Immune Traits Research Articles

Role of CD38 in mediating the effect of Bacillus on acute pancreatitis: a study of mediated Mendelian randomization

BackgroundSome studies suggest a potential link between intestinal flora and acute pancreatitis (AP). However, the causal relationships between specific intestinal flora and AP, and the possible mediating role of immune cell traits, remain unclear.MethodsA genome-wide association study (GWAS) involving 5,959 participants was conducted to identify genetic instrumental variables associated with 473 intestinal flora taxa. Summary statistics for AP were obtained from the UK Biobank. Immune cell traits were also identified using large-scale GWAS summary data. We employed a two-sample bidirectional Mendelian randomization (MR) approach to investigate the causal relationships between intestinal flora, immune cell traits, and AP, with inverse variance weighting (IVW) as the primary statistical method. Sensitivity analyses, including the MR-Egger intercept test, Cochran’s Q test, MR-PRESSO test, and leave-one-out test, were conducted to assess the robustness of our findings. Additionally, we explored whether immune cell traits mediate the pathway from intestinal flora to AP.Results11 positive and 11 negative causal relationships were identified between genetic susceptibility in intestinal flora and AP. Furthermore, 19 positive and 9 negative causal relationships were observed between immune cell traits and AP. Notably, CD38 mediated the causal relationship between Bacillus C and AP.ConclusionsThis study is the first to uncover novel causal relationships between various intestinal flora and acute pancreatitis, emphasizing the mediating role of immune cell traits in the pathway from intestinal flora to AP. It also provides new evidence supporting the conditional pathogenicity of the Bacillus genus.

Causal role of the pyrimidine deoxyribonucleoside degradation superpathway mediation in Guillain-Barré Syndrome via the HVEM on CD4 + and CD8 + T cells

Immune system regulation is a key indicator of the gut microbiota (GM) influencing disease development. The causal role of the GM in Guillain-Barré syndrome (GBS) and whether it can be mediated by immune cells is unknown. Genome-wide association study (GWAS) summary statistics for the GM were obtained from the Dutch Microbiota Project (n = 7,738) and the FINRISK 2002 (FR02) cohort (n = 5,959). Inverse variance weighting method (IVW) were used as the main method to evaluate the causal relationship between GM and GBS. Subsequently, the mediating effects of 731 immune traits were evaluated. Additionally, we also executed the Bayesian Weighting algorithm for verification. Mendelian randomization (MR) analysis determined the protective effect of the pyrimidine deoxyribonucleoside degradation superpathway on GBS (IVW: P = 0.0019, OR = 0.4508). It is worth noting that in the causal effects of pyrimidine deoxyribonucleoside degradation superpathway on GBS, the mediated proportions of herpesvirus entry mediator (HVEM) ( HVEM on CM CD4 + , HVEM on naive CD4 + , HVEM on CD45RA − CD4 + , HVEM on CM CD8br) in the T cell maturation stage on GBS were -0.0398, -0.0452, -0.0414, -0.0425, accounting for 5.00%, 5.67%, 5.19% and 5.34% of the total effect. 11 types of intestinal bacteria might be involved in the pyrimidine deoxyriboside degradation superpathway, including Staphylococcus A fleurettii, AR31,CAG-274 sp000432155, Photobacterium, Acetobacteraceae, Dysgonomonadaceae, NK4A144,Leptospirae, CAG-81 sp000435795, Leptospirales and CAG-873 sp001701165. This study suggests that there is a causal relationship between pyrimidine deoxyribonucleoside degradation superpathway and GBS, which may be mediated by HVEM on CD4 + and CD8 + T cells. As a bidirectional molecular switch, HVEM plays an important role in T cell regulation. 11 intestinal flora were found to be involved in pyrimidine deoxyribonucleoside degradation superpathway, and their changes may be related to the occurrence of GBS. However, extensive research is still warranted before microbiome sequencing can be used for prevention and targeted treatment of GBS.

Causality Between Immune Cells, Metabolites and Breast Cancer: Mendelian Randomization and Mediation Analysis.

Previous studies have shown that immune cells and metabolites are associated with the development of breast cancer, but the causal relationship is unclear. We use Mendelian randomization (MR) to explore potential connections between them. Based on two sample MR studies, we evaluated the causal relationship between 731 immune cell traits, 1400 metabolites and breast cancer. In addition, we evaluated the mediating role of metabolites between immune cells and breast cancer using two-step MR Studies. Pooled GWAS data on 731 immune cell traits (n = 3757), 1400 metabolites (n = 8299) and breast cancer (ncase = 122,977, ncontrol = 105,974) were obtained from publicly available authoritative databases. We mainly used inverse variance weighted (IVW) method combined with Bayesian weighted MR (BWMR), MR-Egger, weighted median, simple mode, and weighted mode methods. The results of MR Studies showed that 3 immune cells and 15 metabolites were associated with an increased risk of breast cancer. 8 immune cells and 11 metabolites are associated with a reduced risk of breast cancer. Mediating MR Analysis showed that 6 metabolites, Tricosanoyl sphingomyelin (d18:1/23:0) levels(Mediated proportion:17.5%), N-palmitoyl-heptadecasphingosine (d17:1/16:0) levels(8.74%), Inosine 5'-monophosphate (IMP) to phosphate ratio(11.3%), Glutamine to asparagine ratio(5.43%), Oleoyl-linoleoyl-glycerol (18:1/18:2) [2] levels(8.48%), and Sphinganine-1-phosphate levels(8.68%), were found to mediate the relationship between immune cells and breast cancer. Our study reveals a potential causal relationship among multiple immune cells traits, metabolites, and breast cancer. It provides valuable clues and potential therapeutic targets for breast cancer biomarker discovery and breast cancer treatment.

Exploring the mediating role of immune cells in the pathogenesis of IgA nephropathy through the inflammatory axis of gut microbiota from a genomic perspective.

IgA nephropathy (IgAN) is a chronic glomerular disease characterized by the deposition of IgA antibodies in the kidney's mesangium. Its pathogenesis involves genetic, immune, and environmental factors, particularly within the mucosal immune system and gut microbiota. Immune cells play a central role in mediating these processes, which this study investigates using Mendelian Randomization (MR) to explore causal relationships among gut microbiota, inflammatory markers, blood cells, and immune cells in IgAN pathogenesis. We conducted a two-sample MR analysis using Genome-Wide Association Study (GWAS) summary data to assess the causal effects of gut microbiota, inflammatory markers, and blood cell traits on IgAN. Data sources included the FinnGen dataset for IgAN and relevant GWAS datasets for immune traits, blood cells, and inflammatory markers. Inverse variance weighting (IVW) was the primary MR method, supported by sensitivity analyses. We particularly examined the mediation effect of immune cells on these exposures' influence on IgAN. Significant associations were found between several factors and IgAN. Gut microbiota traits, such as Firmicutes E and Sporomusales, increased IgAN risk, while Citrobacter A and Herbinix reduced it. Inflammatory markers, including Interleukin-10 and Fibroblast Growth Factor 23, promoted IgAN onset. Blood cell traits like red blood cell perturbation response increased risk, while monocyte perturbation response was protective. Immune traits played a key mediating role, with Transitional %B cells reducing IgAN risk and CD28- CD25 + + CD8br %T cells increasing it. This study highlights the pivotal mediating role of immune cells in the interactions between gut microbiota, inflammatory markers, and IgAN risk. These findings identify potential biomarkers and therapeutic targets, providing new insights into the immune mechanisms underlying IgAN and opportunities for intervention.

Causal Effects of Gut Microbiota on Gout and Hyperuricemia: Insights from Genome-Wide Mendelian Randomization, RNA-Sequencing, 16S rRNA Sequencing, and Metabolomes.

This study investigated the causal relationship between gut microbiota (GM), serum metabolome, and host transcriptome in the development of gout and hyperuricemia (HUA) using genome-wide association studies (GWAS) data and HUA mouse model experiments. &#160;Methods: Mendelian randomization (MR) analysis of GWAS summary statistics was performed using an inverse variance weighted (IVW) approach to determine predict the causal role of the gut microbiota on gout. The HUA mouse model was used to characterize changes in the gut microbiome, host metabolome, and host kidney transcriptome by integrating cecal 16S rRNA sequencing, untargeted serum metabolomics, and host mRNA sequencing.</p> &#160;Results: Our analysis demonstrated causal effects of seven gut microbiota taxa on gout, including genera of Ruminococcus, Odoribacter, and Bacteroides. Thirty-eight, immune cell traits were associated with gout. Dysbiosis of Dubosiella, Lactobacillus,Bacteroides, Alloprevotella, and Lachnospiraceae_NK4A136_group genera were associated with changes in the serum metabolites and kidney transcriptome of the HUA model mice. The changes in the gut microbiome of the HUA model mice correlated significantly with alterations in the levels of serum metabolites such as taurodeoxycholic acid, phenylacetylglycine, vanylglycol, methyl hexadecanoic acid, carnosol, 6-aminopenicillanic acid, sphinganine, p-hydroxyphenylacetic acid, pyridoxamine, and de-o-methylsterigmatocystin, and expression of kidney genes such as CNDP2, SELENOP, TTR, CAR3, SLC12A3, SCD1, PIGR, CD74, MFSD4B5, and NAPSA.</p> &#160;Conclusion: Our study demonstrated a causal relationship between GM, immune cells, and gout. HUA development involved alterations in the vitamin B6 metabolism because of gut microbiota dysbiosis that resulted in altered pyridoxamine and pyridoxal levels, dysregulated sphingolipid metabolism, and excessive inflammation.</p>.

Genomic Variants Associated with Haematological Parameters and T Lymphocyte Subpopulations in a Large White and Min Pig Intercross Population.

The breeding of disease-resistant pigs has consistently been a topic of significant interest and concern within the pig farming industry. The study of pig blood indicators has the potential to confer economic benefits upon the pig farming industry, whilst simultaneously providing valuable insights that can inform the study of human diseases. In this study, an F2 resource population of 489 individuals was generated through the intercrossing of Large White boars and Min pig sows. A total of 17 haematological parameters and T lymphocyte subpopulations were measured, including white blood cell count (WBC), lymphocyte count (LYM), lymphocyte count percentage (LYM%), monocyte count (MID), monocyte count percentage (MID%), neutrophilic granulocyte count (GRN), percentage of neutrophils (GRN%), mean platelet volume (MPV), platelet distribution width (PDW), platelet count (PLT), CD4+/CD8+, CD4+CD8+CD3+, CD4+CD8-CD3+, CD4-CD8+CD3+, CD4-CD8-CD3+, and CD3+. The Illumina PorcineSNP60 Genotyping BeadChip was obtained for all of the F2 animals. Subsequently, a genome-wide association study (GWAS) was conducted using the TASSEL 5.0 software to identify associated variants and candidate genes for the 17 traits. Significant association signals were identified for PCT and PLT on SSC7, with 1 and 11 significant SNP loci, respectively. A single nucleotide polymorphism (SNP) on SSC12 was identified as a significant predictor of the white blood cell (WBC) trait. Significant association signals were detected for the T lymphocyte subpopulations, namely CD4+/CD8+, CD4+CD8+CD3+, CD4+CD8-CD3+, and CD4-CD8+CD3+, with the majority of these signals observed on SSC7. The genes CLIC5, TRIM15, and SLC17A4 were identified as potential candidates for influencing CD4+/CD8+ and CD4-CD8+CD3+. A missense variant, c.2707 G>A, in the SLC17A4 gene has been demonstrated to be significantly associated with the CD4+/CD8+ and CD4-CD8+CD3+ traits. Three missense variants (c.425 A>C, c.500 C>T, and c.733 A>G) have been identified in the TRIM15 gene as being linked to the CD4+/CD8+ trait. Nevertheless, only c.425 A>C has been demonstrated to be significantly associated with CD4-CD8+CD3+. In the CLIC5 gene, one missense variant (c.957 T>C) has been identified as being associated with the CD4+/CD8+ and CD4-CD8+CD3+ traits. Additionally, significant association signals were observed for CD4+CD8+CD3+ and CD4+CD8-CD3+ on SSC2 and 5, respectively. Subsequently, a gene ontology (GO) enrichment analysis was conducted on all genes within the quantitative trait loci (QTL) intervals of platelet count, CD4+/CD8+, and CD4-CD8+CD3+. The MHC class II protein complex binding pathway was identified as the most significant pathway among the three immune traits. These results provide guidance for further research in the field of breeding disease-resistant pigs.

Immune cells mediate the causal relationship between uveitis and colorectal cancer via Mendelian randomization analysis

Colorectal cancer (CRC) is one of the most common and deadly malignancies worldwide, and immune regulation plays a critical role in its development. This study investigates the causal relationships between uveitis, specific immune cell traits, and CRC using Mendelian Randomization (MR) analyses. A total of 21 single nucleotide polymorphisms (SNPs) associated with uveitis were identified, and the analysis revealed that a 1 log-odds increase in uveitis was linked to a statistically significant 3.0% reduction in CRC odds (IVW OR = 0.970, 95% CI: 0.946–0.995, P = 0.021). This protective effect was also observed using the weighted median approach (OR = 0.963, 95% CI: 0.931–0.997, P = 0.034), reinforcing the robustness of the findings. Furthermore, both univariable and multivariable MR analyses highlighted the significant causal influence of specific immune cell traits on CRC odds. Notably, the levels of extracellular monocyte HLA-DR expression emerged as a critical factor, with an associated increase in CRC odds (IVW OR = 1.084, 95% CI: 1.008–1.165, P = 0.030). The proportion of CRC odds mediated by the levels of extracellular monocyte HLA-DR expression, calculated as the ratio of the indirect effect to the total effect using estimates from multivariable MR analyses, was approximately 34.1%(95% CI: 10.23−58.04%). These findings underscore the complex interplay between immune regulation and carcinogenesis, offering insights into potential mechanisms underlying CRC development and suggesting avenues for targeted prevention and therapeutic strategies.

Causal role of immune cells in muscle atrophy: mendelian randomization study

Immune system and inflammation had a great influence on the progression of muscle atrophy. However, the causal relationship with specific immune cell traits remained uncertain. The aim of this study was to elucidate the genetic influences on these associations, providing insights into the underlying mechanisms of muscle atrophy. A bidirectional two-sample Mendelian randomization (MR) analysis was conducted to investigate the causal relationship between immune cell phenotypes and muscle atrophy. Data on immune cell phenotypes were obtained from a research cohort containing data on 731 immune cell phenotypes and data on muscle atrophy were sourced from a Finnish database. MR analysis was performed using the MR-Egger method, weighted median, inverse variance weighting, heterogeneity testing, sensitivity analysis, and multiplicity analysis, with results subjected to false discovery rate(FDR) correction. Additionally, the UK Biobank cohort was utilized as an external validation. A total of 31 immune phenotypes with causal relationships with muscle atrophy were identified, including various phenotypes of conventional dendritic cells, myeloid cells, T cells/B cells/natural killer cells, regulatory cells, and T cell maturation stages. Among them, 12 immune phenotypes were identified as exhibiting a positive causal relationship with muscle atrophy, while 19 immune phenotypes were demonstrated to have a negative causal association, highlighting the complex interactions between immune cells and muscle health. The results of the reverse MR analysis indicated that a negative correlation between muscle atrophy and CD28 on secreting Treg (OR = 0.9038, 95%CI:0.8308 ~ 0.9832, P = 0.0186). A significant positive correlation was revealed by external datasets between the CD25 on IgD + CD38- immune phenotype and the risk of muscle atrophy, which was consistent with the trend observed in the training group (OR = 1.1041, 95% CI: 1.1005–1.1076, P = 0.0263). No evidence of pleiotropy was observed, and the reliability of these findings was demonstrated by the leave-one-out analysis. The findings highlight significant correlations between certain immune cell features and muscle atrophy, providing potential targets for further investigation of immunological mechanisms and therapeutic interventions for this condition.

Causality of immune cells and endometriosis: a bidirectional mendelian randomization study

BackgroundEndometriosis, a prevalent chronic condition, afflicts approximately 10% of women in their reproductive years. Emerging evidence implicates immune cells in the pathogenesis of endometriosis, particularly in angiogenesis, tissue proliferation, and lesion invasion. This investigation employs two-sample Mendelian Randomization (MR) to dissect the bidirectional causal relationships between immune cell profiles and endometriosis.MethodsWe leveraged publicly available genome-wide association study (GWAS) data to elucidate the causal interplay between immune cell traits and endometriosis. Utilizing GWAS summary statistics ranging from accession numbers GCST90001391 to GCST90002121 and endometriosis data from the FinnGen study GWAS (8,288 endometriosis cases and 68,969 controls), we adopted stringent criteria for instrumental variable selection. We applied MR-Egger, weighted median, inverse variance weighted (IVW), and weighted mode methods to derive causal estimates. To address potential heterogeneity and pleiotropy, Cochran’s Q test, MR-Egger intercept, and leave-one-out analyses were executed. Reverse-direction MR and bidirectional MR analyses evaluated potential reciprocal causation and the influence of endometriosis on immune cell composition.ResultsOur analysis identified five immune phenotypes inversely associated with endometriosis risk. These phenotypes comprise: a percentage of CD11c + HLA-DR + + monocytes, CD25 expression on CD39 + CD4 + T cells, elevated CD25 on CD45RA + CD4 + non-regulatory T cells, HLA-DR intensity on HLA-DR + CD8 bright (CD8br) T cells, and the proportion of naïve double-negative (CD4 − CD8− %DN) T cells. In contrast, eleven phenotypes were positively correlated with endometriosis risk, including: CD127 expression on T cells, the proportion of CD24 + CD27 + B cells within lymphocytes, CD25 expression on CD28 + CD4 + T cells, CD28 expression on CD39 + activated regulatory T cells (activated Tregs), the frequency of bright CD33 HLA-DR + CD14 − cells within the CD33br HLA-DR + compartment, CD45 expression on lymphocytes and natural killer (NK) cells, activation status of central memory CD8 bright (CM CD8br) T cells, CX3CR1 expression on monocytes, and the percentage of HLA-DR + NK cells within the NK cell subset. Sensitivity assessments that excluded significant heterogeneity and pleiotropy confirmed the stability of these associations, thereby reinforcing the validity of our findings.ConclusionThis study provides novel evidence of the potential causal impact of specific immune cells on the risk of developing endometriosis. These findings enhance our understanding of endometriosis pathophysiology and may inform innovative approaches for its diagnosis and management. While our findings provide novel insights, limitations such as potential horizontal pleiotropy and reliance on European ancestry data should be considered. Future research should expand to diverse populations and incorporate individual-level data to refine these findings.

Association between immune cells and membranous nephropathy: a two-sample Mendelian randomization study

IntroductionMultiple studies have indicated that immune cells play a significant role in the occurrence and development of membranous nephropathy (MN). However, the causal relationship between the two has not been fully established. To further investigate this, we employed a Mendelian randomization (MR) study design.Material and methodsGenetic instrumental variables for immune cells were sourced from an extensive genome-wide association study (GWAS). MN summary statistics, involving 2,150 cases and 5,829 controls, were obtained from a separate GWAS. The primary analysis employed the inverse-variance weighted (IVW) method. To explore reverse causation, a reverse MR analysis was undertaken. Rigorous sensitivity analyses were conducted to ensure the resilience and reliability of the study's findings.ResultsWe identified eight immunophenotypes associated with a reduced risk of MN and all of them were the protective factors for MN. The sensitivity analyses consistently yielded similar results for these immune traits. In the reverse MR analysis, we did not observe any statistically significant associations between MN and these eight immunophenotypes.ConclusionsOur study, utilizing genetic approaches, provides evidence for a causal relationship between immune cells and MN, which has implications for clinical diagnosis and treatment. Further comprehensive investigations are needed to explore the detailed mechanisms underlying the impact of immune cells on MN.

Identification of immune traits associated with neurodevelopmental disorders by two-sample Mendelian randomization analysis

BackgroundOne of the main causes of health-related issues in children is neurodevelopmental disorders (NDDs), which include attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and Tourette syndrome (TS). Nonetheless, there is relatively little prior research looking at the link between immunological inflammation and NDDs. Our work uses a two-sample Mendelian Randomization (MR) approach to provide a thorough evaluation of the causal effects of immune traits on ADHD, ASD, and TS.MethodsAs exposures, 731 immunological traits’ genetic associations were chosen, and the outcomes were genome-wide association data for ADHD, ASD, and TS. The inverse-variance weighted (IVW), weighted median (WM), and MR-Egger methods were used to conduct MR analysis. The results’ robustness, heterogeneity, and horizontal pleiotropy were confirmed using extensive sensitivity analysis.ResultsWith single-nucleotide polymorphisms serving as instruments and false discovery rate (FDR) correction applied, the study found that significantly higher expression of CD62L on CD62L+ myeloid DC (IVW, OR: 0.926, 95% CI 0.896~0.958, P = 9.42 × 10–6, FDR = 0.007) and suggestively higher absolute cell count (AC) of CD28 + DN (CD4-CD8-) (IVW, OR: 0.852, 95% CI = 0.780 ∼ 0.932, P-value = 4.65 × 10−4, FDR = 0.170) was associated with a lower risk of ADHD. There was no pleiotropy, and the causal relationships were strong according to sensitivity, leave-one-out, and MR-Steiger directionality tests. For ASD and TS, no harmful or protective immune traits were observed.ConclusionsThe results of the study lend credence to the theory that deficiency in CD62L on CD62L+ myeloid DC and CD28 + DN (CD4-CD8) AC may contribute to the onset of ADHD.

Mendelian randomization analysis of the causal relationship between immune cells and keloid

Immune cells play complex roles in the formation of keloid. We aimed to investigate the causal relationship between immune cells and keloid and provide genetic evidence for the association between immune cells and keloid risk. Based on data from GWAS, we performed a comprehensive two-sample Mendelian Randomization (MR) analysis of 731 immune cell traits in 481,912 keloid cases. We used Inverse-Variance Weighted (IVW) method as the primary analysis. Then, a comprehensive sensitivity analysis was adopted to verify the results' robustness, heterogeneity, and horizontal pleiotropy. Finally, reverse MR analysis was performed. The IVW method in forward MR analysis showed that CD66b++ myeloid cell AC was negatively associated with keloid risk (OR &lt; 1, P &lt; 0.05). Consistently, reverse MR analysis showed keloid risk was negatively associated with CD66b++ myeloid cell AC (OR = 0.85, P = 0.012). No significant horizontal pleiotropy or heterogeneity was observed. The results of MR analysis demonstrate a bidirectional causal association between CD66b++ myeloid cell AC and keloid formation, suggesting CD66b++ myeloid cell AC is a protective factor against keloid.

Skin Microbiota, Immune Cell, and Skin Fibrosis: A Comprehensive Mendelian Randomization Study.

Microbiota dysbiosis has been reported to lead to leaky epithelia and trigger numerous dermatological conditions. However, potential causal associations between skin microbiota and skin fibrosis and whether immune cells act as mediators remain unclear. Summary statistics of skin microbiota, immune cells, and skin fibrosis were identified from large-scale genome-wide association studies summary data. Bidirectional Mendelian randomization was performed to ascertain unidirectional causal effects between skin microbiota, immune cells, and skin fibrosis. We performed a mediation analysis to identify the role of immune cells in the pathway from skin microbiota to skin fibrosis. Three specific skin microbiotas were positively associated with skin fibrosis, while the other three were negative. A total of 15 immune cell traits were associated with increased skin fibrosis risk, while 27 were associated with a decreased risk. Moreover, two immune cell traits were identified as mediating factors. Causal associations were identified between skin microbiota, immune cells, and skin fibrosis. There is evidence that immune cells exert mediating effects on skin microbiota in skin fibrosis. In addition, some strains exhibit different effects on skin fibrosis in distinct environments.

Causal Relationships between Circulating Immune Cell Traits and the Risk of Rheumatoid Arthritis and Osteoarthritis: A Bidirectional Two-Sample Mendelian Randomization Study.

Rheumatoid arthritis (RA) and osteoarthritis (OA) are prevalent chronic joint disorders with immunological pathogenesis. However, the causal relationships between circulating immune cells and them remain largely unknown. Therefore, we conducted a bidirectional two-sample Mendelian randomization (MR) study to determine their causal relationship. Genome-wide association study summary statistics were extracted from publicly available databases regarding immune cell phenotypes, RA, and OA. MR analysis was conducted using five MR methods, with inverse-variance-weighted (IVW) as the primary analysis method. False discovery rate correction (FDR) was used to reduce the likelihood of type 1 errors. We also conducted MR-Egger intercept tests to evaluate horizontal pleiotropy. After FDR adjustment of the P values for the IVW method, the CD27 expression on memory B cells was negatively related to the risk of RA (P < 0.001), and the human leukocyte antigen (HLA)--DR expression on CD14+ monocytes was negatively related to the risk of OA (P < 0.001). We also found that RA was negatively associated with the expression of HLA-DR on myeloid dendritic cells (P < 0.001), but significant horizontal pleiotropy was observed. Our study demonstrates a causal relationship between specific immune cell traits and RA as well as OA, providing further insight into the role of immune cells in the pathogenesis of these disorders.

Insights into trait-association of selection signatures and adaptive eQTL in indigenous African cattle

BackgroundAfrican cattle represent a unique resource of genetic diversity in response to adaptation to numerous environmental challenges. Characterising the genetic landscape of indigenous African cattle and identifying genomic regions and genes of functional importance can contribute to targeted breeding and tackle the loss of genetic diversity. However, pinpointing the adaptive variant and determining underlying functional mechanisms of adaptation remains challenging.ResultsIn this study, we use selection signatures from whole-genome sequence data of eight indigenous African cattle breeds in combination with gene expression and quantitative trait loci (QTL) databases to characterise genomic targets of artificial selection and environmental adaptation and to identify the underlying functional candidate genes. In general, the trait-association analyses of selection signatures suggest the innate and adaptive immune system and production traits as important selection targets. For example, a large genomic region, with selection signatures identified for all breeds except N’Dama, was located on BTA27, including multiple defensin DEFB coding-genes. Out of 22 analysed tissues, genes under putative selection were significantly enriched for those overexpressed in adipose tissue, blood, lung, testis and uterus. Our results further suggest that cis-eQTL are themselves selection targets; for most tissues, we found a positive correlation between allele frequency differences and cis-eQTL effect size, suggesting that positive selection acts directly on regulatory variants.ConclusionsBy combining selection signatures with information on gene expression and QTL, we were able to reveal compelling candidate selection targets that did not stand out from selection signature results alone (e.g. GIMAP8 for tick resistance and NDUFS3 for heat adaptation). Insights from this study will help to inform breeding and maintain diversity of locally adapted, and hence important, breeds.

Immune cell traits and causal relationships with cholecystitis: a mendelian randomization analysis.

Cholecystitis, characterized by inflammation of the gallbladder, is intricately linked to immune cells and the cytokines they produce. Despite this association, the specific contributions of immune cells to the onset and progression of cholecystitis remain to be fully understood. To delineate this relationship, we utilized the Mendelian randomization (MR) method to scrutinize the causal connections between 731 immune cell phenotypes and cholecystitis. By conducting MR analysis on 731 immune cell markers from public datasets, this study seeks to understand their potential impact on the risk of cholecystitis. It aims to elucidate the interactions between immune phenotypes and the disease, aiming to lay the groundwork for advancing precision medicine and developing effective treatment strategies for cholecystitis. Taking immune cell phenotypes as the exposure factor and cholecystitis as the outcome event, this study used single nucleotide polymorphisms (SNPs) closely associated with both immune cell phenotypes and cholecystitis as genetic instrumental variables. We conducted a two-sample MR analysis on genome-wide association studies (GWAS) data. Our research thoroughly examined 731 immune cell markers, to determine potential causal relationships with susceptibility to cholecystitis. Sensitivity analyses were performed to ensure the robustness of our findings, excluding the potential impacts of heterogeneity and pleiotropy. To avoid reverse causality, we conducted reverse MR analyses with cholecystitis as the exposure factor and immune cell phenotypes as the outcome event. Among the 731 immune phenotypes, our study identified 21 phenotypes with a causal relationship to cholecystitis (P < 0.05). Of these, eight immune phenotypes exhibited a protective effect against cholecystitis (odds ratio (OR) < 1), while the other 13 immune phenotypes were associated with an increased risk of developing cholecystitis (OR > 1). Additionally, employing the false discovery rate (FDR) method at a significance level of 0.2, no significant causal relationship was found between cholecystitis and immune phenotypes. Our research has uncovered a significant causal relationship between immune cell phenotypes and cholecystitis. This discovery not only enhances our understanding of the role of immune cells in the onset and progression of cholecystitis but also establishes a foundation for developing more precise biomarkers and targeted therapeutic strategies. It provides a scientific basis for more effective and personalized treatments in the future. These findings are expected to substantially improve the quality of life for patients with cholecystitis and mitigate the impact of the disease on patients and their families.

Causal relationship between cancer and immune cell traits: A two-sample mendelian randomization study

BackgroundObservational studies provide evidence of correlations between cancer and the immune system. Previous research has established associations between immune traits and the propensity for developing certain cancers. However, a systematic exploration of these connections remains largely uncharted. Therefore, further investigation is needed to examine the causal association between cancer and immune cell traits using Mendelian randomization (MR) approach. MethodsWe identified genetic instruments for breast cancer (BC), lung cancer (LC), endometrial cancer (EC), ovarian cancer (OC), prostate cancer (PC), and their subtype cancers to investigate their potential causal impact on immune traits. Data on cancer and immune cell traits were obtained from the IEU Open GWAS project. To assess whether these five cancer types and subtype cancers have a causal association with immune cell traits, we conducted two-sample MR analyses. Additionally, we conducted bidirectional MR analyses to examine the direction of causal relationships and adjusted for potentially related pleiotropy through multivariable MR analysis. ResultsWe have identified several causal relationships between different types of cancer and immune traits. We found that breast cancer may influence 49 immune cell traits, endometrial cancer may influence 38, lung cancer may influence 25, ovarian cancer may influence 19, and prostate cancer may influence 28. Among these, breast cancer and lung cancer were associated with four common immune traits: CD25 on IgD− CD38dim, CD25 on sw mem, CD24 on IgD− CD38−, and CD25 on IgD− CD38−. Lung cancer and prostate cancer shared four immune traits: CD25 on IgD+ CD24+, CD25 on IgD+ CD38−, CD66b on CD66b++ myeloid cell, DN (CD4−CD8−) AC. Endometrial cancer and ovarian cancer shared two immune traits: TD DN (CD4−CD8−) %DN, EM DN (CD4−CD8−) %DN. Breast cancer and endometrial cancer shared one immune trait: CD20 on IgD− CD38dim. Endometrial cancer and prostate cancer shared one immune trait: CCR2 on myeloid DC. Lastly, breast cancer, lung cancer, and prostate cancer shared one immune trait: CD25 on CD24+ CD27+. Additionally, we identified specific immune traits that may serve as protective or risk factors for cancers. We found 14 immune traits may influence breast cancer, 9 immune traits may influence endometrial cancer, 22 immune traits may influence lung cancer, 9 immune traits may influence ovarian cancer, and 14 immune traits may influence prostate cancer. Among these, breast cancer and prostate cancer shared three immune traits: HLA DR++ monocyte %monocyte, HLA DR on plasmacytoid DC, and HLA DR on DC. Lung cancer and ovarian cancer shared one immune trait: CD62L− monocyte %monocyte. Prostate cancer and endometrial cancer shared one immune trait: HLA DR on CD33dim HLA DR + CD11b+. Lastly, ovarian cancer and prostate cancer shared one immune trait: CD3 on resting Treg. ConclusionsOur MR study suggests a potential relationship between immune traits and cancers, particularly highlighting 14 immune traits that are simultaneously influenced by two or three of five cancer types, while also indicating that 6 immune traits may simultaneously contribute to the development of two of the cancers. This elucidation enables us to reveal a significant involvement of immune traits in cancer progression, providing critical insights into how immune traits affect cancer susceptibility.

A causal relationship between distinct immune features and acute or chronic pancreatitis: results from a mendelian randomization analysis

ObjectivesThis study aimed to thoroughly examining the causal link between immune traits and four types of pancreatitis, using mendelian randomization. MethodsData on 731 immune traits were collected from the genome-wide association study (GWAS) database as exposure. Information regarding acute pancreatitis (AP), alcohol-induced acute pancreatitis (AAP), chronic pancreatitis (CP), and alcohol-induced chronic pancreatitis (ACP) were acquired from the FinnGen Consortium as outcomes. Mendelian randomization (MR) using inverse variance weighting (IVW) evaluated the links between immune traits and pancreatitis. We evaluated the robustness of the IVW results through sensitivity analyses and validated them using meta-analysis with AP and CP data from the UK Biobank in the GWAS catalog. ResultsA total of 36 immune traits showed significant associations with susceptibility of four types of pancreatitis, including AP (7 traits), AAP (8 traits), CP (14 traits), and ACP (7 traits). Twenty characteristics were found to be potential risk factors for pancreatitis, identified in B Cells (5 traits), conventional dendritic cells (cDCs, 2 traits), maturation stage of T cells (2 traits), monocytes (2 traits), myeloid cells (2 traits), T cells, B cells, natural killer cells (TBNK, 2 traits), and regulatory T cells (Treg cells, 5 traits). Multiple sensitivity analyses confirmed the validity of the findings. Meta-analysis confirmed a solid causal relationship between CX3CR1 on CD14− CD16−of monocyte panel and the susceptibility of CP. ConclusionsOur MR study identified immune traits causally linked to acute and chronic pancreatitis, offering new insights for early clinical intervention and immune cell-targeted therapies.

Bidirectional Mendelian Randomization Reveals Causal Effects of Immune Cell Traits on Endometriosis Risk.

Previous studies have identified associations between immune cell traits and endometriosis, but the causality of these relationships remains uncertain. In this study, we utilized Mendelian randomization (MR) to investigate the causal relationship between immune cell traits and endometriosis for the first time. Seven hundred and thirty-one immune cell signatures associated with single-nucleotide polymorphisms (SNPs) were extracted from a published genome-wide association study (GWAS) involving 472174 individuals, while endometriosis data, including four stages and seven subtypes, were obtained from the FinnGen consortium. Four methods were used for MR. The causal effect of immune cell traits on endometriosis was explored after Bonferroni correction. Significant causal relationship included 92 immune cell traits distributed among B cell (28 cells), cDC (2 cells), maturation stages of T cell (10 cells), monocyte (12 cells), Myeloid cell (5 cells), TBNK (13 cells), and Treg panels (22 cells). One of the most significant findings is that for every 1-standard deviation (SD) increase in CD8 on Central Memory CD8+ T cell, the risks of developing endometriosis of the fallopian tube increased by 72%. In the reverse MR analysis, a one-unit increase in the log odds of endometriosis of the ovary risk corresponded to a decrease in the absolute count of CD4+ CD8dim T cell by 0.10. This study represents the first comprehensive evaluation of the causal effects of immune cell traits on the risk/protection of different stages/subtypes of endometriosis. The findings highlight the complex and significant role of immune-derived factors in the pathogenesis of the disease.

Exploring the complex relationship between attention deficit hyperactivity disorder and the immune system: A bidirectional Mendelian randomization analysis

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition that can be accompanied by alterations in immune markers. However, the intricate nature of the association between ADHD and immune markers remains insufficiently elucidated. To explore the currently ambiguous causal relationship between ADHD and the immune system, we performed a bidirectional Mendelian randomization (MR) analysis of immune cell traits and ADHD under the randomized inverse variance weighting (IVW) method based on genome-wide association study (GWAS) summary data. We found ADHD increased the level of 3 immune cell traits including myeloid dendritic cells (β = 0.28, P = 0.008), monocyte (β = 0.25, P = 0.024) and granulocyte (β = 0.2, P = 0.042). We also identified 1 trait which belongs to B cell panel was a risk factor (odds ratio (OR) = 1.07, P = 0.001) for ADHD onset. Other 5 traits including CD14+ monocyte (OR = 0.98, P = 0.002), immature myeloid-derived suppressor cells (MDSC) (OR = 0.98, P = 0.003), monocyte MDSC (OR = 0.95, P = 0.005), CD33br HLA DR+ (OR = 0.97, P = 0.021) and basophil (OR = 0.96, P = 0.022) were protective factors for ADHD. Here we identified a range of causal relationships extending from ADHD to immune cell traits, underscoring the complex interaction patterns between ADHD and the immune system. Enhanced interventions for protective and risk factors may be beneficial in the prevention and treatment of ADHD.