual Sum and Outlier and leave-one-out analyses.
RESULTS
The risk of vitiligo was found to increase with the elevation of 4 circulating immune cells, as evidenced by the odds ratios (ORs) and 95% confidence intervals (CIs): basophils (OR=1.81; 95% CI: 1.01-3.24, p=0.0450), monocytes (OR=1.67; 95% CI: 1.23-2.26, p=0.0009), eosinophils (OR=1.78; 95% CI: 1.22-2.59, p=0.0028), and neutrophils (OR=1.65; 95% CI: 1.08-2.54, p=0.0208). After removing outliers, the sensitivity analysis of the above indicators did not show heterogeneity and pleiotropy.
CONCLUSION
Our findings illuminate the association between circulating immune cells and vitiligo, offering insights that could guide clinical practices in the treatment of vitiligo.
Topics: Vitiligo; Humans; Mendelian Randomization Analysis; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease
PubMed: 38887286
DOI: 10.3389/fimmu.2024.1391186 -
Nature Aging Jun 2024Models of healthy aging are typically based on the United States and Europe and may not apply to diverse and heterogeneous populations. In this study, our objectives...
Models of healthy aging are typically based on the United States and Europe and may not apply to diverse and heterogeneous populations. In this study, our objectives were to conduct a meta-analysis to assess risk factors of cognition and functional ability across aging populations in Latin America and a scoping review focusing on methodological procedures. Our study design included randomized controlled trials and cohort, case-control and cross-sectional studies using multiple databases, including MEDLINE, the Virtual Health Library and Web of Science. From an initial pool of 455 studies, our meta-analysis included 38 final studies (28 assessing cognition and 10 assessing functional ability, n = 146,000 participants). Our results revealed significant but heterogeneous effects for cognition (odds ratio (OR) = 1.20, P = 0.03, confidence interval (CI) = (1.0127, 1.42); heterogeneity: I = 92.1%, CI = (89.8%, 94%)) and functional ability (OR = 1.20, P = 0.01, CI = (1.04, 1.39); I = 93.1%, CI = (89.3%, 95.5%)). Specific risk factors had limited effects, especially on functional ability, with moderate impacts for demographics and mental health and marginal effects for health status and social determinants of health. Methodological issues, such as outliers, inter-country differences and publication bias, influenced the results. Overall, we highlight the specific profile of risk factors associated with healthy aging in Latin America. The heterogeneity in results and methodological approaches in studying healthy aging call for greater harmonization and further regional research to understand healthy aging in Latin America.
PubMed: 38886210
DOI: 10.1038/s43587-024-00648-6 -
Causal effects between gut microbiota and endometriosis: a two-sample Mendelian randomisation study.Journal of Obstetrics and Gynaecology :... Dec 2024Previous observational evidence has indicated the potential involvement of the gut microbiota (GM) in the development of endometriosis. However, the causal relationship...
BACKGROUND
Previous observational evidence has indicated the potential involvement of the gut microbiota (GM) in the development of endometriosis. However, the causal relationship of the association remains to be investigated.
METHOD
Genome-wide association study (GWAS) data of GM was obtained from the MiBioGen consortium, and GWAS for endometriosis data was from the FinnGen consortium. Initially, a two-sample Mendelian randomisation (MR) analysis was performed to identify specific bacteria associated with endometriosis. Inverse variance-weighted (IVW) was used as the main MR analysis to infer causal relationships. The other four popular MR methods including MR-Egger regression, weighted mode, weighted median, and simple mode were used for secondary confirmation. Subsequently, these selected bacteria were employed as exposure to investigate their causal effects on six sub-types of endometriosis. Furthermore, reverse MR analysis was implemented to evaluate the reverse causal effects. Cochran's Q statistics was used to test the heterogeneity of instrumental variables (IVs); MR-Egger regression was used to test horizontal pleiotropy; MR-PRESSO and leave-one-out sensitivity analysis were applied to find significant outliers.
RESULT
A total of 1131 single nucleotide polymorphisms (SNPs) were collected as IVs for 196 GM taxa with endometriosis as the outcome. We identified 12 causal relationships between endometriosis and GM taxa including 1 phylum, 3 families, 2 orders, and 6 genera (Rikenellaceae RC9 gut group, Eubacterium ruminantium group, Faecalibacterium, Peptococcus, Clostridium sensu stricto 1, and Ruminococcaceae UCG005). Utilizing the Bonferroni method, we identified phylum Cyanobacteria as the strongest associated GM taxa. Subsequently, 6 significant causal effects were uncovered between the 12 selected specific GM and 6 sub-types of endometriosis. Meanwhile, no reverse causal relationship was found. Further, no horizontal pleiotropy and no significant outliers were detected in the sensitive analysis.
CONCLUSIONS
This MR analysis revealed significant causal effects between GM and endometriosis and phylum Cyanobacteria had the strongest association.
Topics: Endometriosis; Humans; Female; Mendelian Randomization Analysis; Genome-Wide Association Study; Gastrointestinal Microbiome; Polymorphism, Single Nucleotide; Causality
PubMed: 38885114
DOI: 10.1080/01443615.2024.2362415