Inverse-variance Weighted Analysis Research Articles

Dried fruit intake and lower risk of type 2 diabetes: a two-sample mendelian randomization study

BackgroundPrevious studies have shown controversy about whether dried fruit intake is associated with type 2 diabetes. This study aimed to examine the potential causal effect of dried fruit intake on type 2 diabetes by conducting a two-sample Mendelian randomization study.MethodsWe used genome-wide association study (GWAS) summary statistics for MR analysis to explore the causal association of dried fruit intake with T2D. The inverse-variance weighted (IVW) method was used as the main analytical method for MR analysis. In addition, the MR-Egger method and the weighted median method were applied to supplement the IVW method. Furthermore, Cochrane’s Q test, MR-Egger intercept test, and leave-one-out analysis were used to perform sensitivity analysis. The funnel plot was used to assess publication bias.ResultsThe results from the IVW analysis indicated that dried fruit intake could reduce the risk of T2D [odds ratio (OR) = 0.392, 95% confidence interval (CI): 0.241–0.636, p-value = 0.0001]. In addition, the result of additional method Weighted median is parallel to the effects estimated by IVW. Furthermore, the sensitivity analysis illustrates that our MR analysis was unaffected by heterogeneity and horizontal pleiotropy. Finally, the results of the leave-one-out method showed the robustness of our MR results. And the funnel plot shows a symmetrical distribution.ConclusionOur study provides evidence for the benefits of dried fruit intake on T2D. Therefore, a reasonable consumption of dried fruit may provide primary prevention.

Dried fruit intake and lower risk of type 2 diabetes: a two-sample mendelian randomization study

BackgroundPrevious studies have shown controversy about whether dried fruit intake is associated with type 2 diabetes. This study aimed to examine the potential causal effect of dried fruit intake on type 2 diabetes by conducting a two-sample Mendelian randomization study.MethodsWe used genome-wide association study (GWAS) summary statistics for MR analysis to explore the causal association of dried fruit intake with T2D. The inverse-variance weighted (IVW) method was used as the main analytical method for MR analysis. In addition, the MR-Egger method and the weighted median method were applied to supplement the IVW method. Furthermore, Cochrane’s Q test, MR-Egger intercept test, and leave-one-out analysis were used to perform sensitivity analysis. The funnel plot was used to assess publication bias.ResultsThe results from the IVW analysis indicated that dried fruit intake could reduce the risk of T2D [odds ratio (OR) = 0.392, 95% confidence interval (CI): 0.241–0.636, p-value = 0.0001]. In addition, the result of additional method Weighted median is parallel to the effects estimated by IVW. Furthermore, the sensitivity analysis illustrates that our MR analysis was unaffected by heterogeneity and horizontal pleiotropy. Finally, the results of the leave-one-out method showed the robustness of our MR results. And the funnel plot shows a symmetrical distribution.ConclusionOur study provides evidence for the benefits of dried fruit intake on T2D. Therefore, a reasonable consumption of dried fruit may provide primary prevention.

No evidence for causal effects of C-reactive protein (CRP) on chronic pain conditions: a Mendelian randomization study.

We conducted a Mendelian randomization (MR) study to examine causal associations of C-reactive protein (CRP) with (1) spinal pain; (2) extent of multisite chronic pain; and (3) chronic widespread musculoskeletal pain. Two-sample MR study. We used summary statistics from publicly available genome-wide association studies (GWAS) conducted in multiple cohorts and biobanks. Genetic instrumental variables were taken from an exposure GWAS of CRP (n=204,402). Outcome GWASs examined spinal pain (n=1,028,947), extent of multisite chronic pain defined as the number of locations with chronic pain (n=387,649), and chronic widespread pain (n=249,843). We examined MR evidence for causal associations using inverse-variance weighted (IVW) analysis and sensitivity analyses using other methods. We calculated odds ratios (ORs), 95% confidence intervals (95% CIs), and p-values, using a Bonferroni correction (p<0.0166) to account for 3 primary comparisons. Greater serum CRP (mg/L) was not significantly causally associated with spinal pain (OR=1.04, 95% CI 1.00-1.08; p=0.07) in IVW analysis. Greater serum CRP also showed no significant causal association with extent of multisite chronic pain in IVW analysis (beta coefficient= 0.014, standard error=0.011; p=0.19). CRP also showed no significant causal association with chronic widespread pain in IVW analysis (OR=1.00, 95% CI 1.00-1.00; p=0.75). All secondary and sensitivity analyses also showed no significant associations. This MR study found no causal association of CRP on spinal pain, the extent of chronic pain, or chronic widespread pain. Future studies examining mechanistic biomarkers for pain conditions should consider other candidates besides CRP.

Hidradenitis suppurativa and cardiovascular diseases: A bidirectional Mendelian randomization study.

Prior investigation has indicated a link between Hidradenitis suppurativa (HS) and cardiovascular diseases (CVDs), yet the causal relationship (CR) between these conditions remains unresolved. This investigation utilized bidirectional Mendelian randomization (MR) analysis to determine the CR between HS and CVDs. Genetic instruments for both conditions were sourced from genome-wide association studies (GWAS). The GWAS summary data for CVD comprised coronary artery disease (CAD), myocardial infarction (MI), coronary atherosclerosis (CA), ischemic stroke (IS), and chronic heart failure (CHF). Four new approaches were added to the inverse variance weighted (IVW) method for the main analysis: weighted median, weighted MR-Egger, simple mode, and weighted mode. The validity of the causal conclusions was verified by sensitivity tests that included leave-one-out analysis, heterogeneity, and pleiotropy. HS and CAD (OR=1.024; 95%CI: 1.002-1.046, P=0.033), MI (OR=1.001; 95%CI: 1.000-1.002, P=0.033), and CA (OR=1.001; 95%CI: 1.000-1.002, P=0.022) were identified to have a positive CR, according to the IVW analysis. Conversely, no significant association was identified between HS and either IS or CHF. Furthermore, the bidirectional analysis indicated no reverse causation between these diseases. The findings of this study suggest a potential CR between HS and CAD, MI, and CA. Additional research is warranted to elucidate the biological mechanisms underlying these associations.

Dissecting the causal role of immunophenotypes in primary sclerosing cholangitis risk: A Mendelian randomization study

Primary sclerosing cholangitis (PSC), a chronic cholestatic liver condition, is frequently associated with inflammatory bowel disease. Specific immune cells have been implicated in PSC pathogenesis with the emergence of the “microbiota” and “gut lymphocyte homing” hypotheses, albeit their identities remain controversial. The first genome-wide association analysis leveraged nonoverlapping data from 3757 Europeans to evaluate 731 immunophenotypes. A genome-wide association analysis comprising 2871 cases and 12,019 controls yielded summary statistics for PSC. An inverse-variance weighted (IVW) analysis was performed to identify immunophenotypes causally related to PSC, and the results were validated using weighted mode, MR-Egger, and weighted median methods. Comprehensive sensitivity analyses were performed to verify the robustness, heterogeneity, and horizontal pleiotropy of the results. IVW analysis revealed 26 immune traits exhibiting causal associations with PSC. CD3 on HLA-DR+ CD4+ (IVW odds ratio [OR]: 0.904; 95% confidence interval [CI]: 0.828–0.986, P = .023) and CD3 on secreting Treg (IVW OR: 0.893; 95% CI: 0.823–0.969, P = .007) were negatively associated with PSC susceptibility and demonstrated high consistency across the 3 validation methods. Moreover, 7 other immune traits, including CD39+ resting Treg absolute cell (IVW OR = 1.083, 95% CI: 1.013–1.157, P = .019), CD39+ secreting Treg absolute cell (IVW OR = 1.063, 95% CI: 1.012–1.118, P = .015), CD3 on naive CD8br (IVW OR = 0.907, 95% CI: 0.835–0.986, P = .022), CD3 on CD39+ activated Treg (IVW OR = 0.927, 95% CI: 0.864–0.994, P = .034), CD28 on resting Treg (IVW OR = 0.724, 95% CI: 0.630–0.833, P = 5.95E-06), and CD39 on CD39+ CD4+ (IVW OR = 1.055, 95% CI: 1.001–1.112, P = .044) exhibited consistent results in the Weighted Median and Weighted Mode validation methods. Moreover, no significant heterogeneity or horizontal pleiotropy was observed across the single nucleotide polymorphisms. The leave-one-out results revealed that sequentially eliminating each single nucleotide polymorphism had no significant influence on model effect estimates or qualitative inference. This study evaluated potential causal links between 731 immune traits and PSC susceptibility. Twenty-six immune traits were identified using the IVW method. Verification across multiple methods revealed 9 immune traits with a plausible causal connection to PSC. These findings may uncover mechanistic pathways and novel therapeutic approaches.

Association of circulating minerals and vitamins with pregnancy complications: a Mendelian randomization study.

Though considerable studies suggesting connections between micronutrients and pregnancy complications, current evidence remains inconsistent and lacks causative confirmation. Our study aimed to explore the causal links between them with a two-sample Mendelian randomization (MR) analysis. Genome-wide association studies (GWAS) data for circulating micronutrients were sourced from GWAS Catalog consortium and PubMed, while data for pregnancy outcomes, including gestational diabetes mellitus (GDM), gestational hypertension (GH), spontaneous abortion (SA), preterm birth (PTB), and stillbirth (SB), were retrieved from the UK Biobank and FinnGen consortia. Causal effects were appraised using inverse variance weighted (IVW), weighted median (WM), and MR-Egger, followed by sensitivity analyses and meta-analysis for validation. Genetically predicted higher vitamin E (OR = 0.993, 95% CI 0.987-0.998; p = 0.005) levels were inversely associated with SA risk. Consistent results were obtained in meta-analysis (OR = 0.99, 95% CI 0.99-1.00; p = 0.005). Besides, a potential positive causality between genetic predisposition to vitamin B12 and SB was identified in both IVW (OR = 0.974, 95% CI 0.953-0.996; p = 0.018) and WM analysis (OR = 0.965, 95% CI 0.939-0.993; p = 0.013). However, no causal relationships were observed between other analyzed circulating micronutrients and pregnancy complications. This study offers compelling evidence of causal associations between circulating levels of vitamins E, B12 and the risk of SA and SB, respectively. These findings are pivotal for pregnancy complications screening and prevention, potentially guiding clinical practice and public health policies toward targeted nutritional interventions.

Genetically Predicted Sleep Traits and Sensorineural Hearing Loss: A Mendelian Randomization Study.

Observational studies suggest a potential association between sleep characteristics, sensorineural hearing loss (SNHL), and sudden SNHL (SSNHL), but causal evidence is scarce. We sought to clarify this issue using two-sample Mendelian randomization analysis. The inverse-variance weighted (IVW) method was performed as primary analysis to assess bidirectional causal associations between sleep traits (chronotype, sleep duration, insomnia, daytime sleepiness, and snoring) and SNHL/SSNHL using publicly available Genome-Wide Association Studies summary data from two large consortia (UK Biobank and FinnGen). Sensitivity analyses, including Mendelian randomization (MR)-Egger, Mendelian randomization pleiotropy residual sum and outlier, weight median, Cochran's Q test, leave-one-out analysis, and potential pleiotropy analysis, were conducted to ensure robustness. IVW analysis found suggestive associations of morning chronotype (odds ratio [OR] = 1.08, 95% confidence interval [CI] = 1.01-1.16, p = 0.031) and daytime sleepiness (OR = 1.88, 95% CI = 1.24-2.87, p = 0.003) with SNHL onset. Additionally, morning chronotype was nominally associated with SSNHL onset using IVW method (OR = 1.37, 95% CI = 1.10-1.71, p = 0.006). However, there was no evidence for the causal effect of SNHL and SSNHL on different sleep traits (all p > 0.05). Sensitivity analysis showed that the results were stable. Within the MR limitations, morning chronotype and daytime sleepiness were underlying causal contributors to the burden of SNHL, indicating that optimal sleep might facilitate the prevention and development of SNHL. 3 Laryngoscope, 2024.

Mendelian randomization analyses reveal no genetic causal effects of major adipokines on systemic lupus erythematosus.

Epidemiological studies have shown that the levels of serum adipokine such as leptin and resistin are associated with the risk of developing systemic lupus erythematosus (SLE). Nevertheless, whether either leptin or resistin has causal impacts on the risk of SLE is still unknown. In this study, two-sample univariable MR analyses and multivariable MR analysis were performed to explore the causal relationships between adipokines and SLE. Additionally, the potential causal effects of SLE on major adipokines were evaluated using reverse MR analyses. The results of inverse-variance weighted (IVW), weighted median, weighted mode and MR‒Egger methods concordantly supported that major adipokines have no causal effects on the risk of SLE. In the multivariable MR IVW analysis with leptin and resistin as covariates, neither leptin (odds ratio (OR) = 3.093, P = 0.067) nor resistin (OR = 0.477, P = 0.311) was identified as an independent risk factor for SLE, which is in line with the univariable MR results. In conclusion, our analyses revealed no evidence to support that these three major adipokines are risk factors for SLE.

Causal relationship between depression and hypercholesterolemia: A bidirectional 2-sample Mendelian randomization study.

Although observational studies have found both a positive and negative association between depression and hypercholesterolemia, the findings are mixed and contradictory. To our knowledge, this is the first study that employs the bidirectional Mendelian randomization (MR) and multivariable MR analysis with extensive genome-wide association studies (GWAS) data to examine the causal effect between depression and hypercholesterolemia. Using summary statistics obtained from GWAS of individuals with European ancestry, we utilize a bidirectional 2-sample MR approach to explore the potential causal association between hypercholesterolemia and depressive symptoms. Multivariable Mendelian randomization analysis was used to examine whether the direct causal effect of depression on the risk of hypercholesterolemia can be affected by traits associated with the increased risk of hypercholesterolemia. This MR analysis utilized inverse variance weighted (IVW), MR-Egger regression, weighted mode, and weighted median methods. Data on the summary level of depression were acquired from a GWAS that involved 500,199 participants. We used summary GWAS datasets for hypercholesterolemia including 206,067 participants. We also used another GWAS databases of hypercholesterolemiat (n = 463,010) to validate our results. By utilizing IVW, it was discovered that there is a possibility of a 31% rise in the risk of hypercholesterolemia due to depression (OR = 1.31, 95% CI = 1.10-1.57, P = .002). We found a consistent causal effect of depression on hypercholesterolemia from the IVW analyses using different hypercholesterolemia datasets. After adjustment of smoking, physical activity, and obesity, there remains significant causal relationship between depression and hypercholesterolemia (OR = 1.25, 95% CI = 1.01-1.54, P = .040). However, we did not find any evidence indicating that hypercholesterolemia leads to depression in the opposite direction. Directional pleiotropy was not observed in the MR-Egger regression analysis. Additionally, the MR-PRESSO analysis validated these discoveries. Neither the leave-one-out sensitivity test nor the funnel plots revealed any outliers. In both the unadjusted and adjusted estimates, depression has a consistent direct causal effect on hypercholesterolemia. Our study has led to an improved comprehension of the causal connections between hypercholesterolemia and depression, which could aid in the prevention and treatment of hypercholesterolemia.

Causal effects of BMI, waist circumference, and body fat percentage on the risk of bladder cancer: A Mendelian randomization study.

The causal role of body mass index (BMI) in bladder cancer (BC) by Mendelian randomization (MR) has not yet been reported. We evaluated the causal associations between the measures of obesity (BMI, waist circumference, and body fat percentage) and BC. We conducted a 2-sample MR analysis to assess the genetic effect of measures of obesity on BC. The BMI dataset (GWAS ID: ukb-b-2303) comprised 454,884 Europeans, and we identified 9,851,867 single nucleotide polymorphisms (SNPs). The waist circumference data (GWAS ID: ukb-b-9405) included 462,166 Europeans and 9,851,867 SNPs. The body fat percentage dataset (GWAS ID: ukb-a-264) contained data from 331,117 Europeans and 10,894,596 SNPs. For the outcome data, the GWAS ID was finn-b-C3_BLADDER, consisting of 1115 cases and 217,677 controls, with 16,380,466 SNPs. The inverse-variance weighted (IVW) model was used as the primary MR analysis. Cochran Q-statistic was used to identify heterogeneity between the SNPs. The MR-Egger and MR-PRESSO methods were employed to assess directional pleiotropy and outlier SNPs. We detected a decisive causal link between BMI and BC by the IVW analysis (odds ratio [OR] = 1.41, 95% confidence interval [CI]: 1.08-1.85, P = .011). The IVW analyses revealed a significant correlation between BC and waist circumference (OR = 1.55, 95% CI: 1.08-2.12, P = .016). However, the IVW method (OR = 1.49, 95% CI: 0.99-2.00, P = .05) did not report any statistical significance between body fat percentage and BC. We did not observe heterogeneity and directional pleiotropy in the 3 pairs of MR studies. The 2-sample MR analysis revealed a conceivable causal association between obesity (BMI, waist circumference) and BC.

Uterine leiomyoma causes an increase in systolic blood pressure: a two-sample Mendelian randomization study.

Hypertension and hypertensive disorders of pregnancy (HDP) are common diseases in women at different stages, which affect women's physical and mental health, and the impact of the latter on the offspring cannot not be ignored. Observational studies have investigated the correlation between uterine leiomyoma (UL) and the above conditions, but the relationship remains unclear. In this study, we employed two-sample Mendelian randomization (MR) analysis to assess the association between UL and hypertension, HDP, as well as blood pressure. We collected genetic association data of UL (35,474 cases), hypertension (129,909 cases), HDP (gestational hypertension with 8,502 cases, pre-eclampsia with 6,663 cases and eclampsia with 452cases), systolic blood pressure (SBP) and diastolic blood pressure (DBP) (both 757,601 participants) from published available genome-wide association studies (GWAS). The single nucleotide polymorphisms (SNPs) associated with UL phenotype were used as instrumental variables, and hypertension, three sub-types of HDP, SBP and DBP were used as outcomes. The inverse-variance weighted (IVW) method was employed as the primary method of causal inference. Heterogeneity was assessed using Cochran's Q test, and sensitivity analyses were conducted using MR-Egger regression and MR pleiotropy residual sum and outlier (MR-PRESSO) tests to evaluate the pleiotropy of instrumental variables. PhenoScanner search was used to remove confounding SNP. Robustness and reliability of the results were assessed using methods such as the weighted median and weighted mode. The IVW analysis revealed a positive correlation between genetically predicted UL and SBP [odds ratio (OR)= 1.67, 95% confidence interval (CI):1.24~2.25, P = 0.0007], and no statistical association was found between UL and hypertension, HDP, or DBP. The MR-Egger regression suggested that the above causal relationships were not affected by horizontal pleiotropy. The weighted median method and weighted model produced similar results to the IVW. Based on large-scale population GWAS data, our MR analysis suggested a causal relationship between UL and SBP. Therefore, women with UL, especially pregnant women, should pay attention to monitoring their blood pressure levels. For patients with hypertension who already have UL, interventions for UL may serve as potential therapeutic methods for managing blood pressure.

Evaluation of bi-directional causal association between obstructive sleep apnoea syndrome and diabetic microangiopathy: a Mendelian randomization study.

The relationship between obstructive sleep apnea syndrome (OSAS) and diabetic microangiopathy remains controversial. This study aimed to use bidirectional two-sample Mendelian Randomization (MR) to assess the causal relationship between OSAS and diabetic microangiopathy. First, we used the Linkage Disequilibrium Score Regression(LDSC) analysis to assess the genetic correlation. Then, the bidirectional two-sample MR study was conducted in two stages: OSAS and lung function-related indicators (forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)) were investigated as exposures, with diabetic microangiopathy as the outcome in the first stage, and genetic tools were used as proxy variables for OSAS and lung function-related measures in the second step. Genome-wide association study data came from the open GWAS database. We used Inverse-Variance Weighted (IVW), MR-Egger regression, Weighted median, Simple mode, and Weighted mode for effect estimation and pleiotropy testing. We also performed sensitivity analyses to test the robustness of the results. Furthermore, we performed multivariate and mediation MR analyses. In the LDSC analysis, We found a genetic correlation between OSAS, FVC, FEV 1, and diabetic microangiopathy. In the MR analysis, based on IVW analysis, genetically predicted OSAS was positively correlated with the incidence of diabetic retinopathy (DR), diabetic kidney disease (DKD), and diabetic neuropathy (DN). In the subgroup analysis of DR, there was a significant causal relationship between OSAS and background diabetic retinopathy (BDR) and proliferative diabetic retinopathy (PDR). The reverse MR did not show a correlation between the incidence of diabetic microangiopathy and OSAS. Reduced FVC had a potential causal relationship with increased incidence of DR and PDR. Reduced FEV1 had a potential causal relationship with the increased incidence of BDR, PDR, and DKD. Multivariate MR analysis showed that the association between OSAS and diabetic microangiopathy remained significant after adjusting for confounding factors. However, we did not find the significant mediating factors. Our results suggest that OSAS may be a cause of the development of diabetic microangiopathy, and OSAS may also be associated with a high risk of diabetic microangiopathy, providing a reference for a better understanding of the prevention of diabetic microangiopathy.

Investigation of the causal association between Parkinson's disease and autoimmune disorders: a bidirectional Mendelian randomization study.

To date, an increasing number of epidemiological evidence has pointed to potential relationships between Parkinson's disease (PD) and various autoimmune diseases (AIDs), however, no definitive conclusions has been drawn about whether PD is causally related to AIDs risk. By employing summary statistics from the latest and most extensive genome-wide association studies (GWAS), we performed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal associations between PD and a variety of 17 AIDs, encompassing multiple sclerosis, neuromyelitis optica spectrum disorder, myasthenia gravis, asthma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, celiac disease, primary biliary cirrhosis, primary sclerosing cholangitis, type 1 diabetes, ankylosing spondylitis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis and vitiligo. Inverse-variance weighted (IVW) was adopted as the main statistical approach to obtain the causal estimates of PD on different AIDs, supplemented by a series of complementary analyses (weighted median, MR Egger regression, and MR-PRESSO) for further strengthening the robustness of results. Our MR findings suggested that genetically predicted higher liability to PD was causally associated with a decreased risk of irritable bowel syndrome (OR = 0.98; 95% CI: 0.96-0.99; P = 0.032). On the contrary, IVW analysis showed a potential positive correlation between genetically determined PD and the incidence of type 1 diabetes (OR = 1.10; 95%CI: 1.02-1.19; P = 0.010). Subsequent MR tests ended up in similar results, confirming our findings were reliable. Additionally, in the reverse MR analyses, we did not identify any evidence to support the causal relationship of genetic predisposition to AIDs with PD susceptibility. In general, a bifunctional role that PD exerted on the risk of developing AIDs was detected in our studies, both protecting against irritable bowel syndrome occurrence and raising the incidence of type 1 diabetes. Future studies, including population-based observational studies and molecular experiments in vitro and in vivo, are warranted to validate the results of our MR analyses and refine the underlying pathological mechanisms involved in PD-AIDs associations.

Unraveling genetic causality between metformin and myocardial infarction on the basis of Mendelian randomization.

In recent years, several studies have explored the effect of metformin on myocardial infarction (MI), but whether metformin has an improvement effect in patients with MI is controversial. This study was aimed to investigate the causal relationship between metformin and MI using Mendelian randomization (MR) analysis. The genome-wide significant (P<5×10-8) single-nucleotide polymorphisms (SNPs) in patients with metformin and patients with MI were screened from the Open genome-wide association study (GWAS) project as instrumental variables (IVs). The study outcomes mainly included MI, old MI, acute MI, acute transmural MI of inferior wall, and acute transmural MI of anterior wall. The inverse variance weighted (IVW) method was applied to assess the main causal effect, and weighted median, simple mode, weighted mode methods, and MR-Egger regression were auxiliary applied for supplementary proof. The causal relationship between metformin and MI was assessed using odds ratios (OR) and 95% confidence intervals (95% CI). A leave-one-out method was used to explore the effect of individual SNPs on the results of IVW analyses, and a funnel plot was used to analyze the potential bias of the study results, thus ensuring the robustness of the results. In total, 16, 84, 39, 26, and 34 SNPs were selected as IVs to assess the genetic association between metformin and outcomes of MI, old MI, acute MI, acute transmural MI of inferior wall, and acute transmural MI of anterior wall, respectively. Treatment with metformin does not affect the risk of acute transmural MI of anterior wall at the genetic level (P>0.05; OR for inverse variance weighted was 1.010). In the cases of MI, old MI, acute MI, and acute transmural MI of inferior wall, metformin may even be a risk factor for patients (P<0.05; ORs for inverse variance weighted were 1.078, 1.026, 1.022 and 1.018 respectively). There was no horizontal pleiotropy or heterogeneity among IVs. The results were stable when removing the SNPs one by one. Metformin is not protective against the risk of myocardial infarction in patients and may even be a risk factor for MI, old MI, acute MI, and acute transmural MI of inferior wall.

No genetic causal association between circulating alpha-tocopherol levels and osteoarthritis, a two-sample Mendelian randomization analysis

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

Associations of dietary factors with gastric cancer risk: insights from NHANES 2003-2016 and mendelian randomization analyses.

Background: Gastric cancer (GC) continues to be one of the leading causes of cancer-related deaths globally. Diet significantly influences the incidence and progression of GC. However, the relationship between dietary intake and GC is inconsistent. Methods: A study was conducted with adults who participated in the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2016 to investigate possible associations between 32 dietary factors and GC. To further detect potential causal relationships between these dietary factors and the risk of GC, a two-sample Mendelian randomization (MR) analysis was conducted. The primary method employed was the inverse variance weighted (IVW) analysis, and its results were further validated by four other methods. Results: Of the 35,098 participants surveyed, 20 had a history of GC. Based on the results of weighted logistic multivariate analysis, it was observed that there was a positive correlation between total fat intake [odds ratio (OR) = 1.09, 95% confidence interval (CI): (1.01-1.17), p = 0.03] and GC as well as negative association of dietary monounsaturated fatty acids (MUFAs) intake [OR = 0.83, 95% CI: (0.76-0.92), p < 0.001]. Further evaluations of the odds of GC across the quartiles of dietary MUFAs showed that the top quartile of total MUFA intake was associated with a lower likelihood of GC in three different models [model1: OR = 0.03, 95% CI: (0.00-0.25), p < 0.01; model2: OR = 0.04, 95% CI: (0.00-0.38), p = 0.01; model3: OR = 0.04, 95% CI: (0.00-0.40), p = 0.01]. For the MR analyses, genetic instruments were selected from the IEU Open GWAS project; IVW analysis showed that GC risk was not associated with MUFAs [OR = 0.82, 95% CI: (0.59-1.14), p = 0.23] or the ratio of MUFAs to total fatty acids [OR = 1.00, 95% CI: (0.75-1.35), p = 0.98]. Similar results were observed when using the other MR methods. Conclusion: The NHANES study revealed that consuming MUFAs was linked to a lower risk of GC, although the results of MR analyses do not provide evidence of a causal relationship. Additional research is therefore necessary to clarify these findings.

Association Between Periodontitis and Adverse Pregnancy Outcomes: Two-Sample Mendelian Randomisation Study

AimThis Mendelian randomisation (MR) study endeavoured to delineate the causal relationship between periodontitis and adverse pregnancy outcomes (APOs), encompassing low birthweight (LBW), pre-term birth (PTB), stillbirth, miscarriage, and gestational hypertension (GH). MethodsUtilising genetic instruments for periodontitis (acute and chronic periodontitis) from the Genome-Wide Association Study (GWAS) database among individuals of European descent, this study explored the causal relationship with adverse pregnancy outcomes, and vice versa. The Inverse Variance Weighted (IVW) method was employed as the primary analytical approach to assess causality, with MR-Egger serving as a sensitivity analysis method. ResultsThe primary analytical method employed in this study, IVW, did not reveal any impact of periodontitis (acute and chronic periodontitis) on PTB, stillbirth, miscarriage, and gestational hypertension, and vice versa. Heterogeneity testing using the MR-Egger method confirmed the null causal hypothesis, with odds ratios (OR) approximating 1, and P-values exceeding 0.05. Notably, the results from the IVW analysis (OR 1.410, CI 1.039-1.915, P-value 0.028) indicate statistically significant evidence supporting a causal relationship between chronic periodontitis and LBW. However, caution is advised in interpreting the causal relationship, considering the non-significant P-values obtained from other methods. ConclusionWithin the limitations of this MR study, the findings do not support the influence of periodontitis on LBW, PTB, stillbirth, miscarriage, and GH, nor vice versa.

Multidimensional plasma lipid composition and its causal association with type 2 diabetes mellitus: A Mendelian randomization study

Background and aimRecent research extends our knowledge of plasma lipid species, building on established links between serum lipid levels and Type 2 Diabetes Mellitus (T2DM) risk. Identifying the causal roles of these lipid species is key to improving T2DM risk assessment. Methods and resultsThis study employs Mendelian randomization (MR) to investigate the causal relationship between 179 lipid species across 13 lipid categories and T2DM. Summary-level data were sourced from genome-wide association studies. The primary analytical methods included the inverse variance weighted (IVW) approach and the Wald ratio, complemented by a series of sensitivity analyses to ensure the robustness of results. The IVW analysis reveals a significant causal association between elevated levels of ceramide (d40:2) (OR = 1.071, 95% CI 1.034–1.109, P = 1.36 × 10−4), sphingomyelin (d38:1) (OR = 1.052, 95% CI 1.028–1.077, P = 1.80 × 10−5), and triacylglycerol (56:8) (OR = 1.174, 95% CI 1.108–1.243, P = 4.65 × 10−8), and an increased risk of T2DM. Conversely, Wald ratio analysis indicates that higher levels of phosphatidylcholine (O-16:1_16:0) (OR = 0.928, 95% CI 0.892–0.966, P = 2.37 × 10−4), phosphatidylcholine (O-16:1_20:4) (OR = 0.932, 95% CI 0.897–0.967, P = 2.37 × 10−4), and phosphatidylcholine (O-18:2_20:4) (OR = 0.872, 95% CI 0.812–0.935, P = 1.24 × 10−4) are significantly associated with a reduced risk of T2DM. Furthermore, suggestive causal evidence for 22 additional lipid species was identified. ConclusionsThis MR study establishes a causal relationship between specific lipid classes in modulating the risk of T2DM. It offers new insights for risk assessment and potential therapeutic targets in T2DM.

Causal relationship between thyroid dysfunction and gastric cancer: a two-sample Mendelian randomization study.

Gastric cancer is one of the most common cancers worldwide, and its development is associated with a variety of factors. Previous observational studies have reported that thyroid dysfunction is associated with the development of gastric cancer. However, the exact relationship between the two is currently unclear. We used a two-sample Mendelian randomization (MR) study to reveal the causal relationship between thyroid dysfunction and gastric cancer for future clinical work. This study is based on a two-sample Mendelian randomization design, and all data are from public GWAS databases. We selected hyperthyroidism, hypothyroidism, free thyroxine (FT4), and thyroid-stimulating hormone (TSH) as exposures, with gastric cancer as the outcome. We used three statistical methods, namely Inverse-variance weighted (IVW), MR-Egger, and weighted median, to assess the causal relationship between thyroid dysfunction and gastric cancer. The Cochran's Q test was used to assess the heterogeneity among SNPs in the IVW analysis results, and MR-PRESSO was employed to identify and remove IVs with heterogeneity from the analysis results. MR-Egger is a weighted linear regression model, and the magnitude of its intercept can be used to assess the horizontal pleiotropy among IVs. Finally, the data were visualized through the leave-one-out sensitivity test to evaluate the influence of individual SNPs on the overall causal effect. Funnel plots were used to assess the symmetry of the selected SNPs, forest plots were used to evaluate the confidence and heterogeneity of the incidental estimates, and scatter plots were used to assess the exposure-outcome relationship. All results were expressed as odds ratios (OR) and 95% confidence intervals (95% CI). P<0.05 represents statistical significance. According to IVW analysis, there was a causal relationship between hypothyroidism and gastric cancer, and hypothyroidism could reduce the risk of gastric cancer (OR=0.936 (95% CI:0.893-0.980), P=0.006).This means that having hypothyroidism is a protective factor against stomach cancer. This finding suggests that hypothyroidism may be associated with a reduced risk of gastric cancer.Meanwhile, there was no causal relationship between hyperthyroidism, FT4, and TSH and gastric cancer. In this study, we found a causal relationship between hypothyroidism and gastric cancer with the help of a two-sample Mendelian randomisation study, and hypothyroidism may be associated with a reduced risk of gastric cancer, however, the exact mechanism is still unclear. This finding provides a new idea for the study of the etiology and pathogenesis of gastric cancer, and our results need to be further confirmed by more basic experiments in the future.

Retinol and retinol binding protein 4 levels and COVID-19: a Mendelian randomization study

BackgroundThe Corona Virus Disease 2019 (COVID-19) pandemic has struck globally. Whether the related proteins of retinoic acid (RA) signaling pathway are causally associated with the risk of COVID-19 remains unestablished. We conducted a two-sample Mendelian randomization (MR) study to assess the associations of retinol, retinol binding protein 4 (RBP4), retinol dehydrogenase 16 (RDH16) and cellular retinoic acid binding protein 1 (CRABP1) with COVID-19 in European population.MethodsThe outcome utilized the summary statistics of COVID-19 from the COVID-19 Host Genetics Initiative. The exposure data were obtained from public genome wide association study (GWAS) database. We extracted SNPs from exposure data and outcome data. The inverse variance weighted (IVW), MR-Egger and Wald ratio methods were employed to assess the causal relationship between exposure and outcome. Sensitivity analyses were performed to ensure the validity of the results.ResultsThe MR estimates showed that retinol was associated with lower COVID-19 susceptibility using IVW (OR: 0.69, 95% CI: 0.53–0.90, P: 0.0065), whereas the associations between retinol and COVID-19 hospitalization or severity were not significant. RBP4 was associated with lower COVID-19 susceptibility using the Wald ratio (OR: 0.83, 95% CI: 0.72–0.95, P: 0.0072). IVW analysis showed RDH16 was associated with increased COVID-19 hospitalization (OR: 1.10, 95% CI: 1.01–1.18, P: 0.0199). CRABP1 was association with lower COVID-19 susceptibility (OR: 0.95, 95% CI: 0.91–0.99, P: 0.0290) using the IVW.ConclusionsWe found evidence of possible causal association of retinol, RBP4, RDH16 and CRABP1 with the susceptibility, hospitalization and severity of COVID-19. Our study defines that retinol is significantly associated with lower COVID-19 susceptibility, which provides a reference for the prevention of COVID-19 with vitamin A supplementation.