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Background: Mitochondrial DNA (mtDNA) plays an important role in autoimmune diseases (AD), yet the relationship between mitochondria and autoimmune disease is controversial. This study employed bidirectional Mendelian randomization (MR) to explore the causal relationship between mtDNA copy number and 13 ADs (including ankylosing spondylitis [AS], Crohn's disease [CD], juvenile rheumatoid arthritis [JRA], polymyalgia rheumatica [PMR], psoriasis [PSO], rheumatoid arthritis [RA], Sjogren's syndrome [SS], systemic lupus erythematosus [SLE], thyrotoxicosis, type 1 diabetes mellitus [T1DM], ulcerative colitis [UC], and vitiligo)., Methods: A two-sample MR analysis was performed to assess the causal relationship between mtDNA copy number and AD. Genome-wide association study (GWAS) for mtDNA copy number were obtained from the UK Biobank (UKBB), while those associated with AD were sourced from the FinnGen Biobank. Inverse variance weighting (IVW) was the primary analysis method, complemented by three sensitivity analyses (MR-Egger, weighted median, weighted mode) to validate the results., Results: IVW MR analysis identified significant associations between mtDNA copy number and CD (OR=2.51, 95% CI 1.56-4.22, P<0.001), JRA (OR=1.87, 95% CI 1.17-7.65, P=0.022), RA (OR=1.71, 95%CI 1.18-2.47, P=0.004), thyrotoxicosis (OR=0.51, 95% CI0.27-0.96, P=0.038), and T1DM (OR=0.51, 95% CI 0.27-0.96, P=0.038). Sensitivity analyses indicated no horizontal pleiotropy., Conclusions: Our study revealed a potential causal relationship between mtDNA copy number and ADs, indicating that these markers may be relevant in exploring new therapeutic approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Fu, Shao and Duan.)

Background: Coffee is a widely consumed beverage with potential benefits for various chronic diseases. Its effect on reducing erectile dysfunction (ED) risk is unclear. This Mendelian randomization (MR) study investigates the impact of coffee/caffeine consumption on ED., Methods: Two sets of coffee consumption-associated genetic variants at the genome-wide significance level were obtained from recent studies of coffee consumption. Taking into account other sources of caffeine, genetic variants associated with caffeine consumption from tea were also obtained. The inverse variance weighted (IVW) method was utilized as the primary analysis. Sensitivity analysis methods and meta-analysis methods were performed to confirm the robustness of the results, while the genetic variants associated with confounders, e.g., diabetes and hypertension, were excluded., Results: Genetically predicted coffee/caffeine consumption was unlikely to be associated with the risk of ED in the Bovijn datasets, with similar directional associations observed in the FinnGen datasets. The combined odds ratio for ED was 1.011 (95% CI 0.841-1.216, p =0.906) for coffee consumption from the genome-wide meta-analysis, 1.049 (95% CI 0.487-2.260, p =0.903) for coffee consumption from the genome-wide association study, and 1.061 (95% CI 0.682-1.651, p =0.793) for caffeine from tea., Conclusion: Using genetic data, this study found no association between coffee/caffeine consumption and the risk of ED., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xiang, Hu, Peng, Luo, Chen and Zhang.)

Purpose: Studies have demonstrated that hormonal imbalance, such as elevated level of estrogen or reduced level of progesterone, was the main inducing factor of uterine leiomyoma (UL) development and some cancers. UL has been reported to be associated with several cancers in observational studies. However, the causal associations between UL and cancers remain unclear., Methods: A two-sample Mendelian randomization (MR) analysis was conducted to investigate the causal associations between UL and 16 site-specific cancers using the public databases. Four methods, namely, the inverse variance weighting (IVW), MR-Egger, weighted median, and weighted mode, were applied in our MR analysis. Sensitivity tests were also performed to evaluate the robustness of these causal associations., Results: The IVW analysis indicated that genetically predicted UL increased the risk of low malignant potential ovarian cancer [odds ratio (OR) = 1.22, 95% confidence interval (CI): 1.06-1.40, p  = 0.004], serous ovarian cancer (OR = 1.29, 95% CI: 1.10-1.52, p  = 0.002), invasive mucinous ovarian cancer (OR = 1.24, 95% CI: 1.08-1.44, p  = 0.003), clear cell ovarian cancer (OR = 1.25, 95% CI: 1.03-1.51, p  = 0.023), breast cancer (OR = 1.07, 95% CI: 1.02-1.11, p  = 0.002), and brain tumor (OR = 1.23, 95% CI: 1.06-1.42, p  = 0.007). Conversely, genetically predicted UL reduced the risk of gastric cancer (OR = 0.91, 95% CI: 0.85-0.98, p = 0.008). The causal effects were consistent in the sensitivity analysis., Conclusions: Our results demonstrated that UL exhibits a causal relationship with high risk of several cancers. We suggest reinforcing the cancer screening in UL patients to enable the early detection of cancers., Competing Interests: The authors declare that no that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhao, Shang, Wu, Li, Peng and Yue.)

Background: Evidence suggests a connection between DNA methylation (DNAm) aging and reproductive aging. However, the causal relationship between DNAm and age at menopause remains uncertain., Methods: Employing established DNAm epigenetic clocks, such as DNAm Hannum age acceleration (Hannum), Intrinsic epigenetic age acceleration (IEAA), DNAm-estimated granulocyte proportions (Gran), DNAm GrimAge acceleration (GrimAgeAccel), DNAm PhenoAge acceleration (PhenoAgeAccel), and DNAm-estimated plasminogen activator inhibitor-1 levels (DNAmPAIadjAge), a bidirectional Mendelian randomization (MR) study was carried out to explore the potential causality between DNAm and menopausal age. The primary analytical method used was the inverse variance weighted (IVW) estimation model, supplemented by various other estimation techniques., Results: DNAm aging acceleration or deceleration, as indicated by Hannum, IEAA, Gran, GrimAgeAccel, PhenoAgeAccel, and DNAmPAIadjAge, did not exhibit a statistically significant causal effect on menopausal age according to forward MR analysis. However, there was a suggestive positive causal association between age at menopause and Gran (Beta = 0.0010; 95% confidence interval (CI): 0.0004, 0.0020) in reverse MR analysis., Conclusion: The observed increase in granulocyte DNAm levels in relation to menopausal age could potentially serve as a valuable indicator for evaluating the physiological status at the onset of menopause., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Xu, Chen, Ding, Liu, Hou, Wu, Men, Bao, He and Li.)

Introduction: A growing body of research has shown a strong connection between circulating inflammatory proteins and Peripheral artery disease (PAD). However, the causal relationship between circulating inflammatory proteins and PAD is still not fully understood. To investigate this association, we conducted a bidirectional Mendelian randomization study., Materials and Methods: Our study utilized genetic variation data obtained from genome-wide association studies (GWAS) datasets. Specifically, the GWAS dataset related to PAD (identifier: finn-b-I9&#95;PAD) included 7,098 cases and 206,541 controls. Additionally, we extracted data on 91 inflammatory proteins from another GWAS dataset (identifiers: GCST90274758-GCST90274848), involving 14,824 participants. To assess the causal relationship between circulating inflammatory proteins and PAD development, we employed methodologies such as inverse variance weighting (IVW), MR Egger regression, and the weighted median approach. Furthermore, sensitivity analyses were conducted to ensure the reliability and robustness of our findings., Results: Two inflammatory proteins were found to be significantly associated with PAD risk: Natural killer cell receptor 2B4 levels (OR, 1.219; 95% CI,1.019~1.457; P=0.03), Fractalkine levels (OR, 0.755; 95% CI=0.591~0.965; P=0.025). PAD had statistically significant effects on 12 inflammatory proteins: C-C motif chemokine 19 levels (OR, 0.714; 95% CI, 0.585 to 0.872; P=0.001), T-cell surface glycoprotein CD5 levels (OR, 0.818; 95% CI, 0.713 to 0.938; P=0.004), CUB domain-containing protein 1 levels (OR, 0.889; 95% CI, 0.809 to 0.977; P=0.015), Fibroblast growth factor 23 levels (OR, 1.129; 95% CI, 1.009 to 1.264; P=0.034), Interferon gamma levels (OR, 1.124; 95% CI, (1.011 to 1.250); P=0.031),Interleukin-15 receptor subunit alpha levels (OR, 1.183; 95% CI,(1.005 to 1.392); P=0.044), Interleukin-17C levels (OR,1.186; 95% CI, (1.048 to 1.342); P=0.007), Interleukin-1-alpha levels (OR, 1.349; 95% CI, (1.032 to 1.765); P=0.029), Interleukin-5 levels (OR, 1.119; 95% CI,(1.003 to 1.248); P=0.043), Latency-associated peptide transforming growth factor beta 1 levels (OR,1.123; 95% CI, (1.020 to 1.236); P=0.018), Matrix metalloproteinase-10 levels (OR, 1.119; 95% CI,(1.015 to 1.233); P=0.024), Signaling lymphocytic activation molecule levels (OR, 0.823; 95% CI, (0.693 to 0.978); P=0.027)., Conclusion: Our research expands on genetic studies exploring the strong association between circulating inflammatory proteins and PAD. This discovery has the potential to inform and shape future clinical and basic research endeavors in this area., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhao, Sun, Huang, Chen and Yan.)

Objective: Emerging evidence suggests alterations in gut microbiota (GM) composition following thyroid nodules (TNs) development, yet the causal relationship remains unclear. Utilizing Mendelian Randomization (MR), this study aims to elucidate the causal dynamics between GM and TNs., Methods: Employing summary statistics from the MiBioGen consortium ( n =18,340) and FinnGen consortium (1,634 TNs cases, 263,704 controls), we conducted univariable and multivariable MR analyses to explore the GM-TNs association. Techniques including inverse variance weighted, MR-Egger regression, weighted median, and MR-PRESSO were utilized for causal inference. Instrumental variable heterogeneity was assessed through Cochran's Q statistic and leave-one-out analysis. Reverse MR was applied for taxa showing significant forward MR associations, with multivariate adjustments for confounders., Results: Our findings suggest that certain microbiota, identified as Ruminococcaceae&#95;NK4A214&#95;group (OR, 1.89; 95%CI, 0.47-7.64; p = 0.040), Senegalimassilia (OR, 1.72; 95%CI, 1.03-2.87; p =0.037), Lachnospiraceae (OR,0.64; 95%CI,0.41-0.99; p =0.045), exhibit a protective influence against TNs' development, indicated by negative causal associations. In contrast, microbiota categorized as Desulfovibrionales (OR, 0.63; 95%CI, 0.41-0.95; p =0.028), Prevotella&#95;7 (OR, 0.79; 95%CI, 0.63-1.00; p =0.049), Faecalibacterium (OR, 0.66; 95%CI, 0.44-1.00; p =0.050), Desulfovibrionaceae (OR, 0.55; 95%CI, 0.35-0.86; p =0.008), Deltaproteobacteria (OR, 0.65; 95%CI, 0.43-0.97; p =0.036) are have a positive correlation with with TNs, suggesting they may serve as risk factors. Reverse MR analyses did not establish significant causal links. After comprehensive adjustment for confounders, taxa Desulfovibrionales (Order), Desulfovibrionaceae (Family), Deltaproteobacteria (Class) remain implicated as potential contributors to TNs' risk., Discussion: This study substantiates a significant causal link between GM composition and TNs development, underscoring the thyroid-gut axis's relevance. The findings advocate for the integration of GM profiles in TNs' prevention and management, offering a foundation for future research in this domain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yan, He, Yu, Shang, Zhang, Bai, Zhu, Xie and Lee.)

Background: Previous observational studies have revealed the strong relationship between fatty acids (FA) and inflammatory bowel disease (IBD). Nonetheless, due to the inherent limitations of retrospective research, the causality between the two has not been clearly established., Methods: Genetic variants associated with the 17 FA indicators were derived from genome-wide association studies. Summary statistics for the discovery cohort and testing cohort for IBD, including ulcerative colitis (UC) and Crohn's disease (CD), were available from IIBDGC and FinnGen, respectively. Bidirectional MR analysis and sensitivity analysis with multiple measures were applied to comprehensively investigate the causal link between FA and IBD., Results: Combining the results of various MR methods, the validation of testing cohort, and the merging of meta-analysis, we demonstrated that genetically predicted Omega-3 FA levels, Ratio of Omega-3 FA to total FA, Docosahexaenoic acid (DHA) levels, and Ratio of DHA to total FA reduced the risk of IBD, UC, and CD. Meanwhile, multivariate MR suggested that the risk effects of Omega-3 FA and DHA for UC and CD were mainly affected by Saturated FA and Monounsaturated fatty acid (MUFA). Furthermore, although there was the causal association between Ratio of MUFA to total FA as well as Ratio of Polyunsaturated fatty acid (PUFA) to MUFA and CD, sensitivity analysis prompted that the findings were not robust. None of the above results had a reverse causal effect., Conclusion: This MR investigation provided evidence of causality between diverse FA and IBD. These findings offered new insights into the treatment and prevention of IBD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhou and Zhou.)

Background: Uveitis, characterized by inflammation of the iris, ciliary body, and choroid, presents a significant global clinical challenge, contributing substantially to visual impairment. Risk factors include autoimmune diseases and immune cell dysfunctions, yet many remain unidentified. Immune cells, notably T cells, B cells, and monocytes, play pivotal roles in uveitis pathogenesis. While biologic agents show promise, comprehensive studies on immune cell types in ocular diseases are lacking. Genome-wide association studies (GWAS) and Mendelian randomization (MR) present promising avenues to elucidate genetic susceptibilities and causal relationships between immune cell traits and uveitis risk., Methods: Two-sample MR analysis was used to evaluate the causal relationship between 731 immune cells and uveitis, and genome-wide significance analysis was performed for genetic variation in 731 immune cells traits (P < 5 × 10 -8 ). Immune characteristics include median fluorescence intensity (MFI), relative cell counts (RC), absolute cell counts (AC), and morphological parameters (MP), which were determined by published GWAS, and public data from the IEU Open GWAS database. The main analysis method of MR is inverse variance weighting (IVW). Heterogeneity and horizontal pleiotropy were also assessed., Results: 5 immunophenotypes, including CD62L-DC %DC, IgD+ CD38 dim %B cell, CD3 on CM CD4+T cell, CD3 on CD45RA-CD4 +T cell, and CD3 on CD39+ CD4+ Treg may increase the risk of uveitis. 5 immunophenotypes, including CD11b on CD33 dim HLA DR-Myeloid cell, HLA DR on CD33 dim HLA DR+ CD11b-myeloid cell, CD14-CD16 + %monocyte, HLA DR on CD14-CD16 + monocyte and PDL-1 on CD14-CD16 + monocyte was negatively associated with the risk of uveitis. Among them, HLA DR on CD14-CD16 + monocyte (OR=0.921, 95%CI =0.875-0.970, P =0.001) and HLA DR on CD33 dim HLA DR+ CD11b- (OR=0.879, 95%CI = 0.833-0.927, P =0.00) were negatively associated with the risk of uveitis in bi-direction., Conclusion: These results indicate that 10 immune cells traits are significantly associated with the risk of developing uveitis and 2 of them were strongly associated with uveitis bi-directionally, after excluding the effects of confounding factors such as some immune diseases, which provided new ideas and therapeutic targets for the study of immune mechanism of uveitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wu, Fang, Zhou, Wang, Li and Dong.)

Objectives: This study aimed to explore the potential causal associations between serum uric acid (SUA) and the risk of colorectal cancer, colon cancer and rectal cancer., Methods: Twenty-six SUA-related single nucleotide polymorphisms which were identified by a large meta-analysis of genome-wide association studies (GWASs) were used as instrumental variables in the two-sample Mendelian randomization (MR) study. Meta-analyses were used to synthesize the results of multiple GWASs which were extracted from the MRC Integrative Epidemiology Unit GWAS database for each type of cancer. The inverse variance weighted (IVW) method was used as the primary MR method to analyze the association between SUA and colorectal cancer risk. Several sensitivity analyses were performed to test the robustness of results., Results: The IVW method showed that there were no causal relationships between SUA and the risk of colorectal cancer [odds ratio (OR): 1.0015; 95% confidence interval (CI): 0.9975-1.0056] and colon cancer (OR: 1.0015; 95% CI: 0.9974-1.0055). The SUA levels were negative correlated with rectal cancer risk (OR: 0.9984; 95% CI: 0.9971-0.9998). The similar results were observed in both males (OR: 0.9987; 95% CI: 0.9975-0.9998) and females (OR: 0.9985; 95% CI: 0.9971-0.9999). The sensitivity analyses suggested no evidence of heterogeneity or horizontal pleiotropy. The leave-one-out analyses showed that one SNP (rs1471633) significantly drove the causal effect of SUA on rectal cancer risk. The MR-Egger regression and weighted median both showed that there were no causal relationships between SUA and the risk of colorectal cancer and its subtypes., Conclusion: Overall, there was no linear causal association between SUA and the risk of colorectal cancer. However, further research is needed to investigate the role of higher SUA levels such as hyperuricemia or gout in the occurrence of colorectal cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhou, Fu, Zhang, Zhang, Lin, Lin, Liu, Xu, Chen and Hu.)

Background: The relationship between blood lipids, lipid-modifying medications, and cancer risk has been under investigation for some time. Recent studies suggest that lipid-lowering medications might influence melanoma outcomes, though findings remain controversial. Our study aims to clarify the potential causal relationship between lipid-lowering drugs commonly used and melanoma incidence through a comprehensive Mendelian randomization (MR) analysis., Methods: Genetic variations within an LDL-related drug target gene (LDL-cholesterol from a genome-wide association study) served as proxies for exposure to lipid-lowering drugs. We conducted a two-sample Mendelian randomization analysis using inverse variance weighting (IVW), MR-Egger, and weighted median approaches. The MR-PRESSO test and pleiotropy&#95;test were utilized to identify and adjust for horizontal pleiotropy. Stability and reliability of the Mendelian randomization findings were assessed using the leave-one-out method, Cochran's Q test, and funnel plot analysis. Odds ratios (OR) were employed to evaluate the causal relationship between genetic proxies of lipid-lowering drugs and melanoma risk., Results: IVW analysis revealed that HMGCR gene expression is linked to a decreased risk of melanoma [OR: 0.624(0.439-0.888); p = 0.008]. Conversely, PCSK9 gene expression is tied to an elevated risk of melanoma [OR: 1.233(1.026-1.484); p = 0.025]. No significant association was observed between NPC1L1 and melanoma., Conclusions: HMGCR inhibitors (statins) may increase melanoma risk, while PCSK9 inhibitors (evolocumab, alirocumab) could potentially decrease melanoma risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Wang, Song, Feng and Hou.)

The goal was to explore the effect of interleukin-6 (IL6) and C reactive protein (CRP) on malignant melanoma (MM) using two-sample Mendelian randomization., Methods: Data for this study were obtained from the IEU Open GWAS project website for genome-wide association study data (GWAS) on interleukin-6, C reactive protein levels and malignant melanoma. Inverse variance weighted (IVW) method was mainly used and supplemented with MR-Egger regression and weighted median. Finally, horizontal multivariate validity and heterogeneity tests were performed to assess the stability and reliability of the results., Results: The results of univariate two-sample MR analyses showed no significant effect of CRP on MM: inverse variance weighting method (OR=0.999, 95% CI: 0.998-1.001, P=0.343), MR-Egger regression (OR= 1.000, 95% CI: 0.998-1.001, P= 0.180), and weighted median method (OR= 0.999, 95% CI: 0.997 to 1.000, P= 0.583), and weighted model (OR= 0.999, 95% CI: 0.998 to 1.001, P= 0.328). Also,IL-6 had no significant effect on MM: inverse variance weighting method (OR= 1.001, 95% CI: 0.999 to 1.002, P=0.461), MR-Egger regression (OR= 1.000, 95% CI: 0.997 to 1.004, P= 0.910), weighted median method (OR= 1.000, 95% CI: 0.998 to 1.002, P= 0.749), and weighted mode (OR= 1.000, 95% CI: 0.998 to 1.002, P= 0.820)., Conclusion: There was no causal relationship between C-reactive protein and IL-6 on the risk of malignant melanoma., Competing Interests: The authors declare the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Zheng and Pan.)

Background: Blood counts and biochemical markers are among the most common tests performed in hospitals and most readily accepted by patients, and are widely regarded as reliable biomarkers in the literature. The aim of this study was to assess the causal relationship between blood counts, biochemical indicators and pulmonary arterial hypertension (PAH)., Methods: A two-sample Mendelian randomization (MR) analysis was performed to assess the causal relationship between blood counts and biochemical indicators with PAH. The genome-wide association study (GWAS) for blood counts and biochemical indicators were obtained from the UK Biobank (UKBB), while the GWAS for PAH were sourced from the FinnGen Biobank. Inverse variance weighting (IVW) was used as the primary analysis method, supplemented by three sensitivity analyses to assess the robustness of the results. And we conducted an observational study using data from National Health and Nutrition Examination Survey (NHANES) 2003-2018 to verify the relationship., Results: The MR analysis primarily using the IVW method revealed genetic variants of platelet count (OR=2.51, 95% CI 1.56-4.22, P<0.001), platelet crit(OR=1.87, 95% CI1.17-7.65, P=0.022), direct bilirubin (DBIL)(OR=1.71, 95%CI 1.18-2.47,P=0.004), insulin-like growth factor (IGF-1)(OR=0.51, 95% CI 0.27-0.96, P=0.038), Lipoprotein A (Lp(a))(OR=0.66, 95% CI 0.45-0.98, P=0.037) and total bilirubin (TBIL)(OR=0.51, 95% CI 0.27-0.96, P=0.038) were significantly associated with PAH. In NHANES, multivariate logistic regression analyses revealed a significant positive correlation between platelet count and volume and the risk of PAH, and a significant negative correlation between total bilirubin and PAH., Conclusion: Our study reveals a causal relationship between blood counts, biochemical indicators and pulmonary arterial hypertension. These findings offer novel insights into the etiology and pathological mechanisms of PAH, and emphasizes the important value of these markers as potential targets for the prevention and treatment of PAH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Fu, Yu, Ma and Yang.)

Background: Metabolic abnormalities are closely tied to the development of ovarian cancer (OC), yet the relationship between anthropometric indicators as risk indicators for metabolic abnormalities and OC lacks consistency., Method: The Mendelian randomization (MR) approach is a widely used methodology for determining causal relationships. Our study employed summary statistics from the genome-wide association studies (GWAS), and we used inverse variance weighting (IVW) together with MR-Egger and weighted median (WM) supplementary analyses to assess causal relationships between exposure and outcome. Furthermore, additional sensitivity studies, such as leave-one-out analyses and MR-PRESSO were used to assess the stability of the associations., Result: The IVW findings demonstrated a causal associations between 10 metabolic factors and an increased risk of OC. Including "Basal metabolic rate" (OR= 1.24, P = 6.86×10 -4 ); "Body fat percentage" (OR= 1.22, P = 8.20×10 -3 ); "Hip circumference" (OR= 1.20, P = 5.92×10 -4 ); "Trunk fat mass" (OR= 1.15, P = 1.03×10 -2 ); "Trunk fat percentage" (OR= 1.25, P = 8.55×10 -4 ); "Waist circumference" (OR= 1.23, P = 3.28×10 -3 ); "Weight" (OR= 1.21, P = 9.82×10 -4 ); "Whole body fat mass" (OR= 1.21, P = 4.90×10 -4 ); "Whole body fat-free mass" (OR= 1.19, P = 4.11×10 -3 ) and "Whole body water mass" (OR= 1.21, P = 1.85×10 -3 )., Conclusion: Several metabolic markers linked to altered fat accumulation and distribution are significantly associated with an increased risk of OC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Han, Xu, Zhou, Chen, Ding, Zhang, Bao, He and Li.)

Objectives: This study aims to investigate the causal relationship between Alzheimer's Disease (AD) and Diabetic Retinopathy (DR)., Methods: Employing Mendelian Randomization (MR), Generalized Summary-data-based Mendelian Randomization (GSMR), and the MR-Steiger test, this study scrutinizes the genetic underpinnings of the hypothesized causal association between AD and DR, as well as its Proliferative DR (PDR) and Non-Proliferative DR (NPDR) subtypes. Comprehensive data from Genome-Wide Association Studies (GWAS) were analyzed, specifically AD data from the Psychiatric Genomics Consortium (71,880 cases/383,378 controls), and DR, PDR, and NPDR data from both the FinnGen consortium (FinnGen release R8, DR: 5,988 cases/314,042 controls; PDR: 8,383 cases/329,756 controls; NPDR: 3,446 cases/314,042 controls) and the IEU OpenGWAS (DR: 14,584 cases/176,010 controls; PDR: 8,681 cases/204,208 controls; NPDR: 2,026 cases/204,208 controls). The study also incorporated Functional Mapping and Annotation (FUMA) for an in-depth analysis of the GWAS results., Results: The MR analyses revealed that genetic susceptibility to AD significantly increases the risk of DR, as evidenced by GWAS data from the FinnGen consortium (OR: 2.5090; 95% confidence interval (CI):1.2102-5.2018, false discovery rate P-value ( P FDR )=0.0201; GSMR: b xy =0.8936, b xy&#95;se =0.3759, P =0.0174), NPDR (OR: 2.7455; 95% CI: 1.3178-5.7197, P FDR =0.0166; GSMR: b xy =0.9682, b xy&#95;se =0.3802, P =0.0126), and PDR (OR: 2.3098; 95% CI: 1.2411-4.2986, P FDR =0.0164; GSMR: b xy =0.7962, b xy&#95;se =0.3205, P =0.0129) using DR GWAS from FinnGen consortium. These results were corroborated by DR GWAS datasets from IEU OpenGWAS. The MR-Steiger test confirmed a significant association of all identified instrumental variables (IVs) with AD. While a potential causal effect of DR and its subtypes on AD was identified, the robustness of these results was constrained by a low power value. FUMA analysis identified OARD1, NFYA, TREM1 as shared risk genes between DR and AD, suggesting a potential genetic overlap between these complex diseases., Discussion: This study underscores the contribution of AD to an increased risk of DR, as well as NPDR and PDR subtypes, underscoring the necessity of a holistic approach in the management of patients affected by these conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ouyang, Yuan, Ju, Chen, Peng and Xu.)

Background: Migraine has an increased prevalence in several immune disorders, but genetic cause-effect relationships remain unclear. Mendelian randomization (MR) was used in this study to explore whether immune diseases are causally associated with migraine and its subtypes., Methods: We conducted a two-sample bidirectional multivariate Mendelian randomization study. Single-nucleotide polymorphisms (SNP) for six immune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), allergic rhinitis (AR), asthma and psoriasis, were used as genetic instrumental variables. Summary statistics for migraine were obtained from 3 databases: the International Headache Genetics Consortium (IHGC), UK Biobank, and FinnGen study. MR analyses were performed per outcome database for each exposure and subsequently meta-analyzed. Reverse MR analysis was performed to determine whether migraine were risk factors for immune diseases. In addition, we conducted a genetic correlation to identify shared genetic variants for these two associations., Results: No significant causal relationship was found between immune diseases and migraine and its subtypes. These results were robust with a series of sensitivity analyses. Using the linkage disequilibrium score regression method (LDSC), we detected no genetic correlation between migraine and immune diseases., Conclusion: The evidence from our study does not support a causal relationship between immune diseases and migraine. The mechanisms underlying the frequent comorbidity of migraine and several immune diseases need to be further elucidated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Duan, International Headache Genetics Consortium (IHGC), Zheng, Zhu, Qu, Liu and Liu.)

Introduction: Circulating cytokines were considered to play a critical role in the initiation and propagation of sarcopenia and frailty from observational studies. This study aimed to find the casual association between circulating cytokines and sarcopenia and frailty from a genetic perspective by two-sample Mendelian randomization (MR) analysis., Methods: Data for 41 circulating cytokines were extracted from the genome-wide association study dataset of 8,293 European participants. Inverse-variance weighted (IVW) method, MR-Egger, and weighted median method were applied to assess the relationship of circulating cytokines with the risk of aging-related syndromes and frailty. Furthermore, MR-Egger regression was used to indicate the directional pleiotropy, and Cochran's Q test was used to verify the potential heterogeneity. The "leave-one-out" method was applied to visualize whether there was a causal relationship affected by only one anomalous single-nucleotide polymorphisms., Results: Genetic predisposition to increasing levels of interleukin-10 (IL-10), IL-12, and vascular endothelial growth factor (VEGF) was associated with the higher risk of low hand grip strength according to the IVW method [R = 1.05, 95% CI = 1.01-1.10, P = 0.028, false discovery rate (FDR)-adjusted P = 1.000; OR = 1.03, 95% CI = 1.00-1.07, P = 0.042, FDR-adjusted P = 0.784; OR = 1.02, 95% CI = 1.00-1.05, P = 0.038, FDR-adjusted P = 0.567]. Furthermore, genetically determined higher macrophage colony-stimulating factors (M-CSFs) were associated with a lower presence of appendicular lean mass (OR = 1.01, 95% CI = 1.00-1.02, P = 0.003, FDR-adjusted P = 0.103). Monokine induced by interferon-γ (MIG) and tumor necrosis factor-beta (TNF-β) were associated with a higher risk of frailty (OR = 1.03, 95% CI = 1.01-1.05, P < 0.0001, FDR-adjusted P  = 0.012; OR = 1.01, 95% CI = 1.00-1.03, P = 0.013, FDR-adjusted P = 0.259). In this study, we did not find heterogeneity and horizontal pleiotropy between the circulating cytokines and the risk of frailty and sarcopenia., Conclusion: Genetic predisposition to assess IL-10, IL-12, and VEGF levels was associated with a higher risk of low hand grip strength and M-CSF with the presence of appendicular lean mass. The high levels of TNF-β and MIG were associated with a higher risk of frailty. More studies will be required to explore the molecular biological mechanisms underlying the action of inflammatory factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Wang, Wan, Kurihara and Wang.)

Background: Numerous observational studies have identified a linkage between the gut microbiota and gastroesophageal reflux disease (GERD). However, a clear causative association between the gut microbiota and GERD has yet to be definitively ascertained, given the presence of confounding variables., Methods: The genome-wide association study (GWAS) pertaining to the microbiome, conducted by the MiBioGen consortium and comprising 18,340 samples from 24 population-based cohorts, served as the exposure dataset. Summary-level data for GERD were obtained from a recent publicly available genome-wide association involving 78 707 GERD cases and 288 734 controls of European descent. The inverse variance-weighted (IVW) method was performed as a primary analysis, the other four methods were used as supporting analyses. Furthermore, sensitivity analyses encompassing Cochran's Q statistics, MR-Egger intercept, MR-PRESSO global test, and leave-one-out methodology were carried out to identify potential heterogeneity and horizontal pleiotropy. Ultimately, a reverse MR assessment was conducted to investigate the potential for reverse causation., Results: The IVW method's findings suggested protective roles against GERD for the Family Clostridiales Vadin BB60 group ( P = 0.027), Genus Lachnospiraceae UCG004 (P = 0.026), Genus Methanobrevibacter ( P = 0.026), and Phylum Actinobacteria (P = 0.019). In contrast, Class Mollicutes ( P = 0.037), Genus Anaerostipes (P = 0.049), and Phylum Tenericutes ( P = 0.024) emerged as potential GERD risk factors. In assessing reverse causation with GERD as the exposure and gut microbiota as the outcome, the findings indicate that GERD leads to dysbiosis in 13 distinct gut microbiota classes. The MR results' reliability was confirmed by thorough assessments of heterogeneity and pleiotropy., Conclusions: For the first time, the MR analysis indicates a genetic link between gut microbiota abundance changes and GERD risk. This not only substantiates the potential of intestinal microecological therapy for GERD, but also establishes a basis for advanced research into the role of intestinal microbiota in the etiology of GERD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Wang, Chen, Lu, Wang, Zhang, Pan, Zhou and Zou.)

Background: Previous research has indicated that there may be a link between Crohn's disease (CD) and breast cancer (BC), but the causality remains unclear. This study aimed to investigate the causal association between CD and BC using Mendelian randomization (MR) analysis., Methods: The summary data for CD (5,956 cases/14,927 controls) was obtained from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). And the summary data for BC (122,977 cases/105,974 controls) was extracted from the Breast Cancer Association Consortium (BCAC). Based on the estrogen receptor status, the cases were classified into two subtypes: estrogen receptor-positive (ER + ) BC and estrogen receptor-negative (ER - ) BC. We used the inverse variance weighted method as the primary approach for two-sample MR. MR-PRESSO method was used to rule out outliers. Heterogeneity and pleiotropy tests were carried out to improve the accuracy of results. Additionally, multivariable MR was conducted by adjusting for possible confounders to ensure the stability of the results., Results: The two-sample MR indicated that CD increased the risks of overall (OR: 1.020; 95% CI: 1.010-1.031; p =0.000106), ER + (OR: 1.019; 95%CI: 1.006-1.034; p =0.006) and ER - BC (OR: 1.019; 95%CI: 1.000-1.037; p =0.046) after removal of outliers by MR-PRESSO. This result was reliable in the sensitivity analysis, including Cochran's Q and MR-Egger regression. In multivariate MR analyses, after adjusting for smoking and drinking separately or concurrently, the positive association between CD and the risks of overall and ER + BC remained, but it disappeared in ER - BC. Furthermore, reverse MR analysis suggested that BC did not have a significant impact on CD risk., Conclusion: Our findings provide evidence for a possible positive association between CD and the risk of BC. However, further studies are needed to fully understand the underlying mechanisms and establish a stronger causal relationship., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yu, Xu, Xu, Huang, Tang, Zeng, Yu, Chen and Sun.)

Background: The existing literature on the relationship of hyperparathyroidism with both blood counts and biochemical indicators primarily comprises observational studies, which have produced inconsistent findings. This study aimed to evaluate the causal relationship between hyperparathyroidism and blood counts and biochemical indicators., Methods: Mendelian randomization (MR) analyses were conducted to investigate the associations between hyperparathyroidism and the identified 55 blood counts and biochemical indicators. The genome-wide association study (GWAS) for hyperparathyroidism data was obtained from FinnGen, while the GWASs for the blood counts and biochemical indicators were sourced from the UK Biobank (UKBB)., Results: The MR analysis using the inverse-variance weighted (IVW) method revealed potential causality between genetically predicted hyperparathyroidism and seven out of 55 blood counts and biochemical indicators. These markers include "Platelet count" (Beta = -0.041; 95% CI: -0.066, -0.016; p = 0.001), "Platelet distribution width (PDW)" (Beta = 0.031; 95% CI: 0.006, 0.056; p = 0.016), "Mean platelet volume (MPV)" (Beta = 0.043; 95% CI: 0.010, 0.076; p = 0.011), "Vitamin D" (Beta = -0.038; 95% CI: -0.063, -0.013; p = 0.003), "Calcium (Ca 2+ )" (Beta = 0.266; 95% CI: 0.022, 0.509; p = 0.033), "Phosphate" (Beta = -0.114; 95% CI: -0.214, -0.014; p = 0.025), and "Alkaline phosphatase (ALP)" (Beta = 0.030; 95% CI: 0.010, 0.049; p = 0.003)., Conclusion: The findings of our study revealed a suggestive causal relationship between hyperparathyroidism and blood cell count as well as biochemical markers. This presents a novel perspective for further investigating the etiology and pathological mechanisms underlying hyperparathyroidism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jiang, Chen, Xu, Ding, Zhang, Bao, He and Li.)

Background: Despite the well-established findings of a higher incidence of retina-related eye diseases in patients with diabetes, there is less investigation into the causal relationship between diabetes and non-retinal eye conditions, such as age-related cataracts and glaucoma., Methods: We performed Mendelian randomization (MR) analysis to examine the causal relationship between type 2 diabetes mellitus (T2DM) and 111 ocular diseases. We employed a set of 184 single nucleotide polymorphisms (SNPs) that reached genome-wide significance as instrumental variables (IVs). The primary analysis utilized the inverse variance-weighted (IVW) method, with MR-Egger and weighted median (WM) methods serving as supplementary analyses., Results: The results revealed suggestive positive causal relationships between T2DM and various ocular conditions, including "Senile cataract" (OR= 1.07; 95% CI: 1.03, 1.11; P =7.77×10 -4 ), "Glaucoma" (OR= 1.08; 95% CI: 1.02, 1.13; P =4.81×10 -3 ), and "Disorders of optic nerve and visual pathways" (OR= 1.10; 95% CI: 0.99, 1.23; P =7.01×10 -2 )., Conclusion: Our evidence supports a causal relationship between T2DM and specific ocular disorders. This provides a basis for further research on the importance of T2DM management and prevention strategies in maintaining ocular health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Xu, Ding, Li, Huang, Bao, Li and Wang.)

Background: Previous observational studies have reported inconsistent findings regarding the incidence of cancer in patients with schizophrenia compared to the general population. The causal relationship between schizophrenia and cancer remains unclear and requires further investigation., Objective: To investigate the causal relationship between schizophrenia and cancer., Methods: In this study, a two-sample Mendelian randomization (MR) analysis was conducted using publicly available genome-wide association studies to determine the causal relationship. The effect estimates were calculated using the random-effects inverse-variance-weighted method., Results: We determined a causal relationship between genetic predisposition to schizophrenia and cancer, with schizophrenia increasing lung cancer (odds ratio (OR) = 1.0007; 95% confidence interval (CI), 1.0001-1.0013; p = 0.0192), thyroid cancer (OR = 1.5482; CI, 1.1112-2.1569; p =0.0098),colorectal cancer (OR = 1.0009; CI, 1.0001-1.0018; p = 0.0344), ovarian cancer (OR = 1.0770; CI, 1.0352-1.1203; p = 0.0002), breast cancer (OR = 1.0011; CI, 1.0001- 1.0022; p =0.0352) and reduced the risk of malignant neoplasm of the stomach (OR = 0.8502; CI, 0.7230-0.9998; p = 0.0496)., Conclusions: This study conducted a two-sample MR analysis and discovered a positive causal relationship between schizophrenia and breast, ovarian, thyroid, lung, and colorectal cancers. On the other hand, an inverse causal relationship was found between schizophrenia and malignant neoplasm of the stomach., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhou, Zhu, Chen, Huang, Feng, Wu, Wei and Gou.)

Background: Observational studies about the association between serum total bilirubin and cholelithiasis are inconsistent. Hence, it is essential to reevaluate the association between serum total bilirubin and cholelithiasis and to verify whether such association is causal or not., Methods: We selected single-nucleotide polymorphisms (SNPs) that are strongly associated with exposure as instrumental variable and conducted a bidirectional two-sample Mendelian randomization (MR) study to explore the causal association between serum total bilirubin and cholelithiasis. We implemented the inverse-variance weighted approach as a primary analysis to combine the Wald ratio estimates. Four additional analyses, namely, MR-Egger regression, weighted median, weighted mode, and MR-pleiotropy residual sum and outlier (PRESSO), were utilized to investigate the causal association and the influence of potential pleiotropy., Results: A total of 116 SNPs were selected as valid instrumental variables to estimate the causal association of serum total bilirubin on cholelithiasis, and causal association between genetically determined serum total bilirubin and cholelithiasis was demonstrated [beta = 0.10; 95% confident interval (CI), 0.07 to 0.14; p < 0.001]. Likewise, the other methods, namely, the weighted median (beta = 0.12; 95% CI, 0.08 to 0.15; p < 0.001), MR-Egger (beta = 0.11; 95% CI, 0.08 to 0.15; p < 0.001), weighted mode (beta = 0.11; 95% CI, 0.08 to 0.15; p < 0.001), and MR-PRESSO approaches, further confirmed that this result (p = 0.054) indicates similar results. In addition, seven SNPs were selected as instrumental variable to estimate causal association of cholelithiasis on serum total bilirubin, and the result supported the causal effect of cholelithiasis to serum total bilirubin (beta = 0.12; 95% CI, 0.09 to 0.15; p < 0.001). At the same time, the other methods, namely, the weighted median (beta = 0.10; 95% CI, 0.06 to 0.13; p < 0.001), MR-Egger (beta = 0.12; 95% CI, 0.07 to 0.18; p = 0.007), weighted mode (beta = 0.09; 95% CI, 0.03 to 0.14, p = 0.019), and MR-PRESSO methods, further confirmed this result (p < 0.001)., Conclusion: Our MR study revealed that the serum total bilirubin was causally associated with the risk of cholelithiasis, and the genetic predisposition to cholelithiasis was causally associated with the increased serum total bilirubin levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sun, Yang, Dai, Zheng, Zhang, Zheng, Wang, Bi, Duan, Wu and Kong.)

Background: Previous observational or retrospective studies have suggested an association between inflammatory bowel disease (IBD) and herpes virus infections. Using Mendelian randomization (MR) approach, our objective was to determine whether there was a causal association between IBD and herpes virus infections., Methods: In genome-wide association study (GWAS) datasets of the International Inflammatory Bowel Disease Genetics Consortium, we obtained genetic instrumental variables for three phenotypes from 34,652 participants (12,882 IBD cases and 21,770 controls), 27,432 participants [6,968 ulcerative colitis (UC) cases and 20,464 controls], and 20,883 participants [5,956 Crohn's disease (CD) cases and 14,927 controls], respectively. Summary statistics for herpes virus infections (chickenpox, herpes zoster, and mononucleosis) were obtained from the FinnGen database. MR results were expressed as odds ratio (OR) with 95% confidence interval (CI)., Results: Our study found no evidence of a causal effect of genetically predicted IBD on herpes virus infections [ P value for inverse variance weighting (IVW): 0.063 to 0.652]. For the subtypes of IBD, UC had a suggestive association with mononucleosis ( P value for IVW: 0.023). It appeared that CD was also weakly associated with mononucleosis ( P value for IVW: 0.058; P value for Weighted median: 0.036). In addition, we found a suggestive causality for CD on chickenpox ( P value for IVW: 0.038). Neither UC ( P value for IVW: 0.574) nor CD ( P value for IVW: 0.168) has a causal effect on herpes zoster. The results of the bidirectional MR analysis did not indicate that herpes virus infections were associated with IBD, UC or CD ( P value for IVW: 0.239 to 0.888)., Conclusion: This study showed a suggestive causality for both CD-chickenpox and UC-mononucleosis, despite no associations reaching a statistical significance value after corrections for multiple testing. There was no evidence of a causal association between IBD and its two subtypes on herpes zoster., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zou, Zhang, Shen, Xu and Zhu.)

Background: Retinal vein occlusion (RVO) is a common retinal vascular disease that can cause severe visual impairment. Many observational studies have shown that type 2 diabetes (T2DM) is associated with RVO, but it remains unknown if the association is causal. The present study aimed to perform Mendelian randomization (MR) analyses to evaluate the causal contribution of genetically predicted T2DM to RVO., Methods: We obtained summary-level data from a genome-wide association study meta-analysis including 48,286 cases and 250,671 controls for T2DM and from a genome wide association study of 372 cases and 182,573 controls in the FinnGen project for RVO. To verify the robustness of the results, an independent validation dataset for T2DM (12,931 cases and 57,196 controls) was used. In addition to the main MR analysis using the inverse variance weighted (fixed effect) approach, sensitivity analyses and multivariable MR adjusting for common risk factors of RVO were conducted., Results: Genetically predicted T2DM was found to be causally associated with RVO risk (odds ratio (OR)=2.823, 95% confidence interval (CI): 2.072-3.847, P =4.868×10 -11 ). This association was supported by sensitivity analyses using the weighted median (OR=2.415, 95% CI: 1.411-4.132, P =1.294×10 -3 ), weighted mode (OR=2.370, 95% CI: 1.321-4.252, P =5.159×10 -3 ), maximum likelihood (OR=2.871, 95% CI: 2.100-3.924, P =3.719×10 -11 ), MR-PRESSO (OR=2.823, 95% CI: 2.135-3.733, P =5.150×10 -10 ), and MR-Egger (OR=2.441, 95% CI: 1.149-5.184, P =2.335×10 -2 ) methods. In addition, this association persisted in multivariable MR after accounting for common RVO risk factors (OR=1.748, 95% CI: 1.238-2.467, P=1.490×10 -3 ). The MR analyses using the validation dataset obtained consistent results., Conclusion: This study indicates that genetically predicted T2DM may have a causal contribution to RVO. Future studies are required to elucidate the underlying mechanisms., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huang.)

Objective: To explore the genetic causal association between osteoporosis (OP) and iron status through Mendelian randomization (MR)., Methods: Publicly available genome-wide association study (GWAS) summary data were used for MR analysis with four iron status-related indicators (ferritin, iron, total iron binding capacity, and transferrin saturation) as exposures and three different types of OP (OP, OP with pathological fracture, and postmenopausal OP with pathological fracture) as outcomes. The inverse-variance weighted (IVW) method was used to analyze the genetic causal association between the four indicators of iron status and OP. The heterogeneity of MR results was determined using IVW and MR-Egger methods. The pleiotropy of MR results was determined using MR-Egger regression. A leave-one-SNP-out test was performed to determine whether the MR results were affected by a single nucleotide polymorphism (SNP). The weighted median method was conducted to further validate our results., Results: Based on IVW, MR-Egger and weighted median models, we found no causal association between iron status (ferritin, iron, total iron binding capacity, or transferrin saturation) and OP (P beta > 0.05 in all models). IVW and MR-Egger analysis of OP with pathological fracture and iron status indicators showed no potential genetic causal association (P beta > 0.05 in the two analyses). The results of the weighted median were consistent with those of IVW (P beta > 0.05 in all analyses). There was no potential genetic causal association between iron status and postmenopausal OP with pathological fracture based on serum iron (P beta >0.05 in all models). No heterogeneity or horizontal pleiotropy was found in any of the analyses. None of the leave-one-out tests in the analyses found any SNP that could affect the results of MR., Conclusion: Our results demonstrate that there is no genetic causal association between OP and iron status, but the effects of other factors were not excluded., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xu, Ma, Chen, Zhang, Zheng, Si, Wu, Liu, Li, Wu and Shen.)

Background: Epidemiological evidence suggests an association between rheumatoid arthritis (RA) and myocardial infarction (MI). However, causality remains uncertain. Therefore, this study aimed to explore the causal association between RA and MI., Methods: Using publicly available genome-wide association study summary datasets, bidirectional two-sample Mendelian randomization (TSMR) was performed using inverse-variance weighted (IVW), weighted median, MR-Egger regression, simple mode, and weighted mode methods., Results: The MR results for the causal effect of RA on MI (IVW, odds ratio [OR] = 1.041, 95% confidence interval [CI]: 1.007-1.076, P = 0.017; weighted median, OR = 1.027, 95% CI: 1.006-1.049, P = 0.012) supported a causal association between genetic susceptibility to RA and an increased risk of MI. MR results for the causal effect of MI on RA (IVW, OR = 1.012, 95% CI: 0.807-1.268, P = 0.921; weighted median, OR = 1.069, 95% CI: 0.855-1.338, P = 0.556) indicated that there was no causal association between genetic susceptibility to MI and an increased risk of RA., Conclusion: Bidirectional TSMR analysis supports a causal association between genetic susceptibility to RA and an increased risk of MI but does not support a causal association between genetic susceptibility to MI and an increased risk of RA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Guo, Wang, Peng and Yuan.)

Backgrounds: Epidemiological studies have repeatedly investigated the association between obesity related anthropometric indicators and body compositions and osteoarthritis (OA). However, the results have remained inconsistent. This work aimed to investigate the genetic correlation and causal associations of obesity related anthropometric indicators and body compositions with knee and hip OA., Methods: Single-nucleotide polymorphisms associated with the exposures were searched from the recent genome-wide association studies (GWAS) to obtain full statistics. Summary-level results of knee and hip OA were from the UK Biobank and arcOGEN. First, linkage disequilibrium score regression (LD score regression) was applied to detect the genetic correlation (rg). We further performed a series of sensitivity analyses as validation of primary mendelian randomization (MR) results and the specific evidence of potential causal effects was defined., Results: We found that genetic components in OA had significant correlation with obesity related traits, except waist-to-hip ratio. In the univariable MR analysis, with the exception of waist-to-hip ratio, obesity related anthropometric indicators were causally associated with increased risks of knee and hip OA. For obesity related body compositions, higher fat-free mass in arm, leg, and whole body increased the risk of knee OA but only fat-free mass in leg showed a significant association with hip OA. Meanwhile trunk fat mass and trunk fat percentage, were associated with knee but not with hip OA. Higher fat mass, and fat percentage in arm, leg, and whole body increased the risk of both knee and hip OA. After adjusting for BMI, the multivariable MR showed maintained results in knee OA. However, in hip OA, only fat mass and fat-free mass in arm, leg, trunk and whole body were significantly associated with the risk of hip OA., Conclusion: The present study suggests genetic evidence for certain causal associations of obesity related anthropometric indicators and body compositions with knee and hip OA, which may provide important insights for the prevention and treatment on OA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Zhu, Liu, Long, Ruan and Zhao.)

Purpose: The effect of hyperglycemia on periodontitis is mainly based on observational studies, and inconsistent results were found whether periodontal treatment favors glycemic control. The two-way relationship between periodontitis and hyperglycemia needs to be further elucidated. This study aims to evaluate the causal association of periodontitis with glycemic traits using bi-directional Mendelian randomization (MR) approach., Methods: Summary statistics were sourced from large-scale genome-wide association study conducted for fasting glucose (N = 133,010), HbA1c (N = 123,665), type 2 diabetes (T2D, N = 659,316), and periodontitis (N = 506,594) among European ancestry. The causal relationship was estimated using the inverse-variance weighted (IVW) model and further validated through extensive complementary and sensitivity analyses., Results: Overall, IVW showed that a genetically higher level of fasting glucose was significantly associated with periodontitis (OR = 1.119; 95% CI = 1.045-1.197; P FDR = 0.048). These linkages remained statistically significant in multivariate MR analyses, after adjusting for body mass index. The reverse direction MR analyses did not exhibit the causal association of genetic liability to periodontitis with any of the glycemic trait tested.P FDR = 0.048). These linkages remained statistically significant in multivariate MR analyses, after adjusting for body mass index. The reverse direction MR analyses did not exhibit the causal association of genetic liability to periodontitis with any of the glycemic trait tested., Conclusions: Our MR study reaffirms previous findings and extends evidence to substantiate the causal effect of hyperglycemia on periodontitis. Future studies with robust genetic instruments are needed to confirm the causal association of periodontitis with glycemic traits., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Chu, Gong, Li, Wu, Jin, Hu and Deng.)

Background: Observational studies suggested that multiple sclerosis (MS) is associated with cardiovascular diseases (CVDs). However, the causal association has not been fully elucidated. Thus, we aim to assess the causality of the associations of MS with risk of CVDs., Methods: A two-sample Mendelian randomization (MR) study was performed to explore the causality. Genetic instruments were identified for MS from a genome-wide association study (GWAS) involving 115,803 individuals. Summary-level data for CVDs were obtained from different GWAS meta-analysis studies. MR analysis was conducted mainly using the inverse-variance weighted (IVW) method. Sensitivity analyses were further performed to ensure the robustness of the results., Results: This MR study found suggestive evidence that genetic liability to MS was associated with an increased risk of coronary artery disease (CAD) [odds ratio (OR), 1.02; 95% confidence interval (CI), 1.00-1.04; p = 0.03], myocardial infarction (MI) (OR, 1.03; 95% CI, 1.00-1.06; p = 0.01), heart failure (HF) (OR, 1.02; 95% CI, 1.00-1.04; p = 0.02), all-cause stroke (AS) (OR, 1.02; 95% CI, 1.00-1.05; p = 0.02), and any ischemic stroke (AIS) (OR, 1.02; 95% CI, 1.00-1.05; p = 0.04). The null-association was observed between MS and the other CVDs. Further analyses found little evidence of pleiotropy., Conclusions: We provided suggestive genetic evidence for the causal associations of MS with increased risk of CAD, MI, HF, AS, and AIS, which highlighted the significance of active monitoring and prevention of cardiovascular risk to combat cardiovascular comorbidities in MS patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Hu, He, Ying and Cui.)