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Identifying potential drug targets for idiopathic pulmonary fibrosis: a mendelian randomization study based on the druggable genes. Respiratory research BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic interstitial lung disease characterized by progressive dyspnea and decreased lung function, yet its exact etiology remains unclear. It is of great significance to discover new drug targets for IPF. METHODS:We obtained the cis-expression quantitative trait locus (cis-eQTL) of druggable genes from eQTLGen Consortium as exposure and the genome wide association study (GWAS) of IPF from the International IPF Genetics Consortium as outcomes to simulate the effects of drugs on IPF by employing mendelian randomization analysis. Then colocalization analysis was performed to calculate the probability of both cis-eQTL of druggable genes and IPF sharing a causal variant. For further validation, we conducted protein quantitative trait locus (pQTL) analysis to reaffirm our findings. RESULTS:The expression of 45 druggable genes was significantly associated with IPF susceptibility at FDR < 0.05. The expression of 23 and 15 druggable genes was significantly associated with decreased forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLco) in IPF patients, respectively. IPF susceptibility and two significant genes (IL-7 and ABCB2) were likely to share a causal variant. The results of the pQTL analysis demonstrated that high levels of IL-7 in plasma are associated with a reduced risk of IPF (OR = 0.67, 95%CI: 0.47-0.97). CONCLUSION:IL-7 stands out as the most promising potential drug target to mitigate the risk of IPF. Our study not only sheds light on potential drug targets but also provides a direction for future drug development in IPF. 10.1186/s12931-024-02848-5
Shared genetic etiology and causality between COVID-19 and venous thromboembolism: evidence from genome-wide cross trait analysis and bi-directional Mendelian randomization study. medRxiv : the preprint server for health sciences Venous thromboembolism (VTE) occurs in up to one third patients with COVID-19. VTE and COVID-19 may share a common genetic architecture, which has not been clarified yet. To fill this gap, we leveraged summary-level genetic data from the latest COVID-19 host genetics consortium and UK Biobank and examined the shared genetic etiology and causal relationship between COVID-19 and VTE. The cross-trait analysis identified 8, 11, and 7 shared loci between VTE and severe COVID-19, COVID-19 hospitalization, SARS-CoV-2 infection respectively, in 13 genes involved in coagulation and immune function and enriched in the lung. Co-localization analysis identified eight shared loci in and genes. Bi-direction Mendelian randomization suggested that VTE was associated with higher risks of all COVID-19 related traits, and SARS-CoV-2 infection was associated with higher risk of VTE. Our study provided timely evidence and novel insights into the genetic etiology between COVID-19 and VTE. 10.1101/2022.05.21.22275413
Association of sleep traits with risk of hypertensive disorders of pregnancy: a mendelian randomization study. Journal of hypertension BACKGROUND:Unhealthy sleep patterns are common during pregnancy and have been associated with an increased risk of developing hypertensive disorders of pregnancy (HDPs) in observational studies. However, the causality underlying these associations remains uncertain. This study aimed to evaluate the potential causal association between seven sleep traits and the risk of HDPs using a two-sample Mendelian randomization study. METHODS:Genome-wide association study (GWAS) summary statistics were obtained from the FinnGen consortium, UK Biobank, and other prominent consortia, with a focus on individuals of European ancestry. The primary analysis utilized an inverse-variance-weighted MR approach supplemented by sensitivity analyses to mitigate potential biases introduced by pleiotropy. Furthermore, a two-step MR framework was employed for mediation analyses. RESULTS:The data analyzed included 200 000-500 000 individuals for each sleep trait, along with approximately 15 000 cases of HDPs. Genetically predicted excessive daytime sleepiness (EDS) exhibited a significant association with an increased risk of HDPs [odds ratio (OR) 2.96, 95% confidence interval (95% CI) 1.40-6.26], and the specific subtype of preeclampsia/eclampsia (OR 2.97, 95% CI 1.06-8.3). Similarly, genetically predicted obstructive sleep apnea (OSA) was associated with a higher risk of HDPs (OR 1.27, 95% CI 1.09-1.47). Sensitivity analysis validated the robustness of these associations. Mediation analysis showed that BMI mediated approximately 25% of the association between EDS and HDPs, while mediating up to approximately 60% of the association between OSA and the outcomes. No statistically significant associations were observed between other genetically predicted sleep traits, such as chronotype, daytime napping, sleep duration, insomnia, snoring, and the risk of HDPs. CONCLUSION:Our findings suggest a causal association between two sleep disorders, EDS and OSA, and the risk of HDPs, with BMI acting as a crucial mediator. EDS and OSA demonstrate promise as potentially preventable risk factors for HDPs, and targeting BMI may represent an alternative treatment strategy to mitigate the adverse impact of sleep disorders. 10.1097/HJH.0000000000003771
How is Obstructive Sleep Apnea Associated with High Blood Pressure and Diabetes Mellitus Type 2? Clues from a Two-Step Mendelian Randomized Study. Nature and science of sleep Background:Obstructive sleep apnea (OSA), high blood pressure (HBP), and type 2 diabetes mellitus (T2DM) have a close clinical relationship, but whether and how OSA affects HBP and T2DM is unclear. Study Design and Methods:Two-step, two-sample Mendelian randomization techniques were applied using single-nucleotide polymorphisms as genetic instruments for exposure and mediators, thus minimizing bias due to confounding factors and reverse causality. The total effect of OSA on HBP and T2DM was categorized into direct and mediating effects based on the mediating factors. Results:Two-sample MR analysis showed that OSA increased the risk of HBP (odds ratio [OR] = 1.010, 95% confidence interval [CI], 1.002-1.018; = 0.0121) and T2DM (OR = 1.140, 95% CI, 1.059-1.228; = 0.0005). In the process of OSA caused by HBP, sex hormone-binding globulin (SHBG) (female, 4.47% mediation; male, 2.76% mediation), total testosterone (TT) (male, 3.72% mediation), bioavailable testosterone (BioT) (female, 7.74% mediation), high-density lipoprotein cholesterol (HDL-C) (3.25% mediation), and apolipoprotein A1 (ApoA1) (1.31% mediation) were individual contributors. SHBG (female, 4.10% mediation; male, 1.58% mediation), TT (male, 3.69% mediation), BioT (female, 2.58% mediation), HDL-C (3.32% mediation), ApoA1 (2.14% mediation), and omega-6 fatty acids (2.33% mediation) may have mediating roles to varying degrees in the process of OSA caused by T2DM. Interpretation:This MR study showed that OSA is a risk factor for HBP and T2DM, and the evaluation of mediators may help further reveal the specific mechanism by which OSA causes HBP and T2DM. 10.2147/NSS.S423331
Genetic Analysis of Obstructive Sleep Apnea and Its Relationship with Severe COVID-19. Annals of the American Thoracic Society Although patients with obstructive sleep apnea (OSA) have a higher risk for coronavirus disease (COVID-19) hospitalization, the causal relationship has remained unexplored. To understand the causal relationship between OSA and COVID-19 by leveraging data from vaccination and electronic health records, genetic risk factors from genome-wide association studies, and Mendelian randomization. We elucidated genetic risk factors for OSA using FinnGen (total  = 377,277), performing genome-wide association. We used the associated variants as instruments for univariate and multivariate Mendelian randomization (MR) analyses and computed absolute risk reduction against COVID-19 hospitalization with or without vaccination. We identified nine novel loci for OSA and replicated our findings in the Million Veteran Program. Furthermore, MR analysis showed that OSA was a causal risk factor for severe COVID-19 ( = 9.41 × 10). Probabilistic modeling showed that the strongest genetic risk factor for OSA at the locus reflected a signal of higher body mass index (BMI), whereas BMI-independent association was seen with the earlier reported locus and a locus, which is a transcriptional regulator with 210-fold enrichment in the Finnish population. Similarly, multivariate MR analysis showed that the causality for severe COVID-19 was driven by BMI (multivariate MR  = 5.97 × 10, β = 0.47). Finally, vaccination reduced the risk for COVID-19 hospitalization more in the patients with OSA than in the non-OSA controls, with respective absolute risk reductions of 13.3% versus 6.3%. Our analysis identified novel genetic risk factors for OSA and showed that OSA is a causal risk factor for severe COVID-19. The effect is predominantly explained by higher BMI and suggests BMI-dependent effects at the level of individual variants and at the level of comorbid causality. 10.1513/AnnalsATS.202303-215OC
Genetically predicted obstructive sleep apnea is causally associated with an increased risk for periodontitis. BMC oral health BACKGROUND:Although obstructive sleep apnea (OSA) and periodontitis are associated, whether this association is causative is uncertain. METHODS:We conducted a bidirectional Mendelian randomization (MR) analysis using data from publically accessible genome-wide association studies. The single-nucleotide polymorphisms (SNPs) for OSA were derived from 16,761 cases and 201,194 controls. The pooled data of periodontitis association involved up to 17,353 individuals. Disease-associated single-nucleotide polymorphisms were selected as an instrumental variable at the genome-wide significance level (p < 5.0 × 10). Subsequently, the causal effects were estimated using three different methods: inverse variance weighting (IVW), MR-Egger, and weighted median. Then, these causal estimates were expressed as dominance ratios [odds ratio (OR)]. RESULTS:The MR analysis revealed that genetically determined OSA promotes the development of periodontitis [ IVW OR = 1.117, 95% confidence interval (CI) = 1.001-1.246, p = 0.048). Furthermore, no causal effect of genetically predicted periodontitis on OSA was noted in the reverse MR analysis (IVW OR = 1, 95% CI: 0.95-1.06, p = 0.87). The trend in results from the MR-Egger regression and weighted median (WM) was consistent with that in results from the IVW method. The robustness of the results was confirmed by the sensitivity analysis. CONCLUSIONS:In summary, the results of our MR investigation suggest an association between OSA and periodontitis, proposing that early screening and treatment of OSA is beneficial for the prevention and prognosis of periodontitis. 10.1186/s12903-023-03338-8
Causal association of gastroesophageal reflux disease with obstructive sleep apnea and sleep-related phenotypes: a bidirectional two-sample Mendelian randomization study. Frontiers in neurology Background:The interactions and associations between obstructive sleep apnea (OSA), sleep-related phenotypes (SRPs), and gastroesophageal reflux disease (GERD) are complex, thus it is hard to explore the effect and direction of causalities. Study objectives:A bidirectional Mendelian randomization (MR) study was performed to explore causal associations of GERD with OSA and SRPs (including insomnia, morningness, sleep duration, ease of getting up, daytime napping, daytime dozing, and snoring). Methods:First, we gathered summary statistics from publicly available databases. Subsequently, we identified single-nucleotide polymorphisms without strong linkage (r ≤ 0.001) by referencing relevant genome-wide association studies that met genome-wide significance criteria. Our primary analysis relied on inverse variance weighted to estimate the causal relationship. To ensure the validity of our findings, we also conducted several sensitivity analyses. These included MR Pleiotropy RESidual Sum and Outlier to detect and correct for potential pleiotropic effects, MR-Egger to assess directional pleiotropy, and weighted median analysis to further evaluate heterogeneity and pleiotropy. For the initial MR analysis, when causality was indicated by the results, instrumental variables that were significantly linked to the aforementioned confounding factors were removed. We will re-analyze the data after excluding outcome-related single nucleotide polymorphisms to confirm that the results are still consistent with the previous results. Results:GERD was found to increase the risk of OSA (OR = 1.53, 95% CI = 1.37-1.70, = 5.3 × 10), insomnia (OR = 1.14, 95% CI = 1.10-1.19, = 1.3 × 10), snoring (OR = 1.09, 95% CI = 1.04-1.13, = 6.3 × 10) and less sleep duration (OR = 0.94, 95% CI = 0.91-0.97, = 3.7 × 10). According to the reverse-direction analysis, there is an elevated risk of GERD associated with OSA (OR = 1.07, 95% CI = 1.02-1.12, = 0.005), insomnia (OR = 1.95, 95% CI = 1.60-2.37, = 1.92 × 10) and snoring (OR = 1.74, 95% CI = 1.37-2.21, = 4.4 × 10). Conclusion:Genetic susceptibility to GERD can elevate the likelihood of experiencing insomnia, snoring, and OSA, in addition to diminishing sleep duration. Conversely, a reverse MR analysis indicates that ameliorating any one of insomnia, snoring, or OSA can mitigate the risk of developing GERD. 10.3389/fneur.2023.1283286
Leveraging genetic discoveries for sleep to determine causal relationships with common complex traits. Sleep Sleep occurs universally and is a biological necessity for human functioning. The consequences of diminished sleep quality impact physical and physiological systems such as neurological, cardiovascular, and metabolic processes. In fact, people impacted by common complex diseases experience a wide range of sleep disturbances. It is challenging to uncover the underlying molecular mechanisms responsible for decreased sleep quality in many disease systems owing to the lack of suitable sleep biomarkers. However, the discovery of a genetic component to sleep patterns has opened a new opportunity to examine and understand the involvement of sleep in many disease states. It is now possible to use major genomic resources and technologies to uncover genetic contributions to many common diseases. Large scale prospective studies such as the genome wide association studies (GWAS) have successfully revealed many robust genetic signals associated with sleep-related traits. With the discovery of these genetic variants, a major objective of the community has been to investigate whether sleep-related traits are associated with disease pathogenesis and other health complications. Mendelian Randomization (MR) represents an analytical method that leverages genetic loci as proxy indicators to establish causal effect between sleep traits and disease outcomes. Given such variants are randomly inherited at birth, confounding bias is eliminated with MR analysis, thus demonstrating evidence of causal relationships that can be used for drug development and to prioritize clinical trials. In this review, we outline the results of MR analyses performed to date on sleep traits in relation to a multitude of common complex diseases. 10.1093/sleep/zsac180
The causal relationship between depression and obstructive sleep apnea: A bidirectional Mendelian randomization study. Journal of psychosomatic research OBJECTIVE:Numerous studies have reported the close association of depression with obstructive sleep apnea (OSA). However, the causal nature and direction remain unclear. This study aimed to identify the genetic causal relationship between depression and OSA using Mendelian randomization (MR). METHODS:Based on publicly available genome-wide association studies data of depression and OSA, we conducted a bidirectional two-sample MR study. The inverse-variance weighted (IVW) was used as the main analysis method. Moreover, multivariable MR was performed to further explore the underlying genetic causality of OSA and depression after adjusting for several potential mediators. RESULTS:The univariable MR analysis revealed a significant causality of depression on the susceptibility of OSA (OR = 1.29, 95%CI:1.11,1.50; p < 0.001). This relationship was evidenced by the phenotypes for broad depression (OR = 3.30, 95%CI: 1.73, 6.29; p < 0.001), probable major depression (OR = 18.79, 95%CI: 5.69, 61.99; p < 0.001), and ICD-10 major depression (OR = 23.67, 95%CI: 4.13, 135.74; p < 0.001). In the reverse direction, no significant causal effect of OSA on depression was found. After adjusting for smoking, alcohol use, obesity, type 2 diabetes, insomnia, age, gender, and codeine, most of these results suggested that depression remained significantly and positively associated with OSA. CONCLUSION:These findings may contribute to the understanding of the etiology of depression and OSA and also suggest the clinical significance of controlling depression for the prevention of OSA. 10.1016/j.jpsychores.2024.111620
Obstructive sleep apnea and mental disorders: a bidirectional mendelian randomization study. BMC psychiatry BACKGROUND:Previous studies have reported associations between obstructive sleep apnea (OSA) and several mental disorders. However, further research is required to determine whether these associations are causal. Therefore, we evaluated the bidirectional causality between the genetic liability for OSA and nine mental disorders by using Mendelian randomization (MR). METHOD:We performed two-sample bidirectional MR of genetic variants for OSA and nine mental disorders. Summary statistics on OSA and the nine mental disorders were extracted from the FinnGen study and the Psychiatric Genomics Consortium. The primary analytical approach for estimating causal effects was the inverse-variance weighted (IVW), with the weighted median and MR Egger as complementary methods. The MR Egger intercept test, Cochran's Q test, Rucker's Q test, and the MR pleiotropy residual sum and outlier (MR-PRESSO) test were used for sensitivity analyses. RESULT:MR analyses showed that genetic liability for major depressive disorder (MDD) was associated with an increased risk of OSA (odds ratio [OR] per unit increase in the risk of MDD, 1.29; 95% CI, 1.11-1.49; P < 0.001). In addition, genetic liability for OSA may be associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD) (OR = 1.26; 95% CI, 1.02-1.56; p = 0.032). There was no evidence that OSA is associated with other mental disorders. CONCLUSION:Our study indicated that genetic liability for MDD is associated with an increased risk of OSA without a bidirectional relationship. Additionally, there was suggestive evidence that genetic liability for OSA may have a causal effect on ADHD. These findings have implications for prevention and intervention strategies targeting OSA and ADHD. Further research is needed to investigate the biological mechanisms underlying our findings and the relationship between OSA and other mental disorders. 10.1186/s12888-024-05754-8
Causal association between obstructive sleep apnea and gastroesophageal reflux disease: A bidirectional two-sample Mendelian randomization study. Frontiers in genetics Correlations between obstructive sleep apnea (OSA) and gastroesophageal reflux disease (GERD) have been detected in previous observational studies. However, this association remains uncertain due to the potential presence of selection and confounding biases. Therefore, this bidirectional two-sample Mendelian randomization (MR) study was conducted to evaluate the causal relationship between OSA and GERD. In this study, instrumental variables (IVs) for OSA were selected from publicly available genetic summary data (27,207 cases and 280,720 controls). Summary statistics for GERD were obtained from a genome-wide association study of 602,604 individuals. The inverse variance weighted (IVW) method was used as the main MR method. The MR-Egger intercept test, MR pleiotropy residual sum and outlier, and leave-one-out analysis were used to detect pleiotropy. Heterogeneity was detected by Cochran's Q test. The IVW results revealed that OSA [odds ratio (OR): 1.19, 95% confidence interval (CI): 1.11-1.28, = 8.88E-07] was causally associated with the incidence of GERD. Moreover, there was evidence of GERD leading to OSA in the IVW analysis (OR: 1.44, 95%CI: 1.33-1.57, = 7.74E-19). No directional pleiotropy was detected by the MR-Egger intercept test (all > 0.05). This study found that OSA is linked to a higher incidence of GERD, and . This finding might be helpful for the screening and prevention of these two diseases. 10.3389/fgene.2023.1111144
Causal Effect of Obstructive Sleep Apnea on Atrial Fibrillation: A Mendelian Randomization Study. Journal of the American Heart Association Background Obstructive sleep apnea (OSA) has shown to be associated with an increased risk of atrial fibrillation in observational studies. Whether this association reflect causal effect is still unclear. The aim of this study was to evaluate the causal effect of OSA on atrial fibrillation. Methods and Results We used a 2-sample Mendelian randomization (MR) method to evaluate the causal effect of OSA on atrial fibrillation. Summary data on genetic variant-OSA association were obtained from a recently published genome-wide association studies with up to 217 955 individuals and data on variant-atrial fibrillation association from another genome-wide association study with up to 1 030 836 individuals. Effect estimates were evaluated using inverse-variance weighted method. Other MR analyses, including penalized inverse-variance weighted, penalized robust inverse-variance weighted, MR-Egger, simple median, weighted median, weighted mode-based estimate and Mendelian Randomization Pleiotropy Residual Sum and Outlier methods were performed in sensitivity analyses. The MR analyses in both the fixed-effect and random-effect inverse-variance weighted models showed that genetically predicted OSA was associated with an increased risk of atrial fibrillation (odds ratio [OR], 1.21; 95% CI, 1.12-1.31, <0.001; OR, 1.21; 95% CI, 1.11-1.32, <0.001) using 5 single nucleotide polymorphisms as the instruments. MR-Egger indicated no evidence of genetic pleiotropy (intercept, -0.014; 95% CI, -0.033 to 0.005, =0.14). Results were robust using other MR methods in sensitivity analyses. Conclusions This MR analysis found that genetically predicted OSA had causal effect on an increased risk of atrial fibrillation. 10.1161/JAHA.121.022560
Thyroid cancer and cardiovascular diseases: a Mendelian randomization study. Frontiers in cardiovascular medicine Background:Multiple observational studies have shown associations between thyroid cancer (TC) and cardiovascular diseases (CVDs). However, the results were inconsistent, and the potential causal genetic relationship remains unclear. Methods:The genetic instruments of TC and CVDs were derived from data obtained through genome-wide association studies (GWAS). We performed the two-sample Mendelian randomization(MR) methods to investigate the causality of TC on CVDs. Summary-level statistics for CVDs, including heart failure (HF), atrial fibrillation (AF), coronary artery disease (CAD), myocardial infarction (MI), ischemic stroke (IS) and venous thromboembolism (VTE). The primary method employed in this MR analysis was the Inverse Variance Weighted (IVW) approach, and four additional algorithms were used: MR-Egger, weighted median, simple mode, and weighted mode. Additionally, we assessed the reliability of the causal relationship through pleiotropy, heterogeneity and leave-one-out sensitivity analysis. Results:In this MR analysis, we only detected causality of genetically predicted TC on HF (IVW method, odds ratio (OR) = 1.00134, 95% confidence interval (CI): 1.00023-1.00244,  = 0.017). However, There were no causal associations of TC with CAD, MI, AF, IS, and VTE. Conclusion:Our results confirmed the causal association between TC and HF. It is crucial to closely monitor the incidence of HF in TC patients and give comprehensive clinical intervention based on conventional treatment. 10.3389/fcvm.2024.1344515
An insight into the causal relationship between sarcopenia-related traits and venous thromboembolism: A mendelian randomization study. PloS one BACKGROUND:As a geriatric syndrome, sarcopenia has a high prevalence in the old population and represents an impaired state of health with adverse health outcomes. A strong clinical interest in its relationship with venous thromboembolism (VTE), which is a complex trait disease with a heterogeneous annual incidence rate in different countries, has emerged. The relationship between sarcopenia and venous thromboembolism has been reported in observational studies but the causality from sarcopenia to VTE remained unclarified. We aimed to assess the causal effect of sarcopenia on the risk of VTE with the two-sample Mendelian randomization (MR) method. METHODS:Two sets of single-nucleotide polymorphisms (SNPs), derived from two published genome-wide association study (GWAS) meta-analyses and genetically indexing muscle weakness and lean muscle mass separately, were pooled into inverse variance weighted (IVW), weighted median and MR-Egger analyses. RESULTS:No evidence was found for the causal effect of genetically predicted muscle weakness (IVW: OR = 0.90, 95% CI = 0.76-1.06, p = 0.217), whole body lean mass (IVW: OR = 1.01, 95% CI = 0.87-1.17, p = 0.881) and appendicular lean mass (IVW: OR = 1.13, 95% CI = 0.82-1.57, p = 0.445) on the risk of VTE. However, both genetically predicted whole-body lean mass and appendicular lean mass can causally influence diabetes mellitus (IVW of whole-body lean mass: OR = 0.87, 95% CI = 0.78-0.96, p = 0.008; IVW of appendicular lean mass: OR = 0.71, 95% CI = 0.54-0.94, p = 0.014) and hypertension (IVW of whole-body lean mass: OR = 0.92, 95% CI = 0.87-0.98, p = 0.007; IVW of appendicular lean mass: OR = 0.84, 95% CI = 0.73-0.96, p = 0.013). CONCLUSIONS:Genetically predicted sarcopenia does not causally influence VTE directly, but it might still have an indirect effect on VTE incidence via diabetes mellitus and hypertension. 10.1371/journal.pone.0303148
Serum Albumin and Circulating Metabolites and Risk of Venous Thromboembolism: A Two-Sample Mendelian Randomization Study. Liu Zhengye,Mi Jiarui Frontiers in nutrition Previous observational studies indicated that the serum albumin levels and circulating metabolites are associated with a high risk of venous thromboembolism (VTE). However, whether these observations reflect causality remained unclear. Hence, we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal associations of serum albumin and circulating metabolites with the risk of VTE. Summary statistics of genetic instruments proxying serum albumin, total protein, and common circulating metabolites were extracted from genome-wide association studies in the European ancestry. Summary-level results of age- and sex-adjusted estimates for associations of the instruments with VTE were derived from the FinnGen consortium. We used the inverse-variance weighted (IVW) method as the primary analysis for univariable MR. Sensitivity analyses were performed to detect horizontal pleiotropy and outliers. Genetically proxied high-serum albumin and total protein levels were suggestive protective factor of VTE, with odds ratio (OR) = 0.69 (CI 0.54-0.89, = 4.7 × 10) and 0.76 (CI 0.61-0.95, = 0.015), respectively. Genetically proxied low-monounsaturated fatty acids and the ratio of monounsaturated fatty acid to total fatty acid are causally associated with increased risk of VTE, with ORs = 0.89 (CI 0.80-0.99, = 0.031) and 0.85 (CI 0.78-0.94, = 9.92 × 10), respectively. There is no indication of causal associations between other circulating metabolites and the risk of VTE. Genetically liability to low-serum albumin and total protein levels, low proxied monounsaturated fatty acids (MUFAs) and the ratio of MUFAs to total fatty acids are associated with the higher risk of VTE. 10.3389/fnut.2021.712600
Association between migraine and venous thromboembolism: a Mendelian randomization and genetic correlation study. Frontiers in genetics Objective:Previous observational studies have reported an increased risk of venous thromboembolism (VTE) among individuals with migraine. This study aimed to investigate the causal effect of migraine on the development of VTE, as well as explore the genetic correlation between them. Methods:We conducted a two-sample Mendelian randomization (MR) study using publicly available summary statistics from large-scale genome-wide association studies for migraine and VTE. Linkage disequilibrium score regression analysis was performed to estimate the genetic correlation between migraine and VTE. Results:There were several shared risk variants (-value < 5 × 10) between migraine and VTE. Linkage disequilibrium score regression analysis found a significant positive genetic correlation between migraine and VTE. The genetic correlations based on two migraine datasets were 0.208 (se = 0.031, -value = 2.91 × 10) and 0.264 (se = 0.040, -value = 4.82 × 10), respectively. Although main MR analysis showed that migraine was associated with an increased risk of VTE (odds ratio = 1.069, 95% confidence interval = 1.022-1.118, -value = 0.004), the association attenuated to non-significance when using several other MR methods and using another set of genetic instruments. In addition, evidence of heterogeneity was found. Reverse MR analysis showed VTE was associated with increased risk of migraine with aura (odds ratio = 1.137, 95% confidence interval = 1.062-1.218, -value = 2.47 × 10) with no evidence of pleiotropy and heterogeneity. Conclusion:We showed suggestive evidence indicating an association between migraine and increased risk of VTE. Additionally, we found robust evidence suggesting that VTE is associated with an increased risk of migraine. The positive genetic correlation indicates that migraine and VTE has shared genetic basis. Further investigations will be necessary to address potential sex-specific effects in the analysis. 10.3389/fgene.2024.1272599
Varicose Veins and Risk of Venous Thromboembolic Diseases: A Two-Sample-Based Mendelian Randomization Study. Frontiers in cardiovascular medicine Background:Varicose veins are found to be associated with increased risk of venous thromboembolism (VTE) in many observational studies, but whether varicose veins are causally associated with VTE remains unclear. Therefore, we used a series of Mendelian randomization (MR) methods to investigate that association. Methods:23 independent single-nucleotide polymorphisms (SNPs) for varicose veins were obtained from the Pan UK Biobank analysis. The outcomes datasets for deep vein thrombosis (DVT), pulmonary embolism (PE) and venous thromboembolism (VTE) were obtained from the FinnGen study. Before analysis, body mass index (BMI) and height were included as confounders in our MR model. Basic MR [inverse-variance weighted (IVW), weight-median, penalized weighted-median and MR-Egger methods] and MR-PRESSO were performed against each outcome using the whole SNPs and SNPs after excluding those associated with confounders. If causal associations were suggested for any outcome, a basic MR validation analysis, a multivariable MR analysis with BMI and height, a Causal Analysis Using Summary Effect estimates (CAUSE), and a two-step MR analysis with BMI and height, would follow. Results:Using 21 qualified SNPs, the IVW method (OR: 1.173, 95% CI: 1.070-1.286, < 0.001, FDR = 0.002), the weighted median method (OR: 1.255, 95% CI: 1.106-1.423, < 0.001, FDR = 0.001), the penalized weighted median method (OR: 1.299, 95% CI: 1.128-1.495, < 0.001, FDR = 0.001) and the MR-PRESSO (OR: 1.165, 95% CI: 1.067-1.273, = 0.003, FDR = 0.009) suggested potential causal effect of varicose veins on DVT, but no cause effect was found for PE and VTE. Excluding SNPs associated with confounders yielded similar results. The causal association with DVT was validated using a self-reported DVT cohort (IVW, OR: 1.107, 95% CI: 1.041-1.178, = 0.001). The causal association maintained after adjustment for height (OR = 1.105, 95% CI: 1.028-1.188, = 0.007), BMI (OR = 1.148, 95% CI: 1.059-1.244, < 0.001) and them both (OR = 1.104, 95% CI: 1.035-1.177, = 0.003). The causal association also survived the strict CAUSE ( = 0.018). Finally, in two-step MR, height and BMI were found to have causal effects on both varicose veins and DVT. Conclusion:Genetically predicted varicose veins may have a causal effect on DVT and may be one of the mediators of obesity and taller height that predispose to DVT. 10.3389/fcvm.2022.849027
Causal relationships between risk of venous thromboembolism and 18 cancers: a bidirectional Mendelian randomization analysis. International journal of epidemiology BACKGROUND:People with cancer experience high rates of venous thromboembolism (VTE). Risk of subsequent cancer is also increased in people experiencing their first VTE. The causal mechanisms underlying this association are not completely understood, and it is unknown whether VTE is itself a risk factor for cancer. METHODS:We used data from large genome-wide association study meta-analyses to perform bidirectional Mendelian randomization analyses to estimate causal associations between genetic liability to VTE and risk of 18 different cancers. RESULTS:We found no conclusive evidence that genetic liability to VTE was causally associated with an increased incidence of cancer, or vice versa. We observed an association between liability to VTE and pancreatic cancer risk [odds ratio for pancreatic cancer: 1.23 (95% confidence interval: 1.08-1.40) per log-odds increase in VTE risk, P = 0.002]. However, sensitivity analyses revealed this association was predominantly driven by a variant proxying non-O blood group, with inadequate evidence to suggest a causal relationship. CONCLUSIONS:These findings do not support the hypothesis that genetic liability to VTE is a cause of cancer. Existing observational epidemiological associations between VTE and cancer are therefore more likely to be driven by pathophysiological changes which occur in the setting of active cancer and anti-cancer treatments. Further work is required to explore and synthesize evidence for these mechanisms. 10.1093/ije/dyad170
Exploring the Two-Way Link between Migraines and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study. Thrombosis and haemostasis BACKGROUND: The objective of this study is to utilize Mendelian randomization to scrutinize the mutual causality between migraine and venous thromboembolism (VTE) thereby addressing the heterogeneity and inconsistency that were observed in prior observational studies concerning the potential interrelation of the two conditions. METHODS: Employing a bidirectional Mendelian randomization approach, the study explored the link between migraine and VTE, incorporating participants of European descent from a large-scale meta-analysis. An inverse-variance weighted (IVW) regression model, with random-effects, leveraging single nucleotide polymorphisms (SNPs) as instrumental variables was utilized to endorse the mutual causality between migraine and VTE. SNP heterogeneity was evaluated using Cochran's Q-test and to account for multiple testing, correction was implemented using the intercept of the MR-Egger method, and a leave-one-out analysis. RESULTS: The IVW model unveiled a statistically considerable causal link between migraine and the development of VTE (odds ratio [OR] = 96.155, 95% confidence interval [CI]: 4.342-2129.458,  = 0.004), implying that migraine poses a strong risk factor for VTE development. Conversely, both IVW and simple model outcomes indicated that VTE poses as a weaker risk factor for migraine (IVW OR = 1.002, 95% CI: 1.000-1.004,  = 0.016). The MR-Egger regression analysis denoted absence of evidence for genetic pleiotropy among the SNPs while the durability of our Mendelian randomization results was vouched by the leave-one-out sensitivity analysis. CONCLUSION: The findings of this Mendelian randomization assessment provide substantiation for a reciprocal causative association between migraine and VTE within the European population. 10.1055/a-2313-0311
Causal effect of renal function on venous thromboembolism: a two-sample Mendelian randomization investigation. Journal of thrombosis and thrombolysis Whether renal function is causally associated with venous thromboembolism (VTE) is not yet fully elucidated. We conducted a two-sample Mendelian randomization (MR) study to determine the causal effect of renal function, measured as estimated glomerular filtration rate (eGFR), on VTE. Single-nucleotide polymorphisms associated with eGFR were selected as instrumental variables at the genome-wide significance level (p < 5 × 10) from a meta-analysis of 122 genome-wide association studies including up to 1,046,070 individuals. Summary-level data for VTE were obtained from the FinnGen consortium (6913 VTE cases and 169,986 non-cases) and UK Biobank study (4620 VTE cases and 356,574 non-cases). MR estimates were calculated using the random-effects inverse-variance weighted method and combined using fixed-effects meta-analysis. Genetically predicted decreased eGFR was significantly associated with an increased risk of VTE in both FinnGen and UK Biobank. For one-unit decrease in log-transformed eGFR, the odds ratios of VTE were 2.93 (95% confidence interval (CI) 1.25, 6.84) and 4.46 (95% CI 1.59, 12.5) when using data from FinnGen and UK Biobank, respectively. The combined odds ratio was 3.47 (95% CI 1.80, 6.68). Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. This MR-study supported a casual role of impaired renal function in VTE. 10.1007/s11239-021-02494-4
Genome-wide meta-analysis identifies 93 risk loci and enables risk prediction equivalent to monogenic forms of venous thromboembolism. Nature genetics We report a genome-wide association study of venous thromboembolism (VTE) incorporating 81,190 cases and 1,419,671 controls sampled from six cohorts. We identify 93 risk loci, of which 62 are previously unreported. Many of the identified risk loci are at genes encoding proteins with functions converging on the coagulation cascade or platelet function. A VTE polygenic risk score (PRS) enabled effective identification of both high- and low-risk individuals. Individuals within the top 0.1% of PRS distribution had a VTE risk similar to homozygous or compound heterozygous carriers of the variants G20210A (c.*97 G > A) in F2 and p.R534Q in F5. We also document that F2 and F5 mutation carriers in the bottom 10% of the PRS distribution had a risk similar to that of the general population. We further show that PRS improved individual risk prediction beyond that of genetic and clinical risk factors. We investigated the extent to which venous and arterial thrombosis share clinical risk factors using Mendelian randomization, finding that some risk factors for arterial thrombosis were directionally concordant with VTE risk (for example, body mass index and smoking) whereas others were discordant (for example, systolic blood pressure and triglyceride levels). 10.1038/s41588-022-01286-7
Association between uric acid and risk of venous thromboembolism in East Asian populations: a cohort and Mendelian randomization study. The Lancet regional health. Western Pacific Background:Serum uric acid (SUA) levels have been associated with an increased risk and recurrence of venous thromboembolism (VTE) in European populations, but the potential causal relationship remains unclear. Large-scale studies on the association between SUA and VTE in East Asian populations are lacking, despite the high prevalence of hyperuricemia in this region. To address this, we conducted a cohort analysis and a two-sample Mendelian randomization (MR) study in East Asian populations. Methods:We collected data on VTE patients from the China Pulmonary Thromboembolism Registry Study (CURES) and compared them to controls obtained from the China Health and Retirement Longitudinal Survey (CHARLS). Propensity score matching (PSM) and cubic-spline models were applied to assess the effect of SUA on VTE risk while adjusting for multiple covariates. We also performed two-sample MR analyses to infer potential causality based on summary statistics from Genome-wide Association Studies (GWAS) of SUA and VTE in the East Asian population. Findings:We found that the SUA levels were higher in VTE patients (317.95 mmol/L) compared to the general population (295.75 mmol/L), and SUA ≥ 325 mmol/L was associated with an increased risk of VTE recurrence ( = 0.0001). The univariable MR suggested a causal relationship between elevated SUA and higher VTE risk ( < 0.05), and multivariable MR showed that elevated SUA levels continued to promote the development of VTE after adjusting for multiple covariates ( < 0.05). Sensitivity analyses produced similar results for these estimations. Interpretation:Our study provides evidence supporting a robust positive association between SUA and VTE in the East Asian population, and MR analyses suggest that this association is likely to be causal. Our findings underscore the importance of monitoring SUA levels in VTE prevention and call for urgent action to address the growing burden of hyperuricemia in the Asia-Pacific region. Funding:This research was funded by Beijing Nova Program (No. Z211100002121057), National Natural Science Foundation of China (No. 82100065 and No. 62350004), CAMS Innovation Fund for Medical Sciences (No. 2021-I2M-1-061 and No. 2021-1-I2M-001), Elite Medical Professionals project of China-Japan Friendship Hospital (No. ZRJY2021-QM12), National Key Research and Development Project (No. 2021YFF1201200 and No. 2022YFC3341004). 10.1016/j.lanwpc.2023.100848
Obesity as a causal risk factor for deep venous thrombosis: a Mendelian randomization study. Klovaite J,Benn M,Nordestgaard B G Journal of internal medicine OBJECTIVE:To test the hypothesis that obesity is causally associated with deep venous thrombosis (DVT). DESIGN:A Mendelian randomization design. SETTING:The Copenhagen General Population Study and the Copenhagen City Heart Study combined. SUBJECTS:Body mass index (BMI) measurements were available for 87, 574 individuals of Danish descent from the adult general population. All subjects completed questionnaires and were genotyped for the FTO rs9939609 variant. MAIN OUTCOME MEASURE:First events of DVT with or without pulmonary embolism (PE). ANALYSIS:The results were assessed using Cox regression, instrumental variable analysis and Poisson regression. RESULTS:Observationally, the risk of DVT increased with increasing BMI (P-trend < 0.0001). The multivariable-adjusted hazard ratio [95% confidence interval (CI)] for DVT was 1.3 (1.1-1.6) in overweight, 1.8 (1.4-2.2) in moderately obese and 3.4 (2.6-4.6) in severely obese compared with normal-weight individuals. For DVT complicated by PE, corresponding hazard ratios (95% CI) were 1.2 (0.8-1.8), 2.1 (1.3-3.5) and 5.1 (2.8-9.2). FTO AA versus TT genotype was associated with a 2.4% increase in BMI with hazard ratios (95% CI) of 1.09 (0.95-1.25) for DVT and 1.54 (1.12-2.10) for DVT complicated by PE. In instrumental variable analysis, the causal odds ratio (95% CI) for an increase in BMI of 1 kg m(-2) was 1.13 (0.92-1.39) for DVT alone and 1.86 (1.14-3.02) for DVT complicated by PE. The absolute 10-year risk of DVT in a high-risk group (i.e. those aged >60 years and homozygous for Factor V Leiden) was 35% in obese individuals and 18% in normal-weight individuals. CONCLUSION:A strong observational association between obesity and DVT with or without PE, supported by a direct genetic association between the obesity-specific locus FTO and DVT with PE, implies that obesity is likely to be causally associated with DVT. 10.1111/joim.12299
Causal effect of serum matrix metalloproteinase levels on venous thromboembolism: a Mendelian randomization study. Epidemiology and health Objectives:Serum matrix metalloproteinase (MMP) levels are associated with cardiovascular diseases. However, the causal associations between serum levels of specific MMPs and venous thromboembolism (VTE) remain unclear. The present study sought to explore the causal relationship between serum MMP levels and VTE by using the Mendelian randomization (MR) method. Methods:In this study 2-sample MR study, the exposure data on serum MMP levels were derived from genome-wide association studies involving 21,758 individuals from 13 cohorts of European descent. The outcome data on VTE, including deep vein thrombosis and pulmonary embolism, were derived from the FinnGen research project. The primary method used was the inverse-variance weighting method. The MR-Egger intercept test and the Cochran Q test were used to evaluate pleiotropy and heterogeneity. Results:Using the inverse-variance weighting method, higher serum MMP-12 levels were found to be associated with an increased risk of VTE (odds ratio, 1.04; 95% confidence interval, 1.01-1.07; p=0.0015). Moreover, there was a weak association between the levels of certain MMPs and VTE. Sensitivity analyses revealed no significant heterogeneity and pleiotropy in our study, and the Steiger directionality test did not reveal a significant reverse causation association. Conclusion:: There is a causal association between MMP-12 levels and VTE, which may have substantial implications for the diagnostic and therapeutic strategies used for VTE. 10.4178/epih.e2024046
The Association between Obstructive Sleep Apnea and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study. Thrombosis and haemostasis BACKGROUND: Despite previous observational studies linking obstructive sleep apnea (OSA) to venous thromboembolism (VTE), these findings remain controversial. This study aimed to explore the association between OSA and VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT), at a genetic level using a bidirectional two-sample Mendelian randomization (MR) analysis. METHODS: Utilizing summary-level data from large-scale genome-wide association studies in European individuals, we designed a bidirectional two-sample MR analysis to comprehensively assess the genetic association between OSA and VTE. The inverse variance weighted was used as the primary method for MR analysis. In addition, MR-Egger, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) were used for complementary analyses. Furthermore, a series of sensitivity analyses were performed to ensure the validity and robustness of the results. RESULTS: The initial and validation MR analyses indicated that genetically predicted OSA had no effects on the risk of VTE (including PE and DVT). Likewise, the reverse MR analysis did not find substantial support for a significant association between VTE (including PE and DVT) and OSA. Supplementary MR methods and sensitivity analyses provided additional confirmation of the reliability of the MR results. CONCLUSION: Our bidirectional two-sample MR analysis did not find genetic evidence supporting a significant association between OSA and VTE in either direction. 10.1055/a-2308-2290
Plasma levels of growth differentiation factor 15 are associated with future risk of venous thromboembolism. Hansen Ellen-Sofie,Hindberg Kristian,Latysheva Nadezhda,Aukrust Pål,Ueland Thor,Hansen John-Bjarne,Brækkan Sigrid K,Morelli Vânia M, Blood Growth differentiation factor 15 (GDF-15), a marker of inflammation and oxidative stress, has emerged as a biomarker for arterial cardiovascular disease. However, the association between GDF-15 and venous thromboembolism (VTE) remains uncertain. We therefore investigated the association between plasma GDF-15 levels and future risk of incident VTE and explored the potential of a causal association using Mendelian randomization (MR). We conducted a population-based nested case-control study comprising 416 VTE patients and 848 age- and sex-matched controls derived from the Tromsø Study. Logistic regression was used to calculate odds ratios (ORs) for VTE across GDF-15 quartiles. For the MR, we used data from the International Network on Venous Thrombosis (INVENT) consortium to examine whether single nucleotide polymorphisms (SNPs) associated with GDF-15 levels with genome-wide significance were related to VTE. We found that the ORs for VTE increased across GDF-15 quartiles (Ptrend = .002). Participants with GDF-15 values in the highest quartile (≥358 pg/mL) had an OR for VTE of 2.05 (95% confidence interval, 1.37-3.08) compared with those with GDF-15 in the lowest quartile (<200 pg/mL) in the age- and sex-adjusted model. ORs remained essentially the same after further adjustment for body mass index, smoking, hormone therapy, physical activity, and C-reactive protein. Similar results were obtained for provoked/unprovoked events, deep vein thrombosis, and pulmonary embolism. GDF-15 levels, as predicted by the SNPs, were not associated with VTE in MR. Our results indicate that high GDF-15 levels are associated with increased risk of VTE, but MR suggests that this association is not causal. 10.1182/blood.2019004572
The causal relationship between metabolic syndrome and its components and cardiovascular disease: A mendelian randomization study. Diabetes research and clinical practice AIM:To investigate the causal relationship between metabolic syndrome (MetS) and its components and 14 cardiovascular diseases using Mendelian randomization (MR). METHODS:We used summary statistics from large-scale genome-wide association studies of MetS, its components, and cardiovascular diseases. We performed a two-sample MR analysis using the inverse-variance weighted method and other sensitivity methods. We also performed multivariate MR to adjust for potential risk factors. RESULTS:Our study found that MetS was causally associated with an increased risk of ischemic stroke, abdominal aortic aneurysm, pulmonary embolism, coronary heart disease, heart failure, and peripheral artery disease. Waist circumference was causally associated with an increased risk of 6 cardiovascular diseases. Type 2 diabetes mellitus, diastolic blood pressure, systolic blood pressure, triglycerides, and high-density lipoprotein cholesterol were all causally associated with coronary heart disease, with varying causal relationships with the remaining 5 cardiovascular diseases. Multivariate MR showed that, except for ischaemic stroke, waist circumference remained causally associated with the remaining five cardiovascular diseases after adjusting for potential confounders. CONCLUSION:Our study provides evidence that metabolic syndrome is causally associated with 6 cardiovascular diseases. Waist circumference is the most important component of these relationships. These findings have implications for the prevention and management of metabolic syndrome and cardiovascular diseases. 10.1016/j.diabres.2024.111679
No Genetic Causality between Tobacco Smoking and Venous Thromboembolism: A Two-Sample Mendelian Randomization Study. Thrombosis and haemostasis BACKGROUND: Given the current debate in clinical research about the relationship between tobacco smoking and the risk of venous thromboembolism (VTE), a Mendelian randomization (MR) study was conducted aimed at elucidating the causal associations of current and past tobacco smoking with the risk of VTE, from the perspective of genetics. METHODS: Two-sample univariate and multivariable MR analyses were designed, using summary-level data from large genome-wide association studies involving European individuals. Causality was primarily assessed using multiplicative fixed-effects or random-effects model and inverse variance weighting, supplemented by MR-Egger regression, MR-PRESSO, Cochran's Q test, and leave-one-out for sensitivity analysis to test the reliability of the results. RESULTS: In the univariate MR analysis, no significant causal effects were found between current tobacco smoking and the risk of VTE, deep vein thrombosis (DVT), and pulmonary embolism (PE). Similarly, no significant causal effects were found between past smoking and VTE, DVT, and PE. As for the multivariable MR analysis, results were consistent with univariate MR analysis, with no significant causal effect of either current or past tobacco smoking on the risk of VTE, DVT, and PE. CONCLUSION: Evidence from both univariate and multivariable MR analyses demonstrated no significant causal relationships between current and past tobacco smoking and VTE, DVT, and PE. This contradicts positive correlations reported in some previous observational studies, which may be explained by other confounding factors. This provided genetic evidence for the conclusion reported in other observational studies that smoking did not affect VTE risk. 10.1055/s-0044-1781425
Evidence for causal effects of neuropsychiatric conditions on risk of venous thromboembolism: A univariable and multivariable Mendelian randomization study. Journal of vascular surgery. Venous and lymphatic disorders BACKGROUND:Substantial observational evidence suggests an association between neuropsychiatric conditions and venous thromboembolism (VTE). However, the causal relationship between these two conditions requires further investigation. Therefore, we used a two-sample Mendelian randomization (MR) approach to assess the bidirectional causal effects between four neuropsychiatric conditions and VTE, deep vein thrombosis, and pulmonary embolism (PE). METHODS:Genetic variants associated with four neuropsychiatric conditions (ie, schizophrenia, major depressive disorder [MDD], bipolar disorder, and epilepsy) and VTE, deep vein thrombosis, and PE were selected. Bidirectional univariable and multivariable MR methods were applied to evaluate the causal relationships among these conditions. The primary causal estimates were obtained using the inverse variance weighted method with multiplicative random effects, supplemented by MR Egger regression, weighted median, simple mode, and weighted mode. Sensitivity analysis was conducted using the MR pleiotropy residual sum, funnel plots, and outlier (MR pleiotropy and residual sum and outlier) method. RESULTS:Univariable MR results showed that genetic susceptibility to MDD increases the risk of VTE and PE (VTE: odds ratio [OR], 1.25; 95% confidence interval [CI], 1.08-1.46; P = .004; PE: OR, 1.36; 95% CI, 1.09-1.69; P = .006) and that PE has an adverse causal effect on MDD (OR, 1.02; 95% CI, 1.00-1.04; P = .026). Adjustment for confounders such as obesity, sleep duration, smoking, physical activity, and alcohol consumption revealed that increased genetic susceptibility to MDD is also associated with VTE and PE. CONCLUSIONS:Our results suggest that genetic susceptibility to MDD might have an adverse causal effect on the risk of VTE and PE and that PE has a reverse causal effect on MDD. Prevention and early diagnosis of depression are crucial in the management of VTE and PE. 10.1016/j.jvsv.2024.101889
Genetic association and causal inference between lung function and venous thromboembolism. Respiratory research BACKGROUND:Previous studies have indicated that lower lung function is related to a higher risk of venous thromboembolism (VTE). However, causal inferences may be affected by confounders, coheritability or reverse causality. We aimed to explore the causal association between lung function and VTE. METHODS:Summary data from public genome-wide association studies (GWAS) for lung function and VTE were obtained from published meta-analysis studies and the FinnGen consortium, respectively. Independent genetic variables significantly related to exposure were filtered as proxy instruments. We adopted linkage disequilibrium score regression (LDSC) and two-sample Mendelian randomization (MR) analyses to infer the genetic backgrounds and causal associations between different lung functions and VTE events. RESULTS:LDSC showed a genetic correlation between forced expiratory volume in one second (FEV1) and deep vein thrombosis (DVT) (rg = - 0.189, P = 0.005). In univariate MR (UVMR), there was suggestive evidence for causal associations of genetically predicted force vital capacity (FVC) with DVT (odds ratio (OR) 0.774; 95% confidence interval (CI) 0.641-0.934) via forwards analysis and genetically predicted pulmonary embolism (PE) with FVC (OR 0.989; 95% CI 0.979-0.999) via reverse analysis. Multivariate MR (MVMR) analyses of lung function-specific SNPs suggested no significant direct effects of lung function on VTE, and vice versa. Of note is the borderline causal effect of PE on FEV1 (OR 0.921; 95% CI 0.848-1.000). CONCLUSIONS:Our findings identified a coheritability of FEV1 (significant) and FVC (suggestive) with DVT. There was no convincing causal relationship between lung function and the risk of VTE events. The borderline causal effect of PE on FEV1 and the significant genetic correlation of FEV1 with DVT may have clinical implications for improving the quality of existing prevention and intervention strategies. 10.1186/s12931-023-02335-3
Causal Associations Between Cardiovascular Risk Factors and Venous Thromboembolism. Seminars in thrombosis and hemostasis OBJECTIVE: The aim of the study is to assess the causal effects of cardiovascular risk factors on venous thromboembolism (VTE) and its subtypes including deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS: A summary-level Mendelian randomization (MR) analysis was performed by extracting data from public and large-scale genome-wide association studies for cardiovascular risk factors (hypertension, systolic blood pressure [SBP], diastolic blood pressure [DBP], total cholesterol, triglycerides, high-density lipoprotein [HDL], low-density lipoprotein [LDL], type 2 diabetes, fasting glucose, body mass index [BMI], smoking, alcohol, and physical activity), VTE, DVT, and PE to identify genetic instruments. RESULTS: BMI (per standard deviation [SD] increase; odds ratio [OR]: 1.39; 95% confidence interval [CI]: 1.25-1.54;  = 8.02 × 10) could increase the VTE risk, whereas SBP (per SD increase; OR: 0.99; 95% CI: 0.98-0.99;  = 0.0005) could decrease the VTE risk. For DVT, BMI (per SD increase; OR: 1.48; 95% CI: 1.28-1.72;  = 1.53 × 10) could increase the risk, whereas physical activity (per SD increase; OR: 0.05; 95% CI: 0.01-0.33;  = 0.0020) could decrease the risk. For PE, BMI (per SD increase; OR: 1.29; 95% CI: 1.12-1.49;  = 0.0005) could increase the risk, whereas SBP (per SD increase; OR: 0.99; 95% CI: 0.98-1.00;  = 0.0032) could decrease the risk. Suggestive evidence between smoking and higher risks of VTE and DVT was also observed. CONCLUSION: Our study supports that BMI is a causal risk factor for VTE, DVT, and PE. SBP is a protective factor for VTE and PE. Physical activity is a protective factor for DVT. However, the effects of other cardiovascular risk factors are not identified. 10.1055/s-0042-1760335
Circulating Cytokines and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study. Thrombosis and haemostasis BACKGROUND: Epidemiological evidence has linked circulating cytokines to venous thromboembolism (VTE). However, it remains uncertain whether these associations are causal due to confounding factors or reverse causality. We aim to explore the causality between circulating cytokines and VTE, encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS: In the current bidirectional Mendelian randomization (MR) study, instrumental variables of 41 circulating cytokines were obtained from the genome-wide association study meta-analyses (8,293 individuals). Summary statistics for the association of VTE (17,048 cases and 325,451 controls), DVT (8,077 cases and 295,014 controls), and PE (8,170 cases and 333,487 controls) were extracted from the FinnGen Study. A multivariable MR study was conducted to adjust for potential confounders. The inverse-variance weighted method was employed as the main analysis, and comprehensive sensitivity analyses were conducted in the supplementary analyses. RESULTS: The MR analysis indicated stromal cell-derived factor-1α was suggestively associated with a reduced risk of VTE (odds ratio [OR]: 0.90; 95% confidence interval [CI]: 0.81-0.99;  = 0.033) and DVT (OR: 0.85; 95% CI: 0.75-0.97;  = 0.015). In addition, suggestive association of granulocyte colony-stimulating factor with PE (OR: 1.20; 95% CI: 1.06-1.37;  = 0.005) was observed. Multivariable MR analysis showed that the effect of cytokines on VTE was partly mediated through hemoglobin A1c and systolic blood pressure. Reverse MR analysis revealed that VTE was linked to decreased levels of several cytokines. CONCLUSION: We provide suggestive genetic evidence supporting the bidirectional causal effect between circulating cytokines and VTE, highlighting the importance of targeting circulating cytokines to reduce the incidence of VTE. 10.1055/s-0043-1777351
Circulating adipokine concentrations and the risk of venous thromboembolism: A Mendelian randomization and mediation analysis. Frontiers in genetics Previous observational studies have suggested that circulating adipokine concentrations are related to a greater risk of venous thromboembolism (VTE). However, it remained unclear whether these observations reflect causality. This study aimed to investigate the causal relationship between circulating adipokine concentrations (including adiponectin, leptin, PAI-1, MCP-1, leptin receptor, and RETN) and the risk of VTE and its subtypes (DVT and PE) and to determine whether circulating adipokine concentrations are a mediator of venous thromboembolic events in obese patients. We used Mendelian randomization (MR) analyses to determine the effects of the body mass index (BMI), adiponectin, leptin, PAI-1, MCP-1, leptin receptor, and RETN levels on VTE, DVT, and PE in a cohort of 11,288 VTE cases, 5,632 DVT cases, 5,130 PE cases, and 254,771 controls. We then assessed the proportion of the effect of obesity on VTE, DVT, and PE explained by circulating leptin levels. Genetically predicted higher BMI was related to increased VTE (OR = 1.45, < 0.001), DVT (OR = 1.63, < 0.001), and PE (OR = 1.37, < 0.001) risk, and higher circulating leptin levels increase odds of VTE (OR = 1.96, q < 0.001), DVT (OR = 2.52, q < 0.001), and PE (OR = 2.26, q = 0.005). In addition, we found that the causal effect between elevated serum adiponectin and the decreased risk of VTE (OR = 0.85, = 0.013, q = 0.053) and PE (OR = 0.81, = 0.032, q = 0.083) and between MCP-1 and the reduced risk of VTE (OR = 0.88, = 0.048, q = 0.143) is no longer significant after FDR adjustment. In MR mediation analysis, the mediation effect of circulating leptin levels in the causal pathway from BMI to PE was estimated to be 1.28 (0.95-1.71, = 0.10), accounting for 39.14% of the total effect. The circulating leptin level is a risk factor for VTE, DVT, and PE, but it might be a potential mediator of BMI on the risk of PE, and thus, interventions on the circulating leptin level in obesity might reduce the risk of PE. Adiponectin is a potential protective factor for both VTE and PE. 10.3389/fgene.2023.1113111
Two-sample Mendelian randomization analysis reveals causal relationships between blood lipids and venous thromboembolism. Haematologica Venous Thromboembolism (VTE) is a complex disease that can be classified into two subtypes: Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE). Previous observational studies have shown associations between lipids and VTE, but causality remains unclear. Hence, by utilizing 241 lipid-related traits as exposures and data from the FinnGen consortium on VTE, DVT, and PE as outcomes, we conducted two-sample Mendelian randomization (MR) analysis to investigate causal relationships between lipids and VTE, DVT and PE. The MR results identified that fatty acid (FA) unsaturation traits (Ratio of bis-allylic bonds to double bonds in lipids, and Ratio of bis-allylic bonds to total fatty acids in lipids) were associated with VTE (OR [95% CI]: 1.21 [1.15-1.27]; 1.21 [1.13-1.30]), DVT (OR [95%CI]: 1.24 [1.16-1.33]; 1.26 [1.16-1.36]) and PE (OR [95%CI]: 1.18 [1.08-1.29]; 1.18 [1.09-1.27]). Phosphatidylcholines exhibit potential causal effects on VTE and PE. Phosphatidylcholine acyl-alkyl C40:4 (PC ae C40:4) was negatively associated with VTE (OR [95% CI]: 0.79 [0.73-0.86]), while phosphatidylcholine diacyl C42:6 (PC aa C42:6) and phosphatidylcholine acyl-alkyl C36:4 (PC ae C36:4) were positively associated with PE (OR [95%CI]: 1.44 [1.20-1.72]; 1.22 [1.10-1.35]). Additionally, we found that medium LDL had a protective effect on VTE. Our study indicates that higher FA unsaturation may increase the risk of VTE, DVT, and PE. Different types of phosphatidylcholine have either promotive or inhibitory effects on VTE and PE, contributing to a better understanding of the risk factors for VTE. 10.3324/haematol.2023.284566
Genetically predicted basal metabolic rate and venous thromboembolism risk: a Mendelian randomization study. Frontiers in nutrition Background:Basal metabolic rate (BMR) is the minimum amount of energy needed by the body to carry out essential physiological functions. The goal of this study was to evaluate whether BMR causally influences venous thromboembolism (VTE) and its subtypes in European individuals. Methods:A two-sample Mendelian randomization (MR) was performed. Within a genome-wide association study (GWAS) involving 454,874 people, genetic variants were chosen as instrumental variables based on their significant associations ( < 5 × 10) with BMR and their limited linkage disequilibrium ( < 0.001). The FinnGen project served as sources for summary statistics of VTE, encompassing different subtypes. Results:Using the multiplicative random-effect inverse variance weighted method, our investigation revealed that one standard deviation higher BMR was associated with VTE (odds ratio [OR] = 1.684, 95% confidence interval [CI]: 1.465-1.936,  = 2.339 × 10), PE (OR = 1.824, 95% CI: 1.512-2.200,  = 3.399 × 10), and DVT of lower extremities (OR = 1.887, 95% CI: 1.562-2.280,  = 4.778 × 10). The consistency of these associations was observed in sensitivity analyses using various MR techniques like Mendelian randomization pleiotropy residual sum and outlier, MR-Egger, weighted median, and contamination mixture method. In addition, multivariable MR revealed direct effects of BMR on VTE and its subtypes when taking body mass index and current tobacco smoking into account. Conclusion:Higher BMR may increase the risk of VTE and its subtypes including PE and DVT of lower extremities. 10.3389/fnut.2023.1263804
Blood pressure and risk of venous thromboembolism: a cohort analysis of 5.5 million UK adults and Mendelian randomization studies. Cardiovascular research AIMS:Evidence for the effect of elevated blood pressure (BP) on the risk of venous thromboembolism (VTE) has been conflicting. We sought to assess the association between systolic BP and the risk of VTE. METHODS AND RESULTS:Three complementary studies comprising an observational cohort analysis, a one-sample and two-sample Mendelian randomization were conducted using data from 5 588 280 patients registered in the Clinical Practice Research Datalink (CPRD) dataset and 432 173 UK Biobank participants with valid genetic data. Summary statistics of International Network on Venous Thrombosis genome-wide association meta-analysis was used for two-sample Mendelian randomization. The primary outcome was the first occurrence of VTE event, identified from hospital discharge reports, death registers, and/or primary care records. In the CPRD cohort, 104 017(1.9%) patients had a first diagnosis of VTE during the 9.6-year follow-up. Each 20 mmHg increase in systolic BP was associated with a 7% lower risk of VTE [hazard ratio: 0.93, 95% confidence interval (CI): (0.92-0.94)]. Statistically significant interactions were found for sex and body mass index, but not for age and subtype of VTE (pulmonary embolism and deep venous thrombosis). Mendelian randomization studies provided strong evidence for the association between systolic BP and VTE, both in the one-sample [odds ratio (OR): 0.69, (95% CI: 0.57-0.83)] and two-sample analyses [OR: 0.80, 95% CI: (0.70-0.92)]. CONCLUSION:We found an increased risk of VTE with lower BP, and this association was independently confirmed in two Mendelian randomization analyses. The benefits of BP reduction are likely to outweigh the harms in most patient groups, but in people with predisposing factors for VTE, further BP reduction should be made cautiously. 10.1093/cvr/cvac135
Plasma Phospholipid Fatty Acids and Risk of Venous Thromboembolism: Mendelian Randomization Investigation. Nutrients Circulating fatty acids may affect thrombosis but epidemiological data on the associations between fatty acids and risk of venous thromboembolism (VTE) are limited and conflicting. We conducted a Mendelian randomization study to examine the causal associations of 10 circulating fatty acids with VTE risk. Genetic variants strongly associated with ten fatty acids and without linkage disequilibrium were selected as instrumental variables from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Genetic associations for VTE and its subtypes were obtained from the International Network Against Venous Thrombosis Consortium (30,234 cases and 172,122 controls) and the FinnGen study (11,288 VTE cases and 254,771 controls). Estimates from the two data sources were combined. Per standard deviation increase in genetically predicted fatty acid levels, the combined odds ratio (OR) of VTE was 0.88 (95% confidence interval [CI] 0.84-0.92) for α-linolenic acid, 0.92 (95% CI 0.90-0.95) for linoleic acid, 0.85 (95% CI 0.78-0.92) for palmitoleic acid, 0.77 (95% CI 0.77-0.84) for oleic acid, 1.16 (95% CI 1.10-1.23) for eicosapentaenoic acid, 1.10 (95% CI 1.06-1.14) for docosapentaenoic acid, 1.06 (95% CI 1.04-1.08) for arachidonic acid, and 1.19 (95% CI 1.11-1.28) for stearic acid. Genetically predicted levels of docosahexaenoic acid or palmitoleic acid were not associated with VTE risk. Four and eight out of ten genetically predicted fatty acid levels were associated with risk of pulmonary embolism and deep vein thrombosis, respectively. This study suggests that strategies targeting at fatty acids may act as prevention approaches for VTE. 10.3390/nu14163354
Gastroesophageal reflux disease and the risk of respiratory diseases: a Mendelian randomization study. Journal of translational medicine BACKGROUND:Observational studies have suggested a suspected association between gastroesophageal reflux disease (GERD) and respiratory diseases, but the causality remains equivocal. The goal of this study was to evaluate the causal role of GERD in respiratory diseases by employing Mendelian randomization (MR) studies. METHODS:We conducted Mendelian randomization analysis based on summary data of genome-wide association studies (GWASs) and three MR statistical techniques (inverse variance weighted, weighted median and MR-Egger) were employed to assess the probable causal relationship between GERD and the risk of respiratory diseases. Sensitivity analysis was also carried out to ensure more trustworthy results, which involves examining the heterogeneity, pleiotropy and leave-one-SNP-out method. We also identified 33 relevant genes and explored their distribution in 26 normal tissues. RESULTS:In the analysis, for every unit increase in developing GERD, the odds ratio for developing COPD, bronchitis, pneumonia, lung cancer and pulmonary embolism rose by 72% (OR = 1.72, 95% CI 1.50; 1.99), 19% (OR = 1.19, 95% CI 1.11; 1.28), 16% (OR = 1.16, 95% CI 1.07; 1.26), 0. 3% (OR = 1.003, 95% CI 1.0012; 1.0043) and 33% (OR = 1.33, 95% CI 1.12; 1.58), respectively, in comparison with non-GERD cases. In addition, neither heterogeneity nor pleiotropy was found in the study. This study also found that gene expression was higher in the central nervous system and brain tissue than in other normal tissues. CONCLUSIONS:This study provided evidence that people who developed GERD had a higher risk of developing COPD, bronchitis, pneumonia, lung cancer and pulmonary embolism. Our research suggests physicians to give effective treatments for GERD on respiratory diseases. By exploring the gene expression, our study may also help to reveal the role played by the central nervous system and brain tissue in developing respiratory diseases caused by GERD. 10.1186/s12967-023-04786-0
The Causality between Diabetes and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study. Thrombosis and haemostasis BACKGROUND: Diabetes was considered as a risk factor for venous thromboembolism (VTE), but conflicting findings have been reported from observational studies. This study aimed at investigating the causal associations of type 1 and type 2 diabetes with VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS: We designed a bidirectional two-sample Mendelian randomization (MR) analysis by using summary-level data from large genome-wide association studies performed in European individuals. Inverse variance weighting with multiplicative random effect method was used to obtain the primary causal estimates, and weighted median, weighted mode, and MR egger regression were replenished as sensitivity analyses to test the robustness of the results. RESULTS: We found no significant causal effects of type 1 diabetes on VTE (odds ratio [OR]: 0.98, 95% confidence interval [CI]: 0.96-1.00,  = 0.043), DVT (OR: 0.98, 95% CI: 0.95-1.00,  = 0.102), and PE (OR: 0.98, 95% CI: 0.96-1.01,  = 0.160). Similarly, no significant associations of type 2 diabetes with VTE (OR: 0.97, 95% CI: 0.91-1.03,  = 0.291), DVT (OR: 0.96, 95% CI: 0.89-1.03,  = 0.255), and PE (OR: 0.97, 95% CI: 0.90-1.04,  = 0.358) were also observed. Results from multivariable MR analysis were consistent with the findings in univariable analysis. In the other direction, the results showed no significant causal effects of VTE on type 1 and type 2 diabetes. CONCLUSION: This MR analysis demonstrated no significant causal associations of type 1 and type 2 diabetes with VTE in both directions, in conflict with previous observational studies reporting positive association, which provided clues for understanding the underlying pathogenesis of diabetes and VTE. 10.1055/a-2040-4850
A Mendelian randomization study of serum uric acid with the risk of venous thromboembolism. Arthritis research & therapy BACKGROUND:Observational studies have linked hyperuricemia with venous thromboembolism (VTE). We aimed to investigate whether there are causal relationships between uric acid levels and VTE and its subtypes, including deep venous thrombosis (DVT) of the lower extremities and pulmonary embolism (PE). METHODS:We utilized Mendelian randomization (MR) analysis to estimate the causal association in European individuals. We extracted two sets of polygenic instruments strongly associated (p < 5 × 10) with uric acid from the CKDGen consortium and UK biobank, respectively. Genetic associations with the risk of VTE, DVT, and PE were obtained from the FinnGen biobank. We used the inverse-variance weighted method as the preliminary estimate. Additionally, we employed MR-Egger, weighted median, and Mendelian randomization pleiotropy residual sum and outlier method as complementary assessments. Sensitivity analyses were performed to test for pleiotropic bias. RESULTS:The genetically instrumented serum uric acid levels had no causal effects on VTE, DVT, and PE. Two sets of polygenic instruments used for exposure, along with three complementary MR methods, also yielded no significant association. CONCLUSIONS:Our MR analysis provided no compelling evidence for a causal relationship of serum uric acid with the risk of VTE. This suggests that uric acid-lowering therapies in patients with hyperuricemia may not be effective in reducing the likelihood of developing VTE. 10.1186/s13075-023-03115-6
Genetic association between smoking and DLCO in idiopathic pulmonary fibrosis patients. BMC pulmonary medicine BACKGROUND:Observational studies have shown that smoking is related to the diffusing capacity of the lungs for carbon monoxide (DLCO) in individuals with idiopathic pulmonary fibrosis (IPF). Nevertheless, further investigation is needed to determine the causal effect between these two variables. Therefore, we conducted a study to investigate the causal relationship between smoking and DLCO in IPF patients using two-sample Mendelian randomization (MR) analysis. METHODS:Large-scale genome-wide association study (GWAS) datasets from individuals of European descent were analysed. These datasets included published lifetime smoking index (LSI) data for 462,690 participants and DLCO data for 975 IPF patients. The inverse-variance weighting (IVW) method was the main method used in our analysis. Sensitivity analyses were performed by MR‒Egger regression, Cochran's Q test, the leave-one-out test and the MR-PRESSO global test. RESULTS:A genetically predicted increase in LSI was associated with a decrease in DLCO in IPF patients [OR = 0.54; 95% CI 0.32-0.93; P = 0.02]. CONCLUSIONS:Our study suggested that smoking is associated with a decrease in DLCO. Patients diagnosed with IPF should adopt an active and healthy lifestyle, especially by quitting smoking, which may be effective at slowing the progression of IPF. 10.1186/s12890-024-02974-2
Identifying factors contributing to increased susceptibility to COVID-19 risk: a systematic review of Mendelian randomization studies. International journal of epidemiology BACKGROUND:To summarize modifiable factors for coronavirus disease 2019 (COVID-19) suggested by Mendelian randomization studies. METHODS:In this systematic review, we searched PubMed, EMBASE and MEDLINE, from inception to 15 November 2021, for Mendelian randomization studies in English. We selected studies that assessed associations of genetically predicted exposures with COVID-19-related outcomes (severity, hospitalization and susceptibility). Risk of bias of the included studies was evaluated based on the consideration of the three main assumptions for instrumental variable analyses. RESULTS:We identified 700 studies through systematic search, of which 50 Mendelian randomization studies were included. Included studies have explored a wide range of socio-demographic factors, lifestyle attributes, anthropometrics and biomarkers, predisposition to diseases and druggable targets in COVID-19 risk. Mendelian randomization studies suggested that increases in smoking, obesity and inflammatory factors were associated with higher risk of COVID-19. Predisposition to ischaemic stroke, combined bipolar disorder and schizophrenia, attention-deficit and hyperactivity disorder, chronic kidney disease and idiopathic pulmonary fibrosis was potentially associated with higher COVID-19 risk. Druggable targets, such as higher protein expression of histo-blood group ABO system transferase (ABO), interleukin (IL)-6 and lower protein expression of 2'-5' oligoadenylate synthetase 1 (OAS1) were associated with higher risk of COVID-19. There was no strong genetic evidence supporting the role of vitamin D, glycaemic traits and predisposition to cardiometabolic diseases in COVID-19 risk. CONCLUSION:This review summarizes modifiable factors for intervention (e.g. smoking, obesity and inflammatory factors) and proteomic signatures (e.g. OAS1 and IL-6) that could help identify drugs for treating COVID-19. 10.1093/ije/dyac076
Mendelian randomisation highlights type 1 diabetes as a causal determinant of idiopathic pulmonary fibrosis. Diabetology & metabolic syndrome BACKGROUND:It is unclear whether type 1 diabetes (T1D) causes idiopathic pulmonary fibrosis (IPF), despite observational research linking the two conditions. Therefore, our study aimed to examine the causal link between T1D and the likelihood of IPF by employing the Mendelian randomization (MR) technique of two-sample Mendelian randomization. METHODS:Using data from two genome-wide association studies (GWAS) with European ancestry, we performed a two-sample MR analysis. These studies involved 18,856 individuals (6,683 cases and 12,173 controls) for T1D and 198,014 individuals (10,028 cases and 196,986 controls) for IPF. We utilized inverse-variance weighted (IVW) analysis as our main approach to determine the association between the risk of IPF and T1D. To evaluate multidirectionality, the MR-Egger regression test was utilized, whereas heterogeneity was assessed using Cochran's Q test. Additionally, a leave-one-out analysis was performed to assess the reliability of the results. RESULTS:38 SNPs linked to T1D were employed as instrumental variables (IVs). Multiple MR methods yielded consistent results, and the MR analysis reveals a significant and positive causal impact of T1D on IPF (MR-IVW, odds ratio [OR] = 1.128, 95% confidence interval [CI] 1.034-1.230; P = 0.006). The limitations of the study include the lack of data from non-European groups and the inability to rule out the possibility of small links. Larger MR experiments are necessary to investigate minute impacts. CONCLUSIONS:The results of this study provide evidence that T1D contributes to the onset and advancement of IPF. This finding may provide important insights into the cause of IPF and possible treatments in the future. 10.1186/s13098-024-01331-x
Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity. EBioMedicine BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19 severity. METHODS:The genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilibrium (LD) score regression. We performed a Mendelian randomization (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility (P<5 × 10) in previous genome-wide association studies (GWAS) were used as instrumental variables (IVs). Effect estimates of those IVs on COVID-19 severity were gathered from the GWAS meta-analysis by the COVID-19 Host Genetics Initiative (4,336 cases & 623,902 controls). FINDINGS:We detected a positive genetic correlation of IPF with COVID-19 severity (rg=0·31 [95% CI 0·04-0·57], P = 0·023). The MR estimates for severe COVID-19 did not reveal any genetic association (OR 1·05, [95% CI 0·92-1·20], P = 0·43). However, outlier analysis revealed that the IPF risk allele rs35705950 at MUC5B had a different effect compared with the other variants. When rs35705950 was excluded, MR results provided evidence that genetically increased risk of IPF has a causal effect on COVID-19 severity (OR 1·21, [95% CI 1·06-1·38], P = 4·24 × 10). Furthermore, the IPF risk-allele at MUC5B showed an apparent protective effect against COVID-19 hospitalization only in older adults (OR 0·86, [95% CI 0·73-1·00], P = 2·99 × 10) . INTERPRETATION:The strongest genetic determinant of IPF, rs35705950 at MUC5B, seems to confer protection against COVID-19, whereas the combined effect of all other IPF risk loci seem to confer risk of COVID-19 severity. The observed effect of rs35705950 could either be due to protective effects of mucin over-production on the airways or a consequence of selection bias due to (1) a patient group that is heavily enriched for the rs35705950 T undertaking strict self-isolation and/or (2) due to survival bias of the rs35705950 non-IPF risk allele carriers. Due to the diverse impact of IPF causal variants on SARS-CoV-2 infection, with a possible selection bias as an explanation, further investigation is needed to address this apparent paradox between variance at MUC5B and other IPF genetic risk factors. FUNDING:Novo Nordisk Foundation and Oak Foundation. 10.1016/j.ebiom.2021.103277
Endocrine and metabolic factors and the risk of idiopathic pulmonary fibrosis: a Mendelian randomization study. Frontiers in endocrinology Background:Previous observational studies have investigated the association between endocrine and metabolic factors and idiopathic pulmonary fibrosis (IPF), yet have produced inconsistent results. Therefore, it is imperative to employ the Mendelian randomization (MR) analysis method to conduct a more comprehensive investigation into the impact of endocrine and metabolic factors on IPF. Methods:The instrumental variables (IVs) for 53 endocrine and metabolic factors were sourced from publicly accessible genome-wide association study (GWAS) databases, with GWAS summary statistics pertaining to IPF employed as the dependent variables. Causal inference analysis encompassed the utilization of three methods: inverse-variance weighted (IVW), weighted median (WM), and MR-Egger. Sensitivity analysis incorporated the implementation of MR-PRESSO and leave-one-out techniques to identify potential pleiotropy and outliers. The presence of horizontal pleiotropy and heterogeneity was evaluated through the MR-Egger intercept and Cochran's Q statistic, respectively. Results:The IVW method results reveal correlations between 11 traits and IPF. After correcting for multiple comparisons, seven traits remain statistically significant. These factors include: "Weight" (OR= 1.44; 95% CI: 1.16, 1.78; =8.71×10), "Body mass index (BMI)" (OR= 1.35; 95% CI: 1.13, 1.62; =1×10), "Whole body fat mass" (OR= 1.40; 95% CI: 1.14, 1.74; =1.72×10), "Waist circumference (WC)" (OR= 1.54; 95% CI: 1.16, 2.05; =3.08×10), "Trunk fat mass (TFM)" (OR=1.35; 95% CI: 1.10,1.65; =3.45×10), "Body fat percentage (BFP)" (OR= 1.55; 95% CI: 1.15,2.08; =3.86×10), "Apoliprotein B (ApoB)" (OR= 0.78; 95% CI: 0.65,0.93; =5.47×10). Additionally, the sensitivity analysis results confirmed the reliability of the MR results. Conclusion:The present study identified causal relationships between seven traits and IPF. Specifically, ApoB exhibited a negative impact on IPF, while the remaining six factors demonstrated a positive impact. These findings offer novel insights into the underlying etiopathological mechanisms associated with IPF. 10.3389/fendo.2023.1321576
The associations between gut microbiota and chronic respiratory diseases: a Mendelian randomization study. Frontiers in microbiology Introduction:Growing evidence indicates that variations in the composition of the gut microbiota are linked to the onset and progression of chronic respiratory diseases (CRDs), albeit the causal relationship between the two remains unclear. Methods:We conducted a comprehensive two-sample Mendelian randomization (MR) analysis to investigate the relationship between gut microbiota and five main CRDs, including chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), sarcoidosis, and pneumoconiosis. For MR analysis, the inverse variance weighted (IVW) method was utilized as the primary method. The MR-Egger, weighted median, and MR-PRESSO statistical methods were used as a supplement. To detect heterogeneity and pleiotropy, the Cochrane and Rucker Q test, MR-Egger intercept test, and MR-PRESSO global test were then implemented. The leave-one-out strategy was also applied to assess the consistency of the MR results. Results:Based on substantial genetic data obtained from genome-wide association studies (GWAS) comprising 3,504,473 European participants, our study offers evidence that several gut microbial taxa, including 14 probable microbial taxa (specifically, 5, 3, 2, 3 and 1 for COPD, asthma, IPF, sarcoidosis, and pneumoconiosis, respectively) and 33 possible microbial taxa (specifically, 6, 7, 8, 7 and 5 for COPD, asthma, IPF, sarcoidosis, and pneumoconiosis, respectively) play significant roles in the formation of CRDs. Discussion:This work implies causal relationships between the gut microbiota and CRDs, thereby shedding new light on the gut microbiota-mediated prevention of CRDs. 10.3389/fmicb.2023.1200937
Association between idiopathic pulmonary fibrosis and risk of different pathological types of lung cancer: a Mendelian randomization study. Journal of cancer research and clinical oncology BACKGROUND:Many epidemiological studies have shown that idiopathic pulmonary fibrosis (IPF) is a risk factor for lung cancer (LC), but these studies do not provide direct evidence of a causal association between the two diseases. We investigated the causal association between IPF and different pathological types of LC based on the Mendelian randomization (MR) study. METHODS:The genome-wide association study (GWAS) data of IPF and LC were obtained from the latest published articles, and instrumental variables (IVs) for analysis were obtained after screening and eliminating the confounders. MR Analysis was carried out with the help of random effects inverse variance weighting (re-IVW), MR-egger, and weighted median method, and a comprehensive sensitivity test was conducted. RESULTS:The results of re-IVW analysis showed that IPF may increase the risk of lung squamous cell carcinoma (LUSC) (OR = 1.045, 95% CI 1.011 to 1.080, P = 0.008). In addition, no causal relationship was found between IPF and overall LC (OR = 0.977, 95% CI 0.933 to 1.023, P = 0.32), lung adenocarcinoma (LUAD) (OR = 0.967, 95% CI 0.903 to 1.036, P = 0.345) and small cell lung carcinoma (SCLC) (OR = 1.081, 95% CI 0.992 to 1.177, P = 0.074). A comprehensive sensitivity analysis ensured the reliability of the study. CONCLUSION:In conclusion, from the perspective of genetic association, we found that IPF is an independent risk factor for LUSC and may increase the risk of LUSC, but no such causal relationship was found in LUAD and SCLC. 10.1007/s00432-023-04727-w
Psoriasis may increase the risk of idiopathic pulmonary fibrosis: a two-sample Mendelian randomization study. Respiratory research BACKGROUND:Although some studies have indicated that Psoriasis could contribute to the risk of idiopathic pulmonary fibrosis (IPF), no study has reported a clear causal association between them. Our aim was to explore the potential relationship between Psoriasis and IPF using Mendelian randomization (MR) design. METHODS:To explore a causal association between Psoriasis and IPF, we used genetic instruments from the largest available genome-wide association study (GWAS) of European ancestry, including psoriasis (5314 cases, 457,619 controls) and IPF (1028 cases, 196,986 controls). Our main analyses were conducted by inverse-variance weighted (IVW) method with random-effects model, with the other complementary four analyses: weighted median method, weighted mode, multivariable MR and MR-Egger approach. RESULTS:The results of IVW methods demonstrated that genetically predicted psoriasis was significantly associated with higher odds of IPF, with an odds ratio (OR) of 1.09 (95%CI, 1.01-1.18; P = 0.02). Weighted median method, weighted mode and multivariable MR also demonstrated directionally similar results (P < 0.05), while the MR-Egger regression did not reveal the impact of psoriasis on IPF (OR = 1.09, 95%CI, 0.98-1.21; P = 0.11). In addition, both funnel plots and MR-Egger intercepts indicated no directional pleiotropic effects between psoriasis and IPF. CONCLUSIONS:Our study provided potential evidence between genetically predicted psoriasis and IPF, which suggests that understanding the mutual risk factors between psoriasis and IPF can facilitate the clinical management of both diseases. 10.1186/s12931-024-02721-5
The causal relationship between physical activity, sedentary time and idiopathic pulmonary fibrosis risk: a Mendelian randomization study. Respiratory research BACKGROUND:Several observational studies have found that physical inactivity and sedentary time are associated with idiopathic pulmonary fibrosis (IPF) risk. However, the causality between them still requires further investigation. Therefore, our study aimed to investigate the causal effect of physical activity (PA) and sedentary time on the risk of IPF via two-sample Mendelian randomization (MR) analysis. METHODS:Multiple genome-wide association study (GWAS) data involving individuals of European ancestry were analyzed. The datasets encompassed published UK Biobank data (91,105-377,234 participants) and IPF data (2018 cases and 373,064 controls) from FinnGen Biobank. The inverse variance weighting (IVW) method was the primary approach for our analysis. Sensitivity analyses were implemented with Cochran's Q test, MR-Egger regression, MR-PRESSO global test, and leave-one-out analysis. RESULTS:Genetically predicted self-reported PA was associated with lower IPF risk [OR = 0.27; 95% CI 0.09-0.82; P = 0.02]. No causal effects of accelerometry-based PA or sedentary time on the risk of IPF were observed. CONCLUSIONS:Our findings supported a protective relationship between self-reported PA and the risk for IPF. The results suggested that enhancing PA may be an effective preventive strategy for IPF. 10.1186/s12931-023-02610-3
Appraising the causal role of smoking in idiopathic pulmonary fibrosis: a Mendelian randomization study. Thorax Smoking has been considered a risk factor for idiopathic pulmonary fibrosis (IPF) in observational studies. To assess whether smoking plays a causal role in IPF, we performed a Mendelian randomization study using genetic association data of 10 382 cases with IPF and 968 080 controls. We found that genetic predisposition to smoking initiation (based on 378 variants) and lifetime smoking (based on 126 variants) were associated with a higher risk of IPF. Our study suggests a potential causal effect of smoking on increasing IPF risk from a genetic perspective. 10.1136/thorax-2023-220012
Genetic association of circulating C-reactive protein levels with idiopathic pulmonary fibrosis: a two-sample Mendelian randomization study. Respiratory research BACKGROUND:Several observational studies have found that idiopathic pulmonary fibrosis (IPF) is often accompanied by elevated circulating C-reactive protein (CRP) levels. However, the causal relationship between them remains to be determined. Therefore, our study aimed to explore the causal effect of circulating CRP levels on IPF risk by the two-sample Mendelian randomization (MR) analysis. METHODS:We analyzed the data from two genome-wide association studies (GWAS) of European ancestry, including circulating CRP levels (204,402 individuals) and IPF (1028 cases and 196,986 controls). We primarily used inverse variance weighted (IVW) to assess the causal effect of circulating CRP levels on IPF risk. MR-Egger regression and MR-PRESSO global test were used to determine pleiotropy. Heterogeneity was examined with Cochran's Q test. The leave-one-out analysis tested the robustness of the results. RESULTS:We obtained 54 SNPs as instrumental variables (IVs) for circulating CRP levels, and these IVs had no significant horizontal pleiotropy, heterogeneity, or bias. MR analysis revealed a causal effect between elevated circulating CRP levels and increased risk of IPF (OR = 1.446, 95% CI 1.128-1.854, P = 0.004). CONCLUSIONS:The present study indicated that elevated circulating CRP levels could increase the risk of developing IPF in people of European ancestry. 10.1186/s12931-022-02309-x
A Causal Atlas on Comorbidities in Idiopathic Pulmonary Fibrosis: A Bidirectional Mendelian Randomization Study. Chest BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a high burden of both pulmonary and extrapulmonary comorbidities. RESEARCH QUESTION:Do these comorbidities have causal relationships with IPF? STUDY DESIGN AND METHODS:We searched PubMed to pinpoint possible IPF-related comorbid conditions. Bidirectional Mendelian randomization (MR) was performed using summary statistics from the largest genome-wide association studies for these diseases to date in a two-sample setting. Findings were verified using multiple MR approaches under different model assumptions, replication datasets for IPF, and secondary phenotypes. RESULTS:A total of 22 comorbidities with genetic data available were included. Bidirectional MR analyses showed convincing evidence for two comorbidities and suggestive evidence for four comorbidities. Gastroesophageal reflux disease, VTE, and hypothyroidism were associated causally with an increased risk of IPF, whereas COPD was associated causally with a decreased risk of IPF. For the reverse direction, IPF showed causal associations with a higher risk of lung cancer, but a reduced risk of hypertension. Follow-up analyses of pulmonary function parameters and BP measures supported the causal effect of COPD on IPF and the causal effect of IPF on hypertension. INTERPRETATION:The present study suggested the causal associations between IPF and certain comorbidities from a genetic perspective. Further research is needed to understand the mechanisms of these associations. 10.1016/j.chest.2023.02.038