Shared genetic correlations between kidney diseases and sepsis.

Background: Clinical studies have indicated a comorbidity between sepsis and kidney diseases. Individuals with specific mutations that predispose them to kidney conditions are also at an elevated risk for developing sepsis, and vice versa. This suggests a potential shared genetic etiology that has not been fully elucidated. Methods: Summary statistics data on exposure and outcomes were obtained from genome-wide association meta-analysis studies. We utilized these data to assess genetic correlations, employing a pleiotropy analysis method under the composite null hypothesis to identify pleiotropic loci. After mapping the loci to their corresponding genes, we conducted pathway analysis using Generalized Gene-Set Analysis of GWAS Data (MAGMA). Additionally, we utilized MAGMA gene-test and eQTL information (whole blood tissue) for further determination of gene involvement. Further investigation involved stratified LD score regression, using diverse immune cell data, to study the enrichment of SNP heritability in kidney-related diseases and sepsis. Furthermore, we employed Mendelian Randomization (MR) analysis to investigate the causality between kidney diseases and sepsis. Results: In our genetic correlation analysis, we identified significant correlations among BUN, creatinine, UACR, serum urate, kidney stones, and sepsis. The PLACO analysis method identified 24 pleiotropic loci, pinpointing a total of 28 nearby genes. MAGMA gene-set enrichment analysis revealed a total of 50 pathways, and tissue-specific analysis indicated significant enrichment of five pairs of pleiotropic results in kidney tissue. MAGMA gene test and eQTL information (whole blood tissue) identified 33 and 76 pleiotropic genes, respectively. Notably, genes PPP2R3A for BUN, VAMP8 for UACR, DOCK7 for creatinine, and HIBADH for kidney stones were identified as shared risk genes by all three methods. In a series of immune cell-type-specific enrichment analyses of pleiotropy, we identified a total of 37 immune cells. However, MR analysis did not reveal any causal relationships among them. Conclusions: This study lays the groundwork for shared etiological factors between kidney and sepsis. The confirmed pleiotropic loci, shared pathogenic genes, and enriched pathways and immune cells have enhanced our understanding of the multifaceted relationships among these diseases. This provides insights for early disease intervention and effective treatment, paving the way for further research in this field.

Genetically predicted elevated circulating 3,4-dihydroxybutyrate levels mediate the association between family Christensenellaceae and osteoporosis risk: a Mendelian randomization study.

Objective: To investigate the impact of gut microbiota on osteoporosis and identify the mediating role of blood metabolites in this process. Methods: This two-sample Mendelian randomization (MR) study utilized summary level data from genome-wide association studies (GWAS). Gut microbiota GWAS data were obtained from the MiBio-Gen consortium meta-analysis (n=13,266), while osteoporosis summary statistics were sourced from the FinnGen consortium R9 release data (7300 cases and 358,014 controls). Metabolite data, including 1400 metabolites or metabolite ratios, were derived from a study involving 8,299 unrelated individuals. The primary MR method employed was the inverse variance weighted (IVW) method. Reverse MR analysis was conducted on bacteria causally associated with osteoporosis in forward MR. The gut microbiota with the smallest p-value was selected as the top influencing factor for subsequent mediation analysis. A two-step MR approach quantified the proportion of the blood metabolite effect on gut microbiota influencing osteoporosis. IVW and Egger methods were used to assess heterogeneity and horizontal pleiotropy. Results: IVW estimates indicated a suggestive effect of family Christensenellaceae on osteoporosis (odds ratio(OR) = 1.292, 95% confidence interval(CI): 1.110-1.503, P =9.198 × 10-4). Reverse MR analysis revealed no significant causal effect of osteoporosis on family Christensenellaceae (OR = 0.947, 95% CI: 0.836-1.072, P =0.386). The proportion of the effect of family Christensenellaceae on osteoporosis mediated by circulating levels of 3,4-dihydroxybutyrate was 9.727%. No significant heterogeneity or horizontal pleiotropy was detected in the instrumental variables used for MR analysis. Conclusion: This study establishes a causal link between family Christensenellaceae and osteoporosis, with a minor proportion of the effect mediated by elevated circulating levels of 3,4-dihydroxybutyrate. Further randomized controlled trials (RCTs) are warranted to validate this conclusion.

An exploration of the causal relationship between 731 immunophenotypes and osteoporosis: a bidirectional Mendelian randomized study.

Background: There are complex interactions between osteoporosis and the immune system, and it has become possible to explore their causal relationship based on Mendelian randomization methods. Methods: Utilizing openly accessible genetic data and employing Mendelian randomization analysis, we investigated the potential causal connection between 731 immune cell traits and the risk of developing osteoporosis. Results: Ten immune cell phenotypes were osteoporosis protective factors and three immune cell phenotypes were osteoporosis risk factors. Specifically, the odds ratio (OR) of IgD+ CD24+ %B cell (B cell panel) risk on Osteoporosis was estimated to be 0.9986 (95% CI = 0.9978~0.9996, P<0.01). The OR of CD24+ CD27+ %B cell (B cell panel) risk on Osteoporosis was estimated to be 0.9991 (95% CI = 0.9984~0.9998, P = 0.021). The OR of CD33- HLA DR+AC (Myeloid cell panel) risk on Osteoporosis was estimated to be 0.9996 (95% CI = 0.9993~0.9999, P = 0.038). The OR of EM CD8br %CD8br (Maturation stages of T cell panel) risk on Osteoporosis was estimated to be 1.0004 (95% CI = 1.0000~1.0008, P = 0.045). The OR of CD25 on IgD+ (B cell panel) risk on Osteoporosis was estimated to be 0.9995 (95% CI = 0.9991~0.9999, P = 0.024). The OR of CD25 on CD39+ activated Treg+ (Treg panel) risk on Osteoporosis was estimated to be 1.001 (95% CI = 1.0001~1.0019, P = 0.038). The OR of CCR2 on CD62L+ myeloid DC (cDC panel) risk on Osteoporosis was estimated to be 0.9992 (95% CI = 0.9984~0.9999, P = 0.048). The OR of CCR2 on CD62L+ plasmacytoid DC (cDC panel) risk on Osteoporosis was estimated to be 0.9993 (95% CI = 0.9987~0.9999, P = 0.035). The OR of CD45 on CD33dim HLA DR+ CD11b- (Myeloid cell panel) risk on Osteoporosis was estimated to be 0.9988 (95% CI = 0.9977~0.9998, P = 0.031). The OR of CD45 on Mo MDSC (Myeloid cell panel) risk on Osteoporosis was estimated to be 0.9992 (95% CI = 0.9985~0.9998, P = 0.017). The OR of SSC-A on B cell (TBNK panel) risk on Osteoporosis was estimated to be 0.9986 (95% CI = 0.9972~0.9999, P = 0.042). The OR of CD11c on CD62L+ myeloid DC (cDC panel) risk on Osteoporosis was estimated to be 0.9987 (95% CI = 0.9978~0.9996, P<0.01). The OR of HLA DR on DC (cDC panel) risk on Osteoporosis was estimated to be 1.0007 (95% CI = 1.0002~1.0011, P<0.01). No causal effect of osteoporosis on immune cells was observed. Conclusions: Our study identified 13 unreported immune phenotypes that are causally related to osteoporosis, providing a theoretical basis for the bone immunology doctrine.

Causal associations between both psoriasis and psoriatic arthritis and multiple autoimmune diseases: a bidirectional two-sample Mendelian randomization study.

Background: Numerous observational studies have identified associations between both psoriasis (PsO) and psoriatic arthritis (PsA), and autoimmune diseases (AIDs); however, the causality of these associations remains undetermined. Methods: We conducted a bidirectional two-sample Mendelian Randomization study to identify causal associations and directions between both PsO and PsA and AIDs, such as systemic lupus erythematosus (SLE), Crohn's disease (CD), ulcerative colitis (UC), multiple sclerosis (MS), uveitis, bullous pemphigoid (BP), Hashimoto's thyroiditis (HT), rheumatoid arthritis (RA), vitiligo, and ankylosing spondylitis (AS). The causal inferences were drawn by integrating results from four regression models: Inverse Variance Weighting (IVW), MR-Egger, Weighted Median, and Maximum Likelihood. Furthermore, we performed sensitivity analyses to confirm the reliability of our findings. Results: The results showed that CD [IVW odds ratio (ORIVW), 1.11; 95% confidence interval (CI), 1.06-1.17; P = 8.40E-06], vitiligo (ORIVW, 1.16; 95% CI, 1.05-1.28; P = 2.45E-03) were risk factors for PsO, while BP may reduce the incidence of PsO (ORIVW, 0.91; 95% CI, 0.87-0.96; P = 1.26E-04). CD (ORIVW, 1.07; 95% CI, 1.02-1.12; P = 0.01), HT (ORIVW, 1.23; 95% CI, 1.08-1.40; P = 1.43E-03), RA (ORIVW, 1.11; 95% CI, 1.02-1.21, P = 2.05E-02), AS (ORIVW, 2.18; 95% CI, 1.46-3.27; P = 1.55E-04), SLE (ORIVW, 1.04; 95% CI, 1.01-1.08; P = 1.07E-02) and vitiligo (ORIVW, 1.27; 95% CI, 1.14-1.42; P = 2.67E-05) were risk factors for PsA. Sensitivity analyses had validated the reliability of the results. Conclusions: Our study provides evidence for potential causal relationships between certain AIDs and both PsO and PsA. Specifically, CD and vitiligo may increase the risk of developing PsO, while CD, HT, SLE, RA, AS, and vitiligo may elevate the risk for PsA. Additionally, it is crucial to closely monitor the condition of PsO patients with specific AIDs, as they have a higher likelihood of developing PsA than those without AIDs. Moving forward, greater attention should be paid to PsA and further exploration of other PsO subtypes is warranted.

Gut microbiota and pancreatic cancer risk, and the mediating role of immune cells and inflammatory cytokines: a Mendelian randomization study.

Introduction: Gut microbiota (GM) influences the occurrence and development of pancreatic cancer (PC), potentially through the involvement of inflammatory cytokines (IC) and immune cells (IM). We aimed to investigate the causal impact of the gut microbiota (GM) on pancreatic cancer (PC) and identify potential IC and IM mediators. Methods: The summary statistics data from whole-genome association studies of gut microbiota, immune cells, inflammatory cytokines, and four types of pancreatic tumors (MNP: Malignant neoplasm of pancreas; BNP: Benign neoplasm of pancreas; ADCP: Adenocarcinoma and ductal carcinoma of pancreas; NTCP: Neuroendocrine tumor and carcinoma of pancreas). Two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and mediation analysis were employed to assess the causal relationship between gut microbiota (GM) and pancreatic cancer (PC), as well as potential IC and IM mediators. Results: The two-sample UVMR analysis showed causal relationships between 20 gut microbiota species and pancreatic cancer, with pancreatic cancer affecting the abundance of 37 gut microbiota species. Mediation analysis revealed that Interleukin-6 (IL-6), "CD4 on naive CD4+ T cell" and "SSC-A on HLA DR+ Natural Killer" mediated the causal effects of gut microbiota on pancreatic cancer. Conclusion: This Mendelian randomization study demonstrates causal relationships between several specific gut microbiota and pancreatic cancer, as well as potential mediators (IC, IM).

Revealing an association between HPV and systemic lupus erythematosus: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: An increasing number of studies have focused on the association between Human papillomavirus (HPV) infection and systemic lupus erythematosus (SLE). However, current evidence is largely based on retrospective studies, which are susceptible to confounding factors and cannot establish causation. METHODS: A bidirectional two-sample Mendelian randomization (MR) design was used to evaluate the causal relationship between HPV and SLE. Mononucleoside polymers (SNPS) with strong evidence for genome-wide association studies (GWAS) were selected from the HPV exposure dataset and used as an instrumental variable (IV) for this study. For the MR Analysis results, the MR-Egger intercept P test, MR-Presso global test, CochranQ test and leave-one test were used for sensitivity analysis. RESULTS: Based on the evidence of MR Analysis, this study finally determined that there was no causal association between HPV16 and HPV18 and SLE. CONCLUSIONS: Possible regulation of HPV infection is not significantly associated with regulation of SLE. These findings provide new insights into the underlying mechanisms of HPV and SLE and need to be validated by further studies.

Circulating inflammatory cytokines and the risk of sepsis: a bidirectional mendelian randomization analysis.

BACKGROUND: Sepsis is a life-threatening condition that is characterized by multiorgan dysfunction and caused by dysregulated cytokine networks, which are closely associated with sepsis progression and outcomes. However, currently available treatment strategies that target cytokines have failed. Thus, this study aimed to investigate the interplay between genetically predicted circulating concentrations of cytokines and the outcomes of sepsis and to identify potential targets for sepsis treatment. METHODS: Data related to 35 circulating cytokines in 31,112 individuals (including 11,643 patients with sepsis) were included in genome-wide association studies (GWASs) from the UK Biobank and FinnGen consortia. A bidirectional two-sample Mendelian randomization (MR) analysis was performed using single nucleotide polymorphisms (SNPs) to evaluate the causal effects of circulating cytokines on sepsis outcomes and other cytokines. RESULTS: A total of 35 inflammatory cytokine genes were identified in the GWASs, and 11 cytokines, including Interleukin-1 receptor antagonist (IL-1ra), macrophage inflammatory protein 1 (MIP1α), IL-16, et al., were associated with sepsis outcome pairs according to the selection criteria of the cis-pQTL instrument. Multiple MR methods verified that genetically predicted high circulating levels of IL-1ra or MIP1α were negatively correlated with genetic susceptibility to risk of sepsis, including sepsis (28-day mortality), septicaemia, streptococcal and pneumonia-derived septicaemia (P ≤ 0.01). Furthermore, genetic susceptibility of sepsis outcomes except sepsis (28-day mortality) markedly associated with the circulating levels of five cytokines, including active plasminogen activator inhibitor (PAI), interleukin 7 (IL-7), tumour necrosis factor alpha (TNF-α), beta nerve growth factor (NGF-ß), hepatic growth factor (HGF) (P < 0.05). Finally, we observed that the causal interaction network between MIP1α or IL-1ra and other cytokines (P < 0.05). CONCLUSIONS: This comprehensive MR analysis provides insights into the potential causal mechanisms that link key cytokines, particularly MIP1α, with risk of sepsis, and the findings suggest that targeting MIP1α may be a potential strategy for preventing sepsis.

Mendelian randomization study on causal association of TEF and circadian rhythm with pulmonary arterial hypertension.

BACKGROUND: Previous research has revealed the potential impact of circadian rhythms on pulmonary diseases; however, the connection between circadian rhythm-associated Thyrotroph Embryonic Factor (TEF) and Pulmonary Arterial Hypertension (PAH) remains unclear. We aim to assess the genetic causal relationship between TEF and PAH by utilizing two sets of genetic instrumental variables (IV) and publicly available Pulmonary Arterial Hypertension Genome-Wide Association Studies (GWAS). METHODS: Total of 23 independent TEF genetic IVs from recent MR reports and PAH GWAS including 162,962 European individuals were used to perform this two-sample MR study. Gain- and loss-of-function experiments were used to demonstrate the role of TEF in PAH. RESULTS: Our analysis revealed that as TEF levels increased genetically, there was a corresponding increase in the risk of PAH, as evidenced by IVW (OR = 1.233, 95% CI: 1.054-1.441; P = 0.00871) and weighted median (OR = 1.292, 95% CI for OR: 1.064-1.568; P = 0.00964) methods. Additionally, the up-regulation of TEF expression was associated with a significantly higher likelihood of abnormal circadian rhythm (IVW: P = 0.0024733, ß = 0.05239). However, we did not observe a significant positive correlation between circadian rhythm and PAH (IVW: P = 0.3454942, ß = 1.4980398). In addition, our in vitro experiments demonstrated that TEF is significantly overexpressed in pulmonary artery smooth muscle cells (PASMCs). And overexpression of TEF promotes PASMC viability and migratory capacity, as well as upregulates the levels of inflammatory cytokines. CONCLUSION: Our analysis suggests a causal relationship between genetically increased TEF levels and an elevated risk of both PAH and abnormal circadian rhythm. Consequently, higher TEF levels may represent a risk factor for individuals with PAH.

Unraveling the causality between gastroesophageal reflux disease and increased cancer risk: evidence from the UK Biobank and GWAS consortia.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common condition characterized by the reflux of stomach contents into the esophagus. Despite its widespread prevalence worldwide, the causal link between GERD and various cancer risks has not been fully established, and past medical research has often underestimated or overlooked this relationship. METHODS: This study performed Mendelian randomization (MR) to investigate the causal relationship between GERD and 19 different cancers. We leveraged data from 129,080 GERD patients and 473,524 controls, along with cancer-related data, obtained from the UK Biobank and various Genome-Wide Association Studies (GWAS) consortia. Single nucleotide polymorphisms (SNPs) associated with GERD were used as instrumental variables, utilizing methods such as inverse variance weighting, weighted median, and MR-Egger to address potential pleiotropy and confounding factors. RESULTS: GERD was significantly associated with higher risks of nine types of cancer. Even after adjusting for all known risk factors-including smoking, alcohol consumption, major depression, and body mass index (BMI)-these associations remained significant, with higher risks for most cancers. For example, the adjusted risk for overall lung cancer was (OR, 1.23; 95% CI: 1.14-1.33), for lung adenocarcinoma was (OR, 1.18; 95% CI: 1.03-1.36), for lung squamous cell carcinoma was (OR, 1.35; 95% CI: 1.19-1.53), and for oral cavity and pharyngeal cancer was (OR, 1.73; 95% CI: 1.22-2.44). Especially noteworthy, the risk for esophageal cancer increased to (OR, 2.57; 95% CI: 1.23-5.37). Mediation analyses further highlighted GERD as a significant mediator in the relationships between BMI, smoking, major depression, and cancer risks. CONCLUSIONS: This study identifies a significant causal relationship between GERD and increased cancer risk, highlighting its role in cancer development and underscoring the necessity of incorporating GERD management into cancer prevention strategies.

Discrepancies between general and central obesity in arterial stiffness: observational studies and Mendelian randomization study.

BACKGROUND: Obesity has been linked to arterial stiffness, while no consensus was reached on the association. We aimed to clarify the association of general and central obesity with arterial stiffness by combining observational studies and Mendelian randomization (MR) study. METHODS: Two cross-sectional studies were performed in UK Biobank and Fuqing Cohort, respectively. Two-sample MR study was conducted using summary data of GWASs from GIANT consortium and UK Biobank. General obesity and central obesity were measured using body mass index (BMI) and waist circumference (WC), respectively. Arterial stiffness was measured by arterial stiffness index (ASI) in UK Biobank or branchial-ankle pulse wave velocity (baPWV) in Fuqing Cohort. RESULTS: Two observational studies found a consistent positive association of BMI and WC with arterial stiffness when adjusting for age, sex, education, smoking, alcohol drinking, physical activity, and LDL cholesterol. However, when additionally adjusting for metabolic traits (i.e., systolic blood pressure, diastolic blood pressure, blood glucose, triglycerides, high-density lipoprotein cholesterol, and WC or BMI), the association with BMI changed to be inverse. As compared to the lowest quintile group, the adjusted ORs across groups of second to fifth quintile were 0.93, 0.90, 0.83, and 0.72 in UK Biobank and 0.88, 0.65, 0.63, and 0.50 in Fuqing Cohort. In contrast, the positive relationship with WC remained stable with the adjusted ORs of 1.23, 1.46, 1.60, and 1.56 in UK Biobank and 1.35, 1.44, 1.77, and 1.64 in Fuqing Cohort. MR analyses provided supportive evidence of the negative association with BMI (OR = 0.97, 95%CI = 0.94-1.00) and the positive association with WC (OR = 1.14, 95%CI = 1.08-1.20). CONCLUSIONS: Observational and genetic analyses provide concordant results that central obesity is independently related to arterial stiffness, while the role of general obesity depends on metabolic status.

Gastroesophageal reflux disease increases the risk of rheumatoid arthritis: a bidirectional two-sample Mendelian randomization study.

Rheumatoid arthritis (RA) is a common autoimmune disease, and some observational studies have indicated an association between Gastroesophageal Reflux Disease (GERD) and RA. However, the causal relationship between the two remains uncertain. We used Mendelian randomization (MR) to assess the causal relationship between GERD and RA. Two-sample Mendelian randomization analysis was performed using pooled data from large-scale genome-wide association studies. In addition, we performed multivariate MR analyses to exclude confounding factors between GERD and RA, including smoking quantity, drinking frequency, BMI, depression, and education attainment. The MR results for GERD on RA suggested a causal effect of the genetic susceptibility of GERD on RA (discovery dataset, IVW, odds ratio [OR] = 1.41, 95% confidence interval [CI] 1.22-1.63, p = 2.81 × 10-6; validation dataset, IVW, OR = 1.38, 95% CI 1.23-1.55, P = 1.76 × 10-8). Multivariate MR analysis also supports this result. But the results of the reverse MR analysis did not reveal compelling evidence that RA can increase the risk of developing GERD. Our bidirectional Two-Sample Mendelian randomization analysis and multivariate MR analysis provide support for the causal effect of GERD on RA. This discovery could offer new insights for the prevention and treatment of RA.

Deciphering the genetics and mechanisms of predisposition to multiple myeloma.

Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.

Large-scale genetic correlation studies explore the causal relationship and potential mechanism between gut microbiota and COVID-19-associated risks.

Recent observational studies suggest that gut microorganisms are involved in the onset and development of coronavirus disease 2019 (COVID-19), but the potential causal relationship behind them remains unclear. Exposure data were derived from the MiBioGen consortium, encompassing 211 gut microbiota (n = 18,340). The outcome data were sourced from the COVID-19 host genetics initiative (round 7), including COVID-19 severity (n = 1,086,211), hospitalization (n = 2,095,324), and susceptibility (n = 2,597,856). First, a two-sample Mendelian randomization (TSMR) was performed to investigate the causal effect between gut microbiota and COVID-19 outcomes. Second, a two-step MR was used to explore the potential mediators and underlying mechanisms. Third, several sensitivity analyses were performed to verify the robustness of the results. Five gut microbes were found to have a potential causality with COVID-19 severity, namely Betaproteobacteria (beta = 0.096, p = 0.034), Christensenellaceae (beta = -0.092, p = 0.023), Adlercreutzia (beta = 0.072, p = 0.048), Coprococcus 1 (beta = 0.089, p = 0.032), Eisenbergiella (beta = 0.064, p = 0.024). Seven gut microbes were found to have a potential causality with COVID-19 hospitalization, namely Victivallaceae (beta = 0.037, p = 0.028), Actinomyces (beta = 0.047, p = 0.046), Coprococcus 2 (beta = -0.061, p = 0.031), Dorea (beta = 0.067, p = 0.016), Peptococcus (beta = -0.035, p = 0.049), Rikenellaceae RC9 gut group (beta = 0.034, p = 0.018), and Proteobacteria (beta = -0.069, p = 0.035). Two gut microbes were found to have a potential causality with COVID-19 susceptibility, namely Holdemanella (beta = -0.024, p = 0.023) and Lachnospiraceae FCS020 group (beta = 0.026, p = 0.027). Multi-omics mediation analyses indicate that numerous plasma proteins, metabolites, and immune factors are critical mediators linking gut microbiota with COVID-19 outcomes. Sensitivity analysis suggested no significant heterogeneity or pleiotropy. These findings revealed the causal correlation and potential mechanism between gut microbiota and COVID-19 outcomes, which may improve our understanding of the gut-lung axis in the etiology and pathology of COVID-19 in the future.

Causal association between Helicobacter pylori infection and Sjogren's syndrome: a bidirectional Mendelian randomization analysis.

BACKGROUND: The results of observational studies indicate a potential link between Helicobacter pylori infection and Sjogren's syndrome (SS), but the causal relationship between them remains unknown. This study applied Mendelian randomization (MR) to evaluate this relationship. METHOD: Genome-wide association study (GWAS) summary statistics on H. pylori infection [sample size=8735 (EBI, https://gwas.mrcieu.ac.uk/ )] and SS [sample size=368,028 (cases=2495, controls=365533) (FinnGen, https://r9.finngen.fi/ )] were analyzed. We used bidirectional MR to evaluate the association between H. pylori infection and SS and identify causation. The major MR analysis method was inverse-variance weighted (IVW) MR, supplemented by MR‒Egger and weighted median approaches. In addition, the stability and reliability of the results were tested using the retention method, heterogeneity test, and horizontal gene pleiotropy test. RESULTS: Evidence of the impact of H. pylori infection on SS risk was found in the IVW results [odds ratio (OR)=1.6705; 95% confidence interval (CI)=1.0966 to 2.5446; P=0.0168]. Evidence of the impact of SS on H. pylori infection risk was also found (OR=1.0158; 95% CI=1.0033 to 1.0285; P=0.0128). CONCLUSION: The results of MR analysis support a causal association between H. pylori infection and SS and indicate that SS can lead to a greater risk of H. pylori infection. Our research will support the development of novel approaches for continued H. pylori and SS-related research and therapy that consider the genetic relationship between H. pylori infection and SS.

Causal role of immune cells in aplastic anemia: Mendelian randomization (MR) study.

Prior research has identified associations between immune cells and aplastic anaemia (AA); however, the causal relationships between them have not been conclusively established. A two-sample Mendelian randomisation analysis was conducted to investigate the causal link between 731 immune cell signatures and AA risk using publicly available genetic data. Four types of immune signatures, including relative cell, absolute cell (AC), median fluorescence intensities and morphological parameters, were considered sensitivity analyses were also performed to verify the robustness of the results and assess potential issues such as heterogeneity and horizontal pleiotropy. Following multiple test adjustments using the False Discovery Rate (FDR) method, no statistically significant impact of any immunophenotype on AA was observed. However, twelve immunophenotypes exhibited a significant correlation with AA without FDR correction (p of IVW < 0.01), of which eight were harmful to AA: CD127- CD8br %T cell (Treg panel), CD25 on IgD + CD38dim (B cell panel), CD38 on naive-mature B cell (B cell panel), CD39 + resting Treg % CD4 Treg (Treg panel), CD39 + secreting Treg AC (Treg panel), CD8 on CD28 + CD45RA- CD8br (Treg panel), HLA DR + NK AC (TBNK panel), Naive DN (CD4-CD8-) AC (Maturation stages of T cell panel); and four were protective to AA: CD86 on CD62L + myeloid DC (cDC panel), DC AC (cDC panel), DN (CD4-CD8-) NKT %T cell (TBNK panel), and TD CD4 + AC (Maturation stages of T cell panel). The results of this study demonstrate a close link between immune cells and AA by genetic means, thereby improving the current understanding of the interaction between immune cells and AA risk and providing guidance for future clinical research.

Unveiling the association between HMG-CoA reductase inhibitors and bladder cancer: a comprehensive analysis using Mendelian randomization, animal models, and transcriptomics.

This study utilized Mendelian randomization (MR) analysis and genome-wide association study (GWAS) data to investigate the association between commonly prescribed drugs and bladder cancer (BLCA) risk. Our results revealed that HMG CoA reductase (HMGCR) inhibitors, specifically simvastatin, are significantly associated with reduced BLCA risk. We further showed that simvastatin could significantly inhibit BLCA proliferation and epithelial-mesenchymal transition in animal models, with transcriptomic data identifying several pathways associated with these processes. Higher expression of HMGCR were linked with BLCA development and progression, and certain blood lipids, such as lipoprotein particles and very low density lipoprotein (VLDL) cholesterol, might influence BLCA risk. These findings suggested that HMGCR inhibitors, particularly simvastatin, could be potential treatment options or adjuvant therapies for BLCA.

Causal effects of plasma metabolites on chronic kidney diseases and renal function: a bidirectional Mendelian randomization study.

Background: Despite the potential demonstrated by targeted plasma metabolite modulators in halting the progression of chronic kidney disease (CKD), a lingering uncertainty persists concerning the causal relationship between distinct plasma metabolites and the onset and progression of CKD. Methods: A genome-wide association study was conducted on 1,091 metabolites and 309 metabolite ratios derived from a cohort of 8,299 unrelated individuals of European descent. Employing a bidirectional two-sample Mendelian randomization (MR) analysis in conjunction with colocalization analysis, we systematically investigated the associations between these metabolites and three phenotypes: CKD, creatinine-estimated glomerular filtration rate (creatinine-eGFR), and urine albumin creatinine ratio (UACR). In the MR analysis, the primary analytical approach employed was inverse variance weighting (IVW), and sensitivity analysis was executed utilizing the MR-Egger method and MR-pleiotropy residual sum and outlier (MR-PRESSO). Heterogeneity was carefully evaluated through Cochrane's Q test. To ensure the robustness of our MR results, the leave-one-out method was implemented, and the strength of causal relationships was subjected to scrutiny via Bonferroni correction. Results: Our thorough MR analysis involving 1,400 plasma metabolites and three clinical phenotypes yielded a discerning identification of 21 plasma metabolites significantly associated with diverse outcomes. Specifically, in the forward MR analysis, 6 plasma metabolites were determined to be causally associated with CKD, 16 with creatinine-eGFR, and 7 with UACR. Substantiated by robust evidence from colocalization analysis, 6 plasma metabolites shared causal variants with CKD, 16 with creatinine-eGFR, and 7 with UACR. In the reverse analysis, a diminished creatinine-eGFR was linked to elevated levels of nine plasma metabolites. Notably, no discernible associations were observed between other plasma metabolites and CKD, creatinine-eGFR, and UACR. Importantly, our analysis detected no evidence of horizontal pleiotropy. Conclusion: This study elucidates specific plasma metabolites causally associated with CKD and renal functions, providing potential targets for intervention. These findings contribute to an enriched understanding of the genetic underpinnings of CKD and renal functions, paving the way for precision medicine applications and therapeutic strategies aimed at impeding disease progression.

Causal relationship between gut microbiota, plasma metabolites, inflammatory cytokines and abdominal aortic aneurysm: a Mendelian randomization study.

BACKGROUND: Complex interconnections are evident among gut microbiota, circulating metabolites, inflammatory cytokines, and the pathogenesis of abdominal aortic aneurysms (AAA), with the causal dynamics yet to be comprehensively elucidated. The primary objective of this study was to elucidate the potential causal relationships involving gut microbiota-mediated plasma metabolites, inflammatory cytokines, and AAA. METHODS: We utilized data from genome-wide association studies predominantly comprising individuals of European ancestry, encompassing four major gut microbiota signatures, 233 plasma metabolite signatures (N = 136,016), 91 inflammatory cytokine signatures (N = 14,824), and AAA signatures (N = 1,458,875). Mendelian randomization (MR), employed in a two-sample format, was utilized as a tool to investigate the potential causal pathways from gut microbiota to the development of AAA. Additionally, a two-step MR approach was employed to dissect the impact of plasma metabolites and inflammatory cytokines on the relationship between gut microbiota and AAA and to ascertain the mediated fractions. RESULTS: Our findings indicate that five phylum or family-identical bacteria, 175 plasma metabolites, and seven inflammatory factors are causally associated with AAA. Among them, five bacterial species from the same phylum or family, identified from different GWAS data, were strongly associated with AAA. Of these, two exhibited negative causality and three exhibited positive causality. We found that the phylum Firmicutes and the families Oscillospiraceae might reduce the risk of AAA, whereas the families Prevotellaceae, Sutterellaceae, and Aminobacteriaceae might increase the risk of AAA. Further screening indicated that phylum Firmicutes id.1672 (GCST90017114) may confer a protective effect against AAA by reducing triglyceride levels in medium/small high-density lipoprotein (HDL). CONCLUSION: MR analysis has delineated a causal pathway from gut microbiota, through plasma circulating metabolites and inflammatory cytokines, to the pathogenesis of AAA. The role of intestinal flora and certain biomarkers may provide a reference for the diagnosis of AAA, and contribute to the prevention, diagnosis, and treatment of AAA disease.

The causal relationship between androgenetic alopecia and serum uric acid: A bidirectional Mendelian randomization analysis.

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. CONCLUSION: 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.