Association between antithrombotic agents use and hepatocellular carcinoma risk: a two-sample mendelian randomization analysis

Although prior observational studies have suggested that patients with non-alcohol fatty liver disease (NAFLD) may have a higher risk of coronary artery calcification (CAC), these findings remain controversial. This study aimed to explore the causal association between NAFLD and CAC at genetic level by two-sample Mendelian randomization (MR) analysis. Utilizing summary-level data from multiple large-scale genome-wide association studies (GWAS) in European populations, a two-sample MR analysis was initially conducted to explore the potential causal association between NAFLD and CAC. The results of the MR analysis were pooled through random-effect meta-analysis. The inverse variance weighting (IVW) method served as the primary approach for MR analysis. Additionally, the weighted median, MR-Egger and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods was applied for sensitivity analysis. Summary-level data on liver fatty content was utilized for validation analysis, while summary-level data on cirrhosis served as positive control, further ensuring the validity and robustness of our findings. Reverse MR analysis was performed to assess the association between CAC and NAFLD, employing instrument variables derived from CAC. The MR analysis indicated that genetically predicted NAFLD had no effects on the risk of CAC (Beta: 0.01, 95% CI: -0.02 to 0.03, P = 0.74). Likewise, the reverse MR analysis found no significant genetic association between CAC and NAFLD (OR: 1.00, 95% CI: 0.96 to 1.06, P = 0.88). Validation analysis yielded consistent results, showing no significant association between fatty liver content and CAC. Our two-sample MR analysis did not support that there is a causal association between NAFLD and CAC at genetic level. The association between NAFLD and CAC reported in some previous observational studies may rely on NAFLD complicated with metabolic disorders, rather than being directly linked to the hepatic steatosis.

BackgroundRecent observational research has documented that dermatomyositis (DM) has lower gut microbial diversity and a distinct taxonomic composition[1]. However, the underlying causality remains unclear.ObjectivesTo explore the potential causal associations between...

BackgroundIrritable bowel syndrome (IBS) is one of the most common functional bowel disorders and dysmetabolism plays an important role in the pathogenesis of disease. Nevertheless, there remains a lack of information regarding the causal relationship between circulating metabolites and IBS. A two-sample Mendelian randomization (MR) analysis was conducted in order to evaluate the causal relationship between genetically proxied 486 blood metabolites and IBS.MethodsA two-sample MR analysis was implemented to assess the causality of blood metabolites on IBS. The study utilized a genome-wide association study (GWAS) to examine 486 metabolites as the exposure variable while employing a GWAS study with 486,601 individuals of European descent as the outcome variable. The inverse-variance weighted (IVW) method was used to estimate the causal relationship of metabolites on IBS, while several methods were performed to eliminate the pleiotropy and heterogeneity. Another GWAS data was used for replication and meta-analysis. In addition, reverse MR and linkage disequilibrium score regression (LDSC) were employed for additional assessment. Multivariable MR analysis was conducted in order to evaluate the direct impact of metabolites on IBS.ResultsThree known and two unknown metabolites were identified as being associated with the development of IBS. Higher levels of butyryl carnitine (OR(95%CI):1.10(1.02–1.18),p = 0.009) and tetradecanedioate (OR(95%CI):1.13(1.04–1.23),p = 0.003)increased susceptibility of IBS and higher levels of stearate(18:0)(OR(95%CI):0.72(0.58–0.89),p = 0.003) decreased susceptibility of IBS.ConclusionThe metabolites implicated in the pathogenesis of IBS possess potential as biomarkers and hold promise for elucidating the underlying biological mechanisms of this condition.

This study sought to investigate the causal effects of circulating C-reactive protein (CRP) level on risk of asthma and its subtypes by two-sample Mendelian randomization (MR) analysis. We utilized single nucleotide polymorphisms (SNPs) associated with both CRP and outcomes of asthma, allergic asthma, and obesity-related asthma as genetic variables via a genome-wide summary association study (GWAS). MR analysis mainly based on the inverse variance weighted (IVW) method was performed to infer the causal relationship between exposure and outcomes. Cochran's Q test and MR-Egger regression analysis were performed to determine respectively the heterogeneity and pleiotropy among instrumental variables (IVs), and leave-one-out analysis was conducted to determine the stability of the MR results. In our study, 42 SNPs were identified as IVs for MR analyses. According to the primary inference results by IVW methods, circulating CRP was demonstrated to be significantly associated with risk of asthma [odds ratio (OR):1.046; 95% confidence interval (95% CI): 1.004-1.090; P = .030] and obesity-related asthma (OR:1.072; 95% CI: 1.009-1.138; P = 0.025), whereas no distinct causality with allergic asthma was found (OR:1.051; 95% CI: 0.994-1.112; P = .081). Sensitivity analyses indicated that there was no horizontal pleiotropy among IVs, and the MR results were proved to be robust by leave-one-out sensitivity analysis, despite the presence of heterogeneity. The present study suggested that higher CRP might genetically predict an increased risk of developing asthma and obesity-related asthma, without causality with allergic asthma.

Prior observational research has indicated a potential link between pediatric asthma and united airways disease (UAD). However, these findings could be subject to confounding factors and reverse causation. Therefore, our study utilizes Mendelian randomization (MR) method to further investigate the causal relationship between pediatric asthma and UAD. We conducted a comprehensive two-sample Mendelian randomization (MR) analysis to investigate the association between pediatric asthma and seven groups of UAD, including chronic sinusitis, chronic rhinitis, nasopharyngitis and pharyngitis, chronic diseases of tonsils and adenoids, chronic laryngitis and laryngotracheitis, chronic bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD). The present study employed a range of methods for two-sample MR analysis, including inverse variance weighted (IVW), MR-Egger regression, Simple mode, weighted median, and weighted models. The conclusion of the MR analysis primarily relies on the IVW results, while other analytical methods are utilized as supplementary evidence to ensure result robustness in this MR analysis. And sensitivity analyses were conducted, including heterogeneity test, horizontal pleiotropy test, MR-PRESSO test, and leave-one-out analysis to validate the results. The results of the MR analysis indicate significant causal effects of pediatric asthma on chronic rhinitis, nasopharyngitis and pharyngitis (IVW: OR = 1.15, 95%CI: 1.05-1.26, p-value = 0.003), chronic diseases of tonsils and adenoids (IVW: OR = 1.07, 95%CI: 1.00-1.15, p-value = 0.038), chronic bronchitis (IVW: OR = 1.51, 95%CI: 1.42-1.62, p-value <0.001), bronchiectasis (IVW: OR = 1.51, 95%CI: (1.30-1.75), p-value <0.001), and COPD (IVW: OR = 1.43, 95%CI: 1.34-1.51, p-value <0.001). However, no significant causal association was observed between pediatric asthma and chronic sinusitis (IVW: OR = 1.00, 95%CI: 1.00-1.00, p-value = 0.085), chronic laryngitis and laryngotracheitis (IVW: OR = 1.05, 95%CI: 0.90-1.21, p-value = 0.558). Our findings support a potential causal relationship between pediatric asthma and UAD, suggesting that pediatric asthma may be a potential risk factor for various UAD.

Association between age at first birth and postpartum depression: A two-sample mendelian randomization analysis

Background: An association between inflammatory bowel disease (IBD) [which includes ulcerative colitis (UC) and Crohn's disease (CD)] and IgA nephropathy (IgAN) has been discovered in observational studies, but the causal relationship is still unknown. The aim of this study was to clarify the causal link between IBD (which includes UC and CD) and IgAN via a two-sample Mendelian randomization (MR) analysis. Methods: Eligible single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) for analyses and were obtained from the publicly available genome-wide association study (GWAS) summary statistics. Inverse-variance weighting (IVW), Mendelian randomization-Egger (MR-Egger) regression, the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test, and the weighted median were utilized to obtain the results. The MR-PRESSO test and MR-Egger regression were also performed to detect and correct horizontal pleiotropy. The Cochran's Q test and "leave-one-out" analysis were also conducted to assess the stability and reliability of the MR results. Results: This study found that IBD, UC, and CD all had significant positive causal effects on IgAN risk (IBD: OR = 1.58, 95% CI 1.15-2.16, p = 4.53 × 10-3; UC: OR = 1.55, 95% CI 1.14-2.11, p = 4.88 × 10-3; CD: OR = 1.57, 95% CI 1.21-2.03, p = 5.97 × 10-4). No significant horizontal pleiotropic effect was found for the causal association between IBD, UC, CD, and the risk of IgAN. Cochran's Q test identified no evidence of heterogeneity for the IV estimates. The "leave-one-out" sensitivity analysis also revealed that the MR results were robust. Conclusion: The results of this two-sample MR analysis supported that IBD, UC, and CD were causally associated with the risk of IgAN, while there was no sufficient evidence for the causal effect of IgAN on IBD, UC, or CD. Our findings provide theoretical support and a new perspective for the diagnosis and treatment of these two diseases.

Prior studies have reported connections between cathepsins (CTS) and gynecological cancers; however, the exact causal links are yet to be fully understood. Leveraging publicly accessible genome-wide association study summary datasets, we performed a two-sample bidirectional Mendelian randomization (MR) and multivariate MR (MVMR) analysis, with the inverse variance weighted (IVW) method as the primary approach. MR analysis demonstrated inverse associations between CTSB and cervical cancer (IVW: odds ratio [OR] = 0.9995, 95% confidence interval [CI] = 0.9991–0.9999, P = .0418), CTSE and ovarian cancer (IVW: OR = 0.9197, 95% CI = 0.8505–0.9944, P = .0358), CTSZ and ovarian cancer (IVW: OR = 0.9449, 95% CI = 0.8938–0.9990, P = .0459), CTSE and high grade serous ovarian cancer (IVW: OR = 0.8939, 95% CI = 0.8248–0.9689, P = .0063), and CTSZ and high grade serous ovarian cancer (IVW: OR = 0.9269, 95% CI = 0.8667–0.9913, P = .0268). A positive correlation was identified between CTSH and clear cell ovarian cancer (IVW: OR = 1.1496, 95% CI = 1.0368–1.2745, P = .0081). Nevertheless, subsequent adjustment for the false discovery rate revealed that none of the P-values retained statistical significance (PFDR > 0.05). MVMR analysis results elucidated that CTSZ was inversely associated with cervical cancer (IVW: OR = 0.9988, 95% CI = 0.9981–0.9996, P = .0022). Moreover, a positive association was noted between CTSF and cervical cancer (IVW: OR = 1.0007, 95% CI = 1.0000–1.0014, P = .0364), and similarly, between CTSS and cervical cancer (IVW: OR = 1.0005, 95% CI = 1.0000–1.0011, P = .0490). CTSO exhibited a positive association with non-endometrioid endometrial cancer (IVW: OR = 1.4405, 95% CI = 1.1864–1.7490, P < .001), and CTSH was positively associated with clear cell ovarian cancer (IVW: OR = 1.1167, 95% CI = 1.0131–1.2310, P = .0263). The MVMR analysis findings reveal that CTSZ emerges as a protective element against cervical cancer, whereas CTSF and CTSS represent risk factors for this disease. CTSO stands out as a risk factor for non-endometrioid endometrial cancer, and CTSH acts as a risk factor for clear cell ovarian cancer. This study elucidates causative connections between CTS and gynecological cancers, providing innovative insights for diagnostic and therapeutic optimization.

Mendelian randomization analysis reveals causal associations between autoimmune diseases and female infertility risk.

Background and Aims Previous epidemiological studies have suggested a potential association between constipation and chronic kidney disease (CKD). The high prevalence of constipation among CKD patients and the longitudinal relationship between constipation and incident CKD support this association. However, the causal relationship between these two conditions remains unclear. To investigate this, we performed a two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary statistics from large biobank datasets. Method GWAS summary data on constipation and CKD were obtained from the FinnGen (DF12) and CKDGen consortium, comprising sample sizes of 500,348 and 480,698, respectively. Constipation was defined using ICD-10 codes and laxative medication purchases, while CKD was defined as a creatinine-based estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m². Genetic instruments for CKD and constipation were selected to evaluate the bidirectional relationship between the two conditions. Independent instrumental variables were identified based on significant associations with the exposure (P &amp;lt; 5 × 10⁻⁸, clumping window of 10,000 kb, and r² &amp;lt; 0.001). Due to the limited number of SNPs associated with constipation, a more relaxed threshold (P &amp;lt; 5 × 10⁻⁶) was applied for instrument selection. Results A total of 19 and 21 independent instrumental variables were selected for constipation and CKD, respectively. The MR analysis did not reveal a significant association between genetically predicted constipation and CKD (inverse-variance weighted [IVW] Or = 1.033, 95% CI: 0.898–1.190). However, reverse MR analysis indicated that genetically predicted CKD was causally associated with an increased risk of constipation (IVW Or = 1.052, 95% CI: 1.003–1.104). No evidence of horizontal pleiotropy was observed. Conclusion Our findings suggest that constipation is not causally associated with CKD; rather, CKD may have a causal impact on the development of constipation.

Primary biliary cholangitis (PBC) is a complex, chronic, cholestatic liver disease with an autoimmune etiology. While plasma metabolites are crucial indicators of physiological and pathological states, their involvement in PBC pathogenesis remains unclear. To address this knowledge gap, we performed a rigorous two-sample Mendelian randomization (MR) analysis to assess the causal associations of 1,400 plasma metabolites with PBC. Genome-wide association data for 1,400 plasma metabolites and PBC were obtained from established public databases. The inverse-variance weighted (IVW) method was the primary method used for MR analysis. Sensitivity analyses and heterogeneity tests were conducted to assess the stability of the MR results. A reverse MR analysis was performed to investigate the possibility of reverse causality. Four plasma metabolites were identified as potential predictors for the occurrence of PBC. Specifically, sphingosine 1-phosphate (OR = 0.65, 95% CI: 0.42-0.98, p = 0.04) and docosadienoate (22:2n6) (OR = 0.57, 95% CI: 0.36-0.90, p = 0.01) were implicated in conferring a protective effect against PBC. Conversely, homoarginine (OR = 1.34, 95% CI: 1.04-1.72, p = 0.02) and campesterol (OR = 1.19, 95% CI: 1.01-1.40, p = 0.03) were associated with an increased risk of PBC. There was no evidence of reverse causality between PBC and the identified plasma metabolites. This study utilized a two-sample Mendelian randomization approach to explore the causal relationship between 1,400 plasma metabolites and PBC. We identified four plasma metabolites that may have a causal relationship with the development of PBC. The metabolites identified hold promise as prognostic indicators and could illuminate novel pathways for therapeutic intervention in PBC.

Objective This study aimed to examine whether rheumatoid arthritis (RA) is causally associated with type 2 diabetes (T2D). Methods We performed a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. We used the publicly available summary statistics datasets from a genomewide association studies (GWAS) meta-analysis of 5,539 autoantibody-positive individuals with RA and 20,169 controls of European descent, and a GWAS dataset of 10,247 individuals with T2D and 53,924 controls, overwhelmingly of European descent as outcomes. Results We selected 10 single-nucleotide polymorphisms from GWAS data on RA as instrumental variables to improve the inference. The IVW method supported a causal association between RA and T2D (β=0.044, standard error [SE]=0.022, p=0.047). The MR-Egger analysis showed a causal association between RA and T2D (β=0.093, SE=0.033, p=0.023). In addition, the weighted median approach supported a causal association between RA and T2D (β=0.056, SE=0.025, p=0.028). The association between RA and T2D was consistently observed using IVW, MR Egger, and weighted median methods. Cochran's Q test indicated no evidence of heterogeneity between instrumental variable estimates based on individual variants and MR-Egger regression revealed that directional pleiotropy was unlikely to have biased the results (in-tercept=−0.030; p=0.101). Conclusion MR analysis supports that RA may be causally associated with an increased risk of T2D.

BackgroundAs the number of COVID-19 deaths continues to rise worldwide, the identification of risk factors for the disease is an urgent issue, and it remains controversial whether atherogenic lipid-related traits including serum apolipoprotein B, low-density lipoprotein (LDL)-cholesterol, and triglyceride levels, are risk factors. The aim of this study was to estimate causal effects of lipid-related traits on COVID-19 risk in the European population using a two-sample Mendelian randomization (MR) approach.MethodsWe used summary statistics from a genome-wide association study (GWAS) that included 441,016 participants from the UK Biobank as the exposure dataset of lipid-related traits and from COVID-19 Host Genetics Initiative GWAS meta-analyses of European ancestry as the outcome dataset for COVID-19 susceptibility (32,494 cases and 1,316,207 controls), hospitalization (8316 cases and 1,549,095 controls), and severity (4792 cases and 1,054,664 controls). We performed two-sample MR analyses using the inverse variance weighted (IVW) method. As sensitivity analyses, the MR-Egger regression, weighted median, and weighted mode methods were conducted as were leave-one-out sensitivity analysis, the MR-PRESSO global test, PhenoScanner searches, and IVW multivariable MR analyses. A P value below 0.0055 with Bonferroni correction was considered statistically significant.ResultsThis MR study suggested that serum apolipoprotein B or LDL-cholesterol levels were not significantly associated with COVID-19 risk. On the other hand, we inferred that higher serum triglyceride levels were suggestively associated with higher risks of COVID-19 susceptibility (odds ratio [OR] per standard deviation increase in lifelong triglyceride levels, 1.065; 95% confidence interval [CI], 1.001–1.13; P = 0.045) and hospitalization (OR, 1.174; 95% CI, 1.04–1.33; P = 0.012), and were significantly associated with COVID-19 severity (OR, 1.274; 95% CI, 1.08–1.50; P = 0.004). Sensitivity and bidirectional MR analyses suggested that horizontal pleiotropy and reverse causation were unlikely.ConclusionsOur MR study indicates a causal effect of higher serum triglyceride levels on a greater risk of COVID-19 severity in the European population using the latest and largest GWAS datasets to date. However, as the underlying mechanisms remain unclear and our study might be still biased due to possible horizontal pleiotropy, further studies are warranted to validate our findings and investigate underlying mechanisms.

The link between salt intake and the risk of gastric cancer remains uncertain, and a causal relationship has not been established. Therefore, clarifying the causal effect of salt intake on the risk of gastric cancer using reliable causal inference methods is necessary. The aim of this study was to assess the causal association between salt intake and cancer by integrating summary-level genome-wide association study (GWAS) data. Two-sample Mendelian randomization (MR) analyses were performed using summary statistics from a GWAS. Inverse-variance weighted (IVW) regression, Mendelian randomization-Egger (MR-Egger) regression, and weighted median analyses were used to evaluate the causal relationship between salt intake and gastric cancer. Moreover, Mendelian Randomization Pleiotropy RESidual Sum of Squares and Outliers and MR-Egger analyses were used to evaluate the level of multipotency, and "leave-one-out" sensitivity analysis was assessed. The IVW method estimate indicated that salt intake was not correlated with gastric cancer incidence. The IVW (β = 0.1008, standard error [SE] = 0.1510, odds ratio [OR] = 1.1061, 95% confidence interval [CI], 0.82-1.48, P = .5042), MR-Egger regression (β = 0.059, SE = 0.5318, OR = 1.0612, 95% CI, 0.37-3.01, P = .9111), and weighted median (β = 0.2639, SE = 0.2298, OR = 1.3020, 95% CI, 0.82-2.04, P = .2508) analyses revealed no causal relationship between salt intake and gastric cancer risk (P > .05). In addition, the funnel plot and MR-Egger analysis (P = .6694 > .05) did not indicate horizontal pleiotropy or heterogeneity. GWAS data from public databases were used in this study, and the causal relationship between salt intake and gastric cancer risk was analyzed via a two-sample MR method. The results revealed no genetic causal relationship between salt intake and gastric cancer.

The causal association between vitamin E status and osteoarthritis (OA) remains controversial in previous epidemiological studies. We employed a Mendelian randomization (MR) analysis to explore the causal relationship between circulating alpha-tocopherol levels (main forms of vitamin E in our body) and OA. The instrumental variables (IVs) of circulating alpha-tocopherol levels were obtained from a Genome-wide association study (GWAS) dataset of 7781 individuals of European descent. The outcome of OA was derived from the UK biobank. Two-sample MR analysis was used to estimate the causal relationship between circulating alpha-tocopherol levels and OA. The inverse-variance weighted (IVW) method was the primary analysis in this analysis. We used the MR-Egger method to determine horizontal pleiotropic in this work. The heterogeneity effect of instrumental IVs was detected by MR-Egger and IVW analyses. Sensitivity analysis was performed by removing single nucleotide polymorphism (SNP) one by one. Three SNPs (rs964184, rs2108622, and rs11057830) (P < 5E−8) strongly associated with circulating alpha-tocopherol levels were used in this analysis. The IVW-random effect indicated no causal relationship between circulating alpha-tocopherol levels and clinically diagnosed OA (OR = 0.880, 95% CI 0.626, 1.236, P = 0.461). Similarly, IVW analysis showed no causal association between circulating alpha-tocopherol levels and self-reported OA (OR = 0.980, 95% CI 0.954, 1.006, P = 0.139). Other methods of MR analyses and sensitivity analyses revealed consistent findings. MR-Egger and IVW methods indicated no significant heterogeneity between IVs. The MR–Egger intercept showed no horizontal pleiotropic. The results of this linear Mendelian randomization study indicate no causal association between genetically predicted alpha-tocopherol levels and the progression of OA. Alpha-tocopherol may not provide beneficial and more favorable outcomes for the progression of OA. Further MR analysis based on updated GWASs with more IVs is required to verify the results of our study.