Bidirectional Two-sample Mendelian Randomization Research Articles

The genetic link between thyroid dysfunction and alopecia areata: a bidirectional two-sample Mendelian randomization study.

Although descriptive studies have found an association between thyroid dysfunction (TD) and alopecia areata (AA), however, the causal relationship between TD and AA remains unclear. The purpose of this studyis to investigate the causal relationship between the two and the specific directions. We performed large-scale, two-sample Mendelian randomization (MR) analyses to examine whether there was an association between TD (such as Graves' disease (GD), Hashimoto's thyroiditis (HT), thyroid cancer (TC), thyroid stimulating hormone (TSH), thyrotropin-releasing hormone (TRH), etc.) and AA. Genome-wide association study (GWAS) summary statistics for TD and AA were from the IEU OpenGwas project. The inverse variance-weighted (IVW) method was used as the primary analysis method to evaluate the causality between TD and AA, supplemented by the weighted median, MR-Egger, simple mode and weighted mode. In addition, sensitivity analyses were performed to assess the reliability of the study results. Our study found that single nucleotide polymorphisms (SNPs) in HT (IVW OR = 1.396, 95% CI 1.030-1.892, P=0.031) and hypothyroidism (IVW OR = 1.431, 95% CI 1.138-1.799, P=0.002) significantly increased the risk of AA. Reverse MR analysis indicated that genetic susceptibility to AA (β=-0.029, 95%CI=-0.051 to -0.007, P=0.009) may be a risk for TRH. Positive MR analysis observed no statistically significant causal relationship between other TD and AA (IVW P>0.05). Reverse MR analysis also showed no statistically significant association between AA and other TD (IVW P>0.05) other than TRH. Furthermore, additional sensitivity analyses were performed, including a leave-one-out test, a heterogeneity test, and a pleiotropy test to assess the robustness of the results. This study provides a very comprehensive analysis of the causal relationship between TD and AA, providing convincing genetic evidence to support the causal relationship between TD and alopecia areata. It reveals some causes of AA patients, which is of great significance for the management and treatment of AA patients.

Causal effect of lifestyle and metabolic indicator with herpes zoster: a two-sample Mendelian randomization study.

Previous observational studies have reported certain causal relationships between factors such as smoking, alcohol consumption, obesity, physical activity, metabolic disorders, and the incidence of herpes zoster (HZ). However, there is controversy regarding the observed results across different studies. Our objective was to investigate the causal effects of these risk factors on the risk of herpes zoster through a Mendelian randomization analysis using two-sample bidirectional approaches. We conducted two-sample bidirectional Mendelian randomization analyses to explore the causal relationships between different lifestyles, obesity assessment indices, metabolic indicators, and the risk of herpes zoster. All exposure and outcome data were sourced from publicly available data from genome-wide association studies. In the inverse-variance weighted (IVW) analysis, body mass index (BMI) (OR: 1.160, 95% CI: 1.030-1.307, p = 0.014), Body fat percentage (BFP) (OR: 1.241, 95% CI: 1.050-1.467, p = 0.011), and whole body fat mass (WBFM) (OR: 1.199, 95% CI: 1.057-1.362, p = 0.005) exhibited positive associations with the risk of HZ. However, usual walking pace (UWP) (OR: 0.498, 95% CI: 0.254-0.976, p = 0.042) demonstrated a significant negative correlation with HZ risk. Other factors including alcohol intake frequency, smoking initiation, smoking status, insomnia, and sleep duration did not show significant causal relationships with HZ. Mendelian randomization studies revealed that BMI, BFP, and WBFM are risk factors for HZ. UWP showed a protective effect against HZ. These findings provide a straightforward method for evaluating future clinical practices aiming to develop personalized management strategies and assess high-risk populations for HZ.

Platelet traits and sepsis risk and prognosis: a bidirectional two-sample Mendelian randomization study.

Sepsis is a critical medical condition characterized by a dysregulated host response to infection. Platelet abnormalities frequently manifest in sepsis patients, but the causal role of platelets in sepsis remains unclear. This study employed a bidirectional two-sample Mendelian randomization (MR) approach to investigate the causal direction between platelets and sepsis. MR analysis was used to investigate the causal effect of four platelet traits - platelet count (PLT), platelet crit (PCT), mean platelet volume (MPV), and platelet distribution width (PDW)- on sepsis risk and prognosis. Additionally, the study explored the reverse causality, assessing the impact of sepsis on these platelet traits. Genetic variants from large-scale genome-wide association studies (GWAS) served as instrumental variables to infer causality. Sensitivity analyses and heterogeneity tests were conducted to ensure the validity and robustness of the results. Genetically predicted decreased PCT (OR = 0.938, p = 0.044) and MPV (OR = 0.410, p = 0.006) were associated with an increased risk of sepsis. In the reverse direction, 28-day sepsis mortality was significantly associated with decreased PLT (OR = 0.986, p = 0.034). No significant causal relationships were observed between sepsis and other platelet traits. This study suggests a causal association between low PCT and MPV levels and increased risk of sepsis. Additionally, sepsis with a poor prognosis was causally linked to decreased PLT. These findings provide novel evidence for the causal relationship between platelet traits and sepsis.

Circulating inflammatory cytokines and gestational diabetes mellitus: Unraveling the role of macrophage migration inhibitory factor (MIF) through a bidirectional mendelian randomization study

BackgroundSeveral studies have identified associations between some of circulating inflammatory cytokines and gestational diabetes mellitus (GDM). However, the causal role of these associations remains unclear and unsystematic. We aimed to provide evidence for the causal relationships between circulating inflammatory cytokines and gestational diabetes mellitus. MethodsWe performed bidirectional two-sample Mendelian randomization (2SMR) to investigate the causal connection between circulating inflammatory cytokines and gestational diabetes mellitus. Publicly accessible data for circulating inflammatory cytokines (8,293 individuals) and gestational diabetes mellitus (123,579 individuals) were obtained from genome-wide association study (GWAS). ResultsOnly one causal association was identified between circulating inflammatory cytokines and GDM. The inverse variance weighting (IVW) method showed that macrophage migration inhibitory factor (MIF) increased the risk of GDM (OR 1.162, 95%CI 1.044,1.293). Moreover, two causal associations were detected between GDM and circulating inflammatory cytokines. GDM was negatively correlated with interferon gamma-induced protein 10 (IP10) (Beta −0.129, 95%CI −0.236,-0.231) and interleukin-18 (IL18) (Beta −0.133, 95%CI −0.241,-0.026). ConclusionMendelian randomization study revealed MIF as a risk factor for gestational diabetes mellitus. This finding offers a new and valuable insight into the pathophysiological mechanisms underlying GDM.

Plasma Proteomes and Genome-Wide Association Data for Causal Protein Identification in Stroke.

Plasma proteins are promising biomarkers and potential drug targets for stroke. This study aimed to explore whether there is a causal relationship between plasma proteins and subtypes of stroke using a Mendelian randomization (MR) approach. A two-sample bidirectional Mendelian randomization approach was employed to investigate the causal link between plasma proteins and stroke. Data on plasma proteins were obtained from three studies, including INTERVAL, and pooled stroke information was sourced from the MEGASTROKE consortium and the UK Biobank dataset, covering four subtypes of stroke. MR analyses were primarily conducted using inverse variance weighting, and sensitivity analyses were also performed. Finally, potential reverse causality was assessed using bidirectional MR. We identified two proteins causally associated with stroke: one as a potential therapeutic target and another as a protective factor. CXCL8 was found to be positively associated with the risk of developing large-artery atherosclerotic (LAA) stroke (OR, 1.005; 95% CI 1.001 to 1.010; p = 0.022), whereas TNFRSF11b was negatively correlated with the risk of developing LAA stroke (OR, 0.937; 95% CI 0.892 to 0.984; p = 0.010), independently of other stroke subtypes. Reverse bivariate analysis did not indicate that ischemic stroke was causally associated with CXCL8 and TNFRSF11b. There is a causal relationship between CXCL8 and TNFRSF11b with LAA stroke, independent of other subtypes. This study offers a new perspective on the genetics of stroke.

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

BackgroundSepsis 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.MethodsData 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.ResultsA 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-β), 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).ConclusionsThis 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.

Unraveling the association between gut microbiota and chemotherapy efficacy: a two-sample Mendelian randomization study.

Emerging evidence has underscored the complex link between gut microbiota and chemotherapy efficacy; however, establishing causality remains elusive due to confounding factors. This study, leveraging bidirectional two-sample Mendelian randomization (MR) analyses, explores the casual relationship between gut microbiota and chemotherapy efficacy. Utilizing genome-wide association study (GWAS) data from the MiBioGen consortium for gut microbiota and IEU Open GWAS for chemotherapy efficacy, we employed genetic variants as instrumental variables (IVs). The inverse variance weighted (IVW) method, weighted median estimator (WME), and MR-Egger regression method were applied, with sensitivity analyses ensuring robustness. Furthermore, we conducted reverse MR analyses between chemotherapy efficacy and identified significant gut microbial taxa. The results indicated that genus Butyricicoccus (OR = 3.7908, 95% CI: 1.4464-9.9350, P = 0.01), Dorea (OR = 3.3295, 95% CI: 1.2794-8.6643, P = 0.01), Hungatella (OR = 2.6284, 95% CI: 1.0548-6.5498, P = 0.04), and Turicibacter (OR = 2.5694, 95% CI: 1.0392-6.3526, P = 0.04) were positively associated with chemotherapy efficacy using the IVW method. Conversely, family Porphyromonadaceae (OR = 0.2283, 95% CI: 0.0699-0.7461, P = 0.01) and genus Eggerthella (OR = 0.4953, 95% CI: 0.2443-1.0043, P = 0.05) exhibited negative associations. WME demonstrated consistent results with IVW method only for genus Eggerthella (OR = 0.3343, 95% CI: 0.1298-0.8610, P = 0.02). No significant heterogeneity or horizontal pleiotropy was observed. Reverse MR analyses revealed no significant causal effect of chemotherapy on identified gut microbiota. This study sheds light on the intricate relationship between gut microbiota, with a particular emphasis on the genus Eggerthella, and chemotherapy efficacy, offering valuable insights for refining cancer treatment strategies.IMPORTANCEGlobal advancements in cancer treatment, particularly in chemotherapy, have notably decreased mortality rates in recent years. However, the correlation between gut microbiota and chemotherapy efficacy remains elusive. Our study, emphasizing the role of genus Eggerthella, represented a crucial advance in elucidating this intricate interplay. The identified associations offer potential therapeutic targets, contributing to global efforts for enhanced treatment precision and improved patient outcomes. Furthermore, our findings hold promise for personalized therapeutic interventions, shaping improved strategies in the ever-evolving landscape of cancer treatment.

Causal roles of skin microbiota in skin cancers suggested by genetic study.

There is evidence from observational studies that skin microbiota is linked to skin cancers. Nevertheless, the causal association between skin microbiota and skin cancers is yet to be fully clarified. A bidirectional two-sample Mendelian randomization (MR) was performed to determine the causal relationship between skin microbiota and skin cancers. A total of 294 skin microbial taxa were identified from the first genome-wide association study across three skin microenvironments of two German population cohorts. Summary data of three skin cancers (malignant melanoma, squamous cell carcinoma, and basal cell carcinoma) were obtained from the FinnGen consortium. Moreover, sensitivity analysis examined horizontal pleiotropy and heterogeneity, and microenvironment-based meta-analysis confirmed the reliability of the results. We identified 65 nominal causalities and 5 strong causal associations between skin microbiota and skin cancers. Among them, the class Bacilli revealed a bidirectional positive relationship with malignant melanoma. The class Betaproteobacteria and class Gammaproteobacteria demonstrated a causal association with an elevated risk of malignant melanoma and basal cell carcinoma, respectively. In the reverse MR analysis, malignant melanoma was associated with a lower abundance of phylum Bacteroidetes. There were no indications of significant heterogeneity in instrumental variables or evidence of horizontal pleiotropy. Our MR analysis indicated bidirectional causal associations between skin microbiota and skin cancers, and had the potential to offer novel perspectives on the mechanistic of microbiota-facilitated carcinogenesis.

Genetic insights into the gut microbiota and risk of psoriasis: a bidirectional mendelian randomization study.

Growing evidence indicates a potential association between the gut microbiome and psoriasis. Nevertheless, the precise nature of these associations and whether they constitute causal relationships remain unclear. A rigorous bidirectional two-sample Mendelian randomization study was undertaken to establish a putative causal link between gut microbiota and psoriasis. We drew upon publicly available datasets containing summary statistics from GWAS to accomplish this. Utilizing various analytical techniques, including inverse variance weighting, MR-Egger, weighted median, weighted model, and MR-PRESSO, we sought to validate the putative causal association between gut microbiota and psoriasis. A reverse Mendelian randomization analysis was conducted to further investigate the relationship. After conducting a forward Mendelian randomization analysis, a causal relationship was established between 19 gut microbiota and psoriasis. Furthermore, the reverse MR study revealed causality between psoriasis and 13 gut microbiota. Notably, no substantial heterogeneity of instrumental variables or horizontal pleiotropy was observed. This research suggests a potential genetic association and causal nexus between gut microorganisms and psoriasis, indicating potential implications for the clinical management and therapy of psoriasis. Additional observational studies with a larger population sample size and animal model experiments are imperative to fully elucidate this association's underlying mechanisms.

Bidirectional two-sample Mendelian randomization analysis identifies causal associations between migraine and five psychiatric disorders.

The question of whether a correlation exists between migraine and five psychiatric disorders, including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), anorexia nervosa (AN), bipolar disorder (BIP), and schizophrenia (SCZ), remains a matter of controversy. Hence, this research aims to investigate whether there is a possible association between migraine and five psychiatric disorders. We performed a bidirectional 2-sample Mendelian randomization (MR) analysis to assess the causality between migraine and five psychiatric disorders. Genetic associations of PTSD, MDD, AN, BIP, and SCZ were obtained from the Psychiatric Genomics Consortium (PGC) database and genetic associations of migraine with aura and migraine without aura were obtained from the FinnGen dataset. We used the inverse-variance weighted (IVW), weighted median, weighted mode, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and MR Egger regression methods to evaluate the association of genetically predicted exposure with the risk of outcome. MR demonstrated that MDD was associated with a high risk of migraine without aura (OR = 1.930578, 95% confidence interview (CI): 1.224510, 3.043550, p < 0.05), but BIP was related to a low risk of migraine without aura (OR = 0.758650, 95%CI: 0.639601, 0.899858, p < 0.05). According to the results of reverse MR, migraine with aura was associated with a high risk of BIP (OR = 1.019100, 95%CI: 1.002538, 1.035935, p < 0.05), and migraine without aura was associated with an increased risk of AN (OR = 1.055634, 95%CI: 1.023859, 1.088394, p < 0.05). Our results provide evidence of the potential causal association between migraine and some psychiatric disorders. It may contribute to the prevention of migraine and some psychiatric disorders.

Exploring the causal relationships between cholelithiasis, cholecystitis, cholecystectomy, and gastroesophageal reflux disease: A bidirectional two-sample mendelian randomization study.

Biliary disorders and gastroesophageal reflux disease (GERD) frequently coexist. However, precise linkages between these conditions remain to be clarified. Univariable Mendelian randomization (MR), Bayesian weighted MR (BWMR) along with multivariable MR approaches were conducted using genetic instruments to evaluate the causality involving biliary disorders and GERD. Furthermore, an investigation was conducted on the potential mediating roles of biliary disorders (or GERD), on the linkage involving body mass index (BMI) and GERD (or biliary disorders). Univariable MR analyses revealed significant causal effects of genetically predicted cholelithiasis (odds ratio (OR)=1.04, P=0.0001), cholecystitis (OR=1.06, P=0.0004), and cholecystectomy (OR=2.56, P=1.05×10-6) on GERD. These findings were replicated in the FinnGen cohort and were also confirmed by BWMR and multivariable MR analyses. Additionally, mediation analyses demonstrated that cholelithiasis and cholecystitis acted as partial mediators, linking BMI causally to GERD. Conversely, GERD exhibited causal effect on cholelithiasis (OR=1.52, P=9.17×10-30) and cholecystitis (OR=1.90, P=3.32×10-28), which remained significant after BWMR and multivariable MR analyses. Mediation analyses further revealed significant mediating effect of GERD on how BMI influenced cholelithiasis/cholecystitis. Our study elucidates the bidirectional causal linkages involving cholelithiasis, cholecystitis, cholecystectomy, and GERD. These results highlight the significance of GERD risk assessment in individuals suffering from biliary diseases and vice versa.

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.

Identifying the genetic association between the cerebral cortex and fibromyalgia.

Fibromyalgia (FM) is a central sensitization syndrome that is strongly associated with the cerebral cortex. This study used bidirectional two-sample Mendelian randomization (MR) analysis to investigate the bidirectional causality between FM and the cortical surface area and cortical thickness of 34 brain regions. Inverse variance weighted (IVW) was used as the primary method for this study, and sensitivity analyses further supported the results. The forward MR analysis revealed that genetically determined thinner cortical thickness in the parstriangularis (OR = 0.0567mm, PIVW = 0.0463), caudal middle frontal (OR = 0.0346mm, PIVW = 0.0433), and rostral middle frontal (OR = 0.0285mm, PIVW = 0.0463) was associated with FM. Additionally, a reduced genetically determined cortical surface area in the pericalcarine (OR = 0.9988mm2, PIVW = 0.0085) was associated with an increased risk of FM. Conversely, reverse MR indicated that FM was associated with cortical thickness in the caudal middle frontal region (β = -0.0035mm, PIVW = 0.0265), fusiform region (β = 0.0024mm, SE = 0.0012, PIVW = 0.0440), the cortical surface area in the supramarginal (β = -9.3938mm2, PIVW = 0.0132), and postcentral regions (β = -6.3137mm2, PIVW = 0.0360). Reduced cortical thickness in the caudal middle frontal gyrus is shown to have a significant relationship with FM prevalence in a bidirectional causal analysis.

Association of vitamin D with risk of warts: A retrospective and Mendelian randomization study.

The clinical strategy of oral supplementation of Vitamin D (VD) as a preventive and therapeutic measure for warts needs further exploration. The clinical data of patients with skin diseases who visited the Children's Hospital affiliated with Chongqing Medical University from February 2018 to June 2024 were collected. The serum VD levels in patients with warts (common warts, flat warts, and plantar warts) and patients with other common skin diseases (atopic dermatitis, psoriasis, alopecia areata, vitiligo, and chronic urticaria) were compared. Two-sample bidirectional Mendelian randomization (MR) analysis was performed to investigate potential causal associations between VD and warts. The average serum VD level of children with warts was 23.27±7.07ng/mL, which showed no statistically significant difference compared to children with other common skin diseases. The inverse variance weighted (IVW) method analysis indicated a positive causal relationship between VD and warts (Odds Ratio [OR]=1.86, [95% CI: 1.19-2.92], p=0.007). Sensitivity analysis did not show any indication of horizontal pleiotropy or heterogeneity. The MR-PRESSO method did not identify any outliers. The levels of serum VD in children with warts do not significantly decrease compared to children with other common skin conditions. The evidence from the MR analysis indicates a positive causal relationship between VD and warts, suggesting caution in supplementing VD for children with warts who have normal or elevated serum VD levels. Further clinical studies are needed for validation in the future.

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

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. 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. Based on the evidence of MR Analysis, this study finally determined that there was no causal association between HPV16 and HPV18 and SLE. 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.

Exploring causal correlations between blood inflammatory cytokines and low back pain: a Mendelian randomization

PurposeLow back pain (LBP) is a common and recurring public health problem that affects sufferers both physically and mentally and warrants further research. A succession of studies have suggested a plausible role for inflammatory cytokines in the pathogenesis of LBP. To date, there is no conclusive mechanism explaining how inflammatory cytokines affects LBP.MethodsA bidirectional two-sample Mendelian randomization (MR) investigation was undertaken in two stages. The initial phase encompassed 41 inflammatory cytokines as the exposure, with LBP as the outcome, and the subsequent phase adopted the inverse approach. A total of 41 blood inflammatory cytokines were extracted from the genome-wide association study meta-analysis database, encompassing 8,293 individuals. Data pertaining to LBP were acquired from the Finnish biobank. Primary findings were computed using inverse-variance weighting (IVW), while sensitivity analyses accounting for pleiotropy and invalid instruments were conducted utilizing the weighted-median estimator, MR-Egger, and MR Pleiotropy RESidual Sum and Outlier.ResultsOur results suggest that higher levels of Macrophage migration inhibitory factor (MIF) as well as lower levels of C-C motif chemokine ligand 3 (CCL3) are associated with an increased risk of LBP (odds ratio [OR] = 1.134, 95% confidence interval [CI ]= 1.032–1.245, P = 0.009; OR = 0.887, 95% CI = 0.803–0.980, P = 0.018). Moreover, there was no heterogeneity and horizontal pleiotropy observed in the sensitivity analysis. In contrast, in studies of the effect of LBP on inflammatory cytokines, genetically determined LBP had no causal effect on 41 inflammatory cytokines (IVW P > 0.05).ConclusionsOur study confirms that the levels of circulating MIF and CCL3 may be regarded as valuable circulating inflammatory biomarkers for the management of LBP in clinical practice and as potential molecules for future mechanistic investigation and drug target identification.

Associations between immune cell traits and autoimmune thyroid diseases: a bidirectional two-sample mendelian randomization study.

Autoimmune thyroid diseases (AITDs), mainly including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are common autoimmune disorders characterized by abnormal immune responses targeting the thyroid gland. We conducted a bidirectional two-sample MR analysis using the largest dataset of peripheral immune cell phenotypes from Sardinia, and the AITD dataset from the 10th round of the FinnGen and the UK Biobank project. Instrumental variables (IVs) were rigorously selected based on the three assumptions of MR and analyzed using the Wald ratio, inverse-variance weighted (IVW), MR-Egger, and weighted median methods. Additionally, sensitivity analyses were performed using Cochrane's Q, the Egger intercept, the MR-PRESSO, and the leave-one-out (LOO) method to ensure the robustness of the results. The Steiger test was utilized to identify and exclude potential reverse causation. The results showed that 3, 3, and 11 immune cell phenotypes were significantly associated with the risk of AITD. In GD, the proportion of naive CD4-CD8- (DN) T cells in T cells and the proportion of terminally differentiated CD4+T cells in T cells showed the strongest inducing and protective effects, respectively. In HT, lymphocyte count and CD45 on CD4+T cells showed the strongest inducing and protective effects, respectively. In autoimmune hypothyroidism, CD127 CD8+T cell count and terminally differentiated DN T cell count exhibited the strongest inducing and protective effects, respectively. Through MR analysis, our study provides direct genetic evidence of the impact of immune cell traits on AITD risk and lays the groundwork for potential therapeutic and diagnostic target discovery.

A commentary on 'Complex causal association between genetically predicted 731 immunocyte phenotype and osteonecrosis: a bidirectional two-sample Mendelian randomization analysis'.

A commentary on 'Complex causal association between genetically predicted 731 immunocyte phenotype and osteonecrosis: a bidirectional two-sample Mendelian randomization analysis'.

Association between cathepsins and skin cancers: A bidirectional two-sample Mendelian randomization study.

Several cathepsins have been identified as being involved in the development of cancer. Nevertheless, the connection between cathepsins and skin cancers remained highly elusive. A bidirectional Mendelian randomization (MR) analysis was performed to investigate the causal association between cathepsins and skin malignancies. The genome-wide association studies (GWAS) data for cathepsins, malignant melanoma (MM), and basal cell carcinoma (BCC) were obtained from European research. The primary method employed was inverse variance weighted. In addition, MR-Egger, weighted median, weighted mode, and simple mode were also executed. Sensitivity analysis was performed using Cochran's Q test, MR-Egger, and MR-PRESSO. From univariable MR (UVMR), cathepsin H, and S were determined to have a causal relationship with BCC. Additionally, cathepsin H was identified as associated with MM. Multivariable MR (MVMR) showed that after correcting for risk factors of skin carcinoma, cathepsin H was detected to be protective against BCC, whereas cathepsin S has been observed as a risk factor for BCC. No substantial pleiotropy and heterogeneity were identified in the sensitivity analysis. This study was the first to establish a direct link between cathepsins and skin malignancies. Cathepsin H and S have the potential to serve as new biomarkers for BCC, offering valuable assistance in the prompt identification, treatment, and prevention of the disease. Nevertheless, additional clinical trials are required to validate our findings.

Rheumatoid arthritis and adverse pregnancy outcomes: a bidirectional two-sample mendelian randomization study

BackgroundThere is growing evidence of bidirectional associations between rheumatoid arthritis and adverse pregnancy outcomes (APOs) in observational studies, but little is known about the causal direction of these associations. Therefore, we explored the potential causal relationships between rheumatoid arthritis and APOs using a bidirectional two-sample Mendelian randomization (MR) in European and Asian populations.MethodsWe conducted a bidirectional two-sample Mendelian randomization analysis using available summary statistics from released genome-wide association studies. Summary statistics for instrument–outcome associations were retrieved from two separate databases for rheumatoid arthritis and adverse pregnancy outcomes, respectively. The inverse-variance weighted method was used as the primary MR analysis, and cML-MA-BIC was used as the supplementary analysis. MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and Cochran Q statistic method were implemented as sensitivity analyses approach to ensure the robustness of the results.ResultsOur study showed that a higher risk of rheumatoid arthritis in the European population was associated with gestational hypertension (OR: 1.04, 95%CI: 1.02–1.06), pre-eclampsia (OR: 1.06, 95%CI: 1.01–1.11), fetal growth restriction (OR: 1.08, 95%CI: 1.04–1.12), preterm delivery (OR:1.04, 95%CI: 1.01–1.07). Furthermore, we found no evidence that APOs had causal effects on rheumatoid arthritis in the reverse MR analysis. No association between rheumatoid arthritis and APOs was found in East Asian population. There was no heterogeneity or horizontal pleiotropy.ConclusionsThis MR analysis provides the positive causal association from rheumatoid arthritis to gestational hypertension, pre-eclampsia, fetal growth restriction and preterm delivery genetically. It highlights the importance of more intensive prenatal care and early intervention among pregnant women with rheumatoid arthritis to prevent potential adverse obstetric outcomes.