Proteomic insights into the associations between obesity, lifestyle factors, and coronary artery disease.

BACKGROUND: We aimed to investigate the protein pathways linking obesity and lifestyle factors to coronary artery disease (CAD). METHODS: Summary-level genome-wide association statistics of CAD were obtained from the CARDIoGRAMplusC4D consortium (60,801 cases and 123,504 controls) and the FinnGen study (R8, 39,036 cases and 303,463 controls). Proteome-wide Mendelian randomization (MR) analysis was conducted to identify CAD-associated blood proteins, supplemented by colocalization analysis to minimize potential bias caused by linkage disequilibrium. Two-sample MR analyses were performed to assess the associations of genetically predicted four obesity measures and 13 lifestyle factors with CAD risk and CAD-associated proteins' levels. A two-step network MR analysis was conducted to explore the mediating effects of proteins in the associations between these modifiable factors and CAD. RESULTS: Genetically predicted levels of 41 circulating proteins were associated with CAD, and 17 of them were supported by medium to high colocalization evidence. PTK7 (protein tyrosine kinase-7), RGMB (repulsive guidance molecule BMP co-receptor B), TAGLN2 (transgelin-2), TIMP3 (tissue inhibitor of metalloproteinases 3), and VIM (vimentin) were identified as promising therapeutic targets. Several proteins were found to mediate the associations between some modifiable factors and CAD, with PCSK9, C1S, AGER (advanced glycosylation end product-specific receptor), and MST1 (mammalian Ste20-like kinase 1) exhibiting highest frequency among the mediating networks. CONCLUSIONS: This study suggests pathways explaining the associations of obesity and lifestyle factors with CAD from alterations in blood protein levels. These insights may be used to prioritize therapeutic intervention for further study.

Sex-specific effect of serum urate levels on coronary heart disease and myocardial infarction prevention: A Mendelian randomization study.

BACKGROUND AND AIMS: Observational studies have examined serum urate levels in relation to coronary heart disease (CHD) and myocardial infarction (MI). Whether these associations are causal remains controversial, due to confounding factors and reverse causality. We aim to investigate the causality of these associations using Mendelian randomization method. METHODS AND RESULTS: Instrumental variables were obtained from the largest genome-wide association studies of serum urate (457,690 individuals) to date. Summary statistics were from CARDIoGRAMplusC4D consortium (60,801 CHD cases; 43,676 MI cases), FinnGen (21,012 CHD cases; 12,801 MI cases), UK Biobank (10,157 CHD cases; 7018 MI cases), and Biobank Japan (29,319 CHD cases). Inverse-variance weighted method was applied as the main results. Other statistical methods and reverse MR analysis were conducted in the supplementary analyses. Elevated genetically determined serum urate levels were associated with increased risks of CHD and MI. The association pattern remained for the datasets in FinnGen, the combined results of three independent data sources (CHD: odds ratio (OR), 1.10; 95%CI, 1.06-1.15; p = 4.2 × 10-6; MI: OR, 1.12; 95%CI, 1.07-1.18; p = 2.7 × 10-6), and East Asian population. Interestingly, sex-specific subgroup analyses revealed that these associations kept in men only, but not among women in individuals of European ancestry. No consistent evidence was found for the causal effect of CHD or MI on serum urate levels. CONCLUSION: We provide consistent evidence for the causal effect of genetically predicted serum urate levels on CHD and MI, but not the reverse effect. Urate-lowering therapy may be of cardiovascular benefit in the prevention of CHD and MI, especially for men.

Association of mental health with the risk of coronary artery disease in patients with diabetes: A mendelian randomization study.

BACKGROUND AND AIMS: Observational studies have shown an association between mental health and coronary artery disease (CAD) in patients with diabetes. Nevertheless, whether these associations are causal is still unknown. In this two-sample Mendelian randomization (MR) study, we aimed to assess the causality between mental health and CAD in patients with diabetes. METHODS AND RESULTS: Single-nucleotide polymorphisms (SNPs) associated with: depression (807,553 individuals), anxiety (83,556 individuals) and neuroticism (329,821 individuals) were identified from the largest genome-wide association studies (GWAS). Summary-level data for CAD were extracted from the recently published GWAS of 15,666 diabetic patients (3968 CAD cases and 11,696 controls). The inverse-variance weighted (IVW) method was used for the main analysis. Sensitivity analyses included weighted median, maximum likelihood, and the MR-Egger method. Genetic liability to depression was significantly associated with a higher risk of CAD in patients with diabetes (odds ratio [OR], 1.286; 95%CI，1.018-1.621；p = 0.035). For anxiety and neuroticism, no causal association with CAD in patients with diabetes was observed. Consistent results were obtained in most sensitivity analyses. CONCLUSIONS: This MR study provides genetic evidence that depression is a potential risk factor for CAD in patients with diabetes. However, anxiety and neuroticism were not causally associated with CAD in patients with diabetes. Mental health treatments should be enhanced to prevent CAD in patients with diabetes.

Genetic liability to sedentary behavior in relation to myocardial infarction and heart failure: A mendelian randomization study.

BACKGROUND AND AIMS: Observational studies have indicated that sedentary behavior is associated with myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF). Nevertheless, whether these associations are causal remain controversial, due to confounding factors (e.g., physical activity) and reverse causality. METHODS AND RESULTS: Instrumental variables were obtained from the largest genome-wide association studies of sedentary behavior (408,815 individuals) to date. We obtained summary statistics of MI from the CARDIoGRAMplusC4D consortium (171,875 individuals), HF from the HERMES Consortium (977,323 individuals), and AF from the Atrial Fibrillation Consortium (588,190 individuals). The inverse-variance weighted method was applied to obtain Mendelian randomization (MR) estimates, and other statistical methods were conducted in the sensitivity analyses. The main analyses were repeated using data from the FinnGen study. Multivariable MR analysis and mediation analysis were performed to evaluate the role of physical activity and other confounders. Genetically determined television watching was associated with MI (odds ratio [OR], 1.38; 95% CI, 1.19-1.59; p = 1.9 × 10-5) and HF (OR, 1.23; 95%CI, 1.09-1.38; p = 7.0 × 10-4) but not AF. The main results kept robust in most sensitivity analyses. The effect of sedentary behavior on MI and HF was partly mediated by body mass index (BMI). No consistent evidence was found for the causal effect of computer use and driving on MI, HF, or AF. CONCLUSIONS: Genetic liability to prolonged television watching is associated with higher risks of MI and HF. Interventions for reducing television watching time, such as public education and awareness campaigns, should be further investigated.

Causal relationship of serum nutritional factors with osteoarthritis: a Mendelian randomization study.

OBJECTIVES: OA is the most common form of arthritis worldwide and has a major impact on the quality of life among the older population. This study aimed at determining the potential causal effects of several serum nutritional factors on OA. METHODS: A total of seven serum nutritional factors were identified from genome-wide association studies. Summary statistics for OA were obtained from UK Biobank (194 153 for women and 166 988 for men) and a large genome-wide association studies meta-analysis based on the European population (455 221, 393 873 and 403 124 for overall, hip and knee OA, respectively). Two-sample Mendelian randomization approach was used to estimate the causal association between the selected nutritional factors and the risk of OA. RESULTS: The Mendelian randomization analyses suggested that serum calcium levels were inversely associated with overall OA (95% CI, 0.595, 0.850), hip OA (95% CI, 0.352, 0.799) and knee OA (95% CI, 0.461, 0.901). Serum retinol levels were also inversely associated with hip OA (95% CI, 0.257, 0.778). Moreover, sex-specific associations were observed between serum calcium levels (95% CI, 0.936, 0.998), iron levels (95% CI, 1.000, 1.012), selenium levels (95% CI, 0.923, 0.999) and OA in women. CONCLUSION: In this study, an inverse causal association between serum calcium levels and OA was established. Serum retinol levels were inversely associated with hip OA. In addition, we provide evidence for the causal effect of serum calcium, iron and selenium on the risk of OA in women.

Genetically Predicted Sex Hormone-Binding Globulin and Bone Mineral Density: A Mendelian Randomization Study.

Previous observational studies have identified various risk factors associated with the development of osteoporosis, including sex hormone-binding globulin (SHBG). The aim of this study was to determine the potential causal effects of circulating SHBG concentrations on bone mineral density (BMD). Two-sample Mendelian randomization (MR) approach was applied in analyses. From summary-level data of genome-wide association studies (GWAS), we selected 11 single-nucleotide polymorphisms (SNPs) associated with SHBG levels as instrumental variable, and used summary statistics for BMD at forearm (FA) (n = 8143), femoral neck (FN) (n = 32,735), lumbar spine (LS) (n = 28,498) and heel (HL) (n = 394,929), and total-body BMD of different age-stages (15 or less, 15-30, 30-45, 45-60, 60 or more years old) (n = 67,358). Inverse causal associations was observed between SHBG levels and FA BMD (Effect = - 0.26; 95% CI - 0.49 to - 0.04; P = 0.022), HL eBMD (Effect = - 0.09; 95% CI - 0.12 to - 0.06; P = 3.19 × 10-9), and total-body BMD in people aged 45-60 years (Effect = - 0.16; 95% CI - 0.31 to - 2.4 × 10-3; P = 0.047) and over 60 years (Effect = - 0.19; 95% CI - 0.33 to - 0.05; P = 0.006). Our study demonstrates that circulating SHBG concentrations are inversely associated with FA and HL eBMD, and total-body BMD in people aged over 45 years, suggesting that the role of SHBG in the development of osteoporosis might be affected by chronological age of patients and skeletal sites.

Genetically predicted serum uric acid levels and the risk of coronary artery disease in patients with diabetes: A Mendelian randomization study.

BACKGROUND AND AIMS: Serum uric acid (SUA) levels have been reported to be associated with an increased risk of coronary artery disease (CAD) among patients with diabetes in observational study. Whether this relationship is causal remains unclear. The current study aimed to explore the causal association between SUA and the risk of CAD in patients with diabetes. METHODS AND RESULTS: A two-sample Mendelian randomization (MR) approach was employed to evaluate the causal effect of SUA on the risk of CAD in patients with diabetes. A total of 28 single nucleotide polymorphisms (SNPs) related to SUA were identified as instruments. Genetic association with CAD were obtained from a recently published genome-wide association study (GWAS) of 15,666 patients with diabetes (3968 CAD cases and 11,696 controls). The fixed-effects inverse variance-weighted method was employed to estimate the causal effect for the primary analysis, and other robust methods were employed for sensitivity analyses. In addition, the whole analyses were repeated using 9 non-pleiotropic SNPs. Genetic determined SUA levels were not significantly associated with the risk of CAD in patients with diabetes in the primary analysis (odds ratio = 1.13, 95% confidence interval: 0.98-1.16, P = 0.09). Consistent results were observed in the sensitivity analyses using various robust methods. In addition, this finding was confirmed by the repeated analyses using 9 non-pleiotropic SNPs. CONCLUSIONS: This two-sample MR study does not support a causal effect of genetically predicted SUA levels on the risk of CAD in patients with diabetes.

The impact of serum 25-hydroxyvitamin D, calcium, and parathyroid hormone levels on the risk of coronary artery disease in patients with diabetes: a Mendelian randomization study.

BACKGROUND: To investigate the causal association between serum 25-hydroxyvitamin D (25OHD), calcium (Ca), and parathyroid hormone (PTH) levels and the risk of coronary artery disease (CAD) in patients with diabetes using a Mendelian randomization approach. METHODS: Genetic signatures associated with serum 25OHD, Ca, and PTH levels were extracted from recently published genome-wide association study (GWAS), including 79,366, 39,400, 29,155 individuals, respectively. Genetic association estimates for CAD in patients with diabetes were obtained from a GWAS of 15,666 individuals with diabetes (3,968 CAD cases, 11,696 controls). The inverse-variance-weighted method was employed for the primary analysis, and other robust methods were applied for sensitivity analyses. RESULTS: Six, seven and five single nucleotide polymorphisms were identified as instrumental variables for serum 25OHD, Ca and PTH levels, respectively. There was no significant association between genetically predicted serum 25OHD levels and the risk of CAD in patients with diabetes (odds ratio (OR) = 1.04, 95% confidence interval (CI): 0.58 - 1.87, P = 0.888). Similarly, genetically predicted serum Ca (OR = 1.83, 95% CI: 0.62 - 5.35, P = 0.273) and PTH levels (OR = 1.27, 95% CI: 0.67 - 2.44, P = 0.464) were not significantly associated with the risk of CAD in patients with diabetes. These findings were robust in sensitivity analyses. CONCLUSIONS/INTERPRETATION: Serum 25OHD, Ca and PTH levels may not be causally associated with the risk of CAD in patients with diabetes.

The impact of growth differentiation factor 15 on the risk of cardiovascular diseases: two-sample Mendelian randomization study.

BACKGROUND: Growth differentiation factor 15 (GDF-15), a stress responsive cytokine, belongs to transforming growth factor ß cytokine superfamily. Some evidence support that it's involved in inflammation, coagulation, oxidative stress, endothelial dysfunction, and hemostasis. However, it's still controversial whether GDF-15 directly contributes to the morbidity and mortality of patients suffered with cardiovascular disease (CVD). Besides prospective cohort study and randomized controlled trial, Mendelian randomization (MR) is a genetic epidemiological method that exploits genetic variants as unbiased proxies for modifiable to determine the causal relationships between exposures and health outcomes. Herein, we introduced a two-sample MR approach to evaluate the causal relationships of circulating GDF-15 levels with major CVDs incidence. METHODS: Genetic instruments and summary statistics for two-sample MR analysis were obtained from 5 independent large genome-wide association studies (GWAS) to investigate the causal correlation between circulating GDF-15 levels and 9 CVDs, respectively. Conventional inverse variance weighted method was adopted to evaluate the causality of GDF-15 with different outcomes; weighted median and MR egger were used for sensitivity analyses. RESULTS: Among 9 SNPs identified from 5 GWASs in 2.6 million individuals, 5 SNPs (rs1227731, rs3195944, rs17725099, rs888663, rs749451) coming from chromosome 19 and containing the PGPEP1 and GDF-15 genes were employed. Based on the instruments, circulating GDF-15 levels significantly linked to the increased risk of cardioembolic stroke, atrial fibrillation, coronary artery disease and myocardial infarction. However, no significant causal association was observed for circulating GDF-15 levels with the incidence of any ischemic stroke, large-artery atherosclerotic stroke, small vessel stroke, heart failure and nonischemic cardiomyopathy. CONCLUSIONS: The MR study provides with genetic evidence for the causal relationship of circulating GDF-15 levels with the increased risk of cardioembolic stroke, atrial fibrillation, coronary artery disease and myocardial infarction, but not any ischemic stroke, large-artery atherosclerotic stroke, small vessel stroke, heart failure and nonischemic cardiomyopathy. It indicates that GDF-15 might be a promising biomarker or potential therapeutic target for some CVDs.

Seven psychiatric traits and the risk of increased carotid intima-media thickness: a Mendelian randomization study.

Background: Numerous observational studies have suggested an association between psychiatric traits and carotid intima-media thickness (cIMT). However, whether these associations have a causal relationship remains unknown, largely due to issues of reverse causality and potential confounders. This study aims to elucidate the potential causal role of psychiatric traits in the risk of arterial injury as measured by cIMT. Methods: We utilized instrumental variables for attention deficit/hyperactivity disorder (ADHD, n = 226,534), bipolar disorder (n = 353,899), major depressive disorder (n = 142,646), post-traumatic stress disorder (n = 174,494), obsessive-compulsive disorder (n = 9,725), autism spectrum disorder (n = 173,773), and anxiety disease (n = 17,310), derived from the largest corresponding genome-wide association studies (GWAS). Summary statistics for cIMT associations were obtained from a meta-analysis combining GWAS data from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortia (n = 71,128) and the UK Biobank study (n = 45,185). The inverse-variance weighted method served as the primary analytical tool, supplemented by additional statistical methods in the secondary analyses to corroborate the findings. Adjustments were made according to the Bonferroni correction threshold. Results: The Mendelian randomization analyses indicated a suggestive causal link between genetically predicted ADHD and cIMT (beta = 0.05; 95% confidence interval, 0.01-0.09; p = 0.018). Sensitivity analyses largely concurred with this finding. However, no significant associations were found between other psychiatric traits and cIMT. Conclusions: This study provides insights into the risk effect of ADHD on cIMT, suggesting that arteriopathy and potential associated complications should be considered during the treatment and monitoring of patients with ADHD.

Circulating Cytokines and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study.

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; p = 0.033) and DVT (OR: 0.85; 95% CI: 0.75-0.97; p = 0.015). In addition, suggestive association of granulocyte colony-stimulating factor with PE (OR: 1.20; 95% CI: 1.06-1.37; p = 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.

Dual-Activated Photoacoustic Probe for Reliably Detecting Hydroxyl Radical in Ischemic Cardiovascular Disease in Mouse and Human Samples.

Cardiovascular disease (CVD) is a chronic disease characterized by the accumulation of lipids and fibrous tissue within the arterial walls, potentially leading to vascular obstruction and an increased risk of heart disease and stroke. Hydroxyl radicals play a significant role in the formation and progression of CVD as they can instigate lipid peroxidation, resulting in cellular damage and inflammatory responses. However, precisely detecting hydroxyl radicals in CVD lesions presents significant challenges due to their high reactivity and short lifespan. Herein, we present the development and application of a novel activatable optical probe, Cy-OH-LP, designed to detect hydroxyl radicals in lipid-rich environments specifically. Built on the Cy7 molecular skeleton, Cy-OH-LP exhibits near-infrared absorption and fluorescence characteristics, and its specific response to hydroxyl radicals enables a turn-on signal in both photoacoustic and fluorescence spectra. The probe demonstrated excellent selectivity and stability in various tests. Furthermore, Cy-OH-LP was successfully applied in an in vivo model to detect hydroxyl radicals in mouse models, providing a potential tool for diagnosing and monitoring AS. The biosafety of Cy-OH-LP was also verified, showing low cytotoxicity and no significant organ damage in mice. The findings suggest that Cy-OH-LP is a promising tool for the specific detection of hydroxyl radicals in lipid-rich environments, providing new possibilities for research and clinical applications in the field of oxidative stress-related diseases.

Genetic liability to mental disorders in relation to the risk of hypertension.

Background: Observational studies have indicated that psychosocial factors contribute to hypertension; however, the causality of these associations remains unclear due to reverse causality and confounders. We aim to assess the causal associations of mental health disorders with hypertension. Methods: Instrumental variables of anxiety disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, depression, obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, and subjective well-being measure were obtained from the corresponding largest genome-wide association studies. Summary statistics for the association of essential hypertension were obtained from the FinnGen Study (42,857 cases and 162,837 controls) and UK Biobank cohort (54,358 cases and 408,652 controls). The multiplicative random-effects inverse-variance weighted method was utilized as the primary analysis and three other statistical methods were conducted in the supplementary analyses. The results were combined using the fixed-effects method. Results: In the pooled analyses, genetic liability to depression was associated with higher risk of hypertension (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.17-1.35; p < 0.001). Besides, a suggestive association was found between genetically predicted higher weighted neuroticism sum-score and increased risk of hypertension (OR, 1.16; 95% CI, 1.02-1.33; p < 0.05). No associations were found for other mental health disorders. Sensitivity analyses revealed consistent evidence as the main results. Conclusion: We provide consistent evidence for the causal effect of genetic liability to depression on hypertension, which highlights the importance of blood pressure measurement and monitoring in patients with depression.

Apolipoprotein B and interleukin 1 receptor antagonist: reversing the risk of coronary heart disease.

Aims: Epidemiological evidence for the link of interleukin 1 (IL-1) and its inhibition with cardiovascular diseases (CVDs) remains controversial. We aim to investigate the cardiovascular effects of IL-1 receptor antagonist (IL-1Ra) and underlying mechanisms. Methods: Genetic variants identified from a genome-wide association study involving 30,931 individuals were used as instrumental variables for the serum IL-1Ra concentrations. Genetic associations with CVDs and cardiometabolic risk factors were obtained from international genetic consortia. Inverse-variance weighted method was utilized to derive effect estimates, while supplementary analyses employing various statistical approaches. Results: Genetically determined IL-1Ra level was associated with increased risk of coronary heart disease (CHD; OR, 1.07; 95% CI: 1.03-1.17) and myocardial infarction (OR, 1.13; 95% CI: 1.04-1.21). The main results remained consistent in supplementary analyses. Besides, IL-1Ra was associated with circulating levels of various lipoprotein lipids, apolipoproteins and fasting glucose. Interestingly, observed association pattern with CHD was reversed when adjusting for apolipoprotein B (OR, 0.84; 95%CI: 0.71-0.99) and slightly attenuated on accounting for other cardiometabolic risk factors. Appropriate lifestyle intervention was found to lower IL-1Ra concentration and mitigate the heightened CHD risk it posed. Conclusion: Apolipoprotein B represents the key driver, and a potential target for reversal of the causal link between serum IL-1Ra and increased risk of CHD/MI. The combined therapy involving IL-1 inhibition and lipid-modifying treatment aimed at apolipoprotein B merit further exploration.

Appraising the Effects of Metabolic Traits on the Risk of Glaucoma: A Mendelian Randomization Study.

Metabolic traits are associated with the risk of developing glaucoma in observational studies. To assess whether theses associations reflect causality, we conducted a Mendelian randomization (MR) study. Our study included up to 20,906 glaucoma cases and 438,188 controls. Genetic instruments associated with the concerned 11 exposures at the genome-wide significance level were selected from corresponding genome-wide association studies. Summary-level data for glaucoma were obtained from the UK Biobank, the GERA study, and the FinnGen consortium. Univariable and multivariable MR analyses were conducted separately in two populations. Our results showed that higher genetic liability to type 2 diabetes (T2D) was causally and independently associated with an increased risk of glaucoma (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.06-1.16; p = 4.4 × 10-6). The association for T2D persisted after multivariable adjustment. In addition, higher genetically predicted systolic blood pressure (SBP), fasting glucose (FG), and HbA1c, were also suggestively associated with glaucoma risk. The OR was 1.08 (95% CI, 1.01-1.16; p = 0.035) for SBP, 1.24 (95% CI, 1.05-1.47; p = 0.011) for FG, and 1.28 (95% CI, 1.01-1.61; p = 0.039) for HbA1c. No evidence was observed to support the causal effects of body mass index and blood lipids for glaucoma. This study suggests a causal role for diabetes, as well as possible roles for higher SBP, FG, and HbA1c in the development of glaucoma. Further validation is needed to assess the potential of these risk factors as pharmacological targets for glaucoma prevention.

Smoking and coronary artery disease risk in patients with diabetes: A Mendelian randomization study.

Background: Previous observational studies have shown an association between smoking and coronary artery disease (CAD) in patients with diabetes. Whether this association reflects causality remains unestablished. This study aimed to explore the causal effect of smoking on CAD in patients with diabetes. Methods: Genetic signatures for smoking were extracted from a large genome-wide association study (GWAS), consisted of up to 1.2 million participants. Four smoking phenotypes were included: smoking initiation, cigarettes per day, age at initiation of regular smoking, and smoking cessation. Genetic associations with CAD in patients with diabetes were extracted from another GWAS, which included 15,666 participants (3,968 CAD cases and 11,696 controls). The analyses were performed using the univariable and multivariable Mendelian randomization (MR) method. Results: MR analysis revealed that smoking initiation was positively related to CAD risk in patients with diabetes (OR = 1.322, 95% CI = 1.114 - 1.568, P = 0.001), but this association was attenuated when adjusted for cardiovascular risk factors (OR = 1.212, 95% CI = 1.008 - 1.457, P = 0.041). Age at initiation of regular smoking was negatively related to CAD in patients with diabetes (OR = 0.214, 95% CI = 0.070 - 0.656, P = 0.007), but this association became insignificant when adjusted for cardiovascular risk factors. Conclusions: This study supported the effect of smoking initiation on the risk of CAD in patients with diabetes.

Serum urate and heart failure: a bidirectional Mendelian randomization study.

AIMS: Observational studies indicate that serum urate level is associated with heart failure (HF). However, whether this association is causal remains controversial, due to confounding factors and reverse causality. We aim to evaluate the causal relationship of genetically predicted serum urate level with HF. METHODS AND RESULTS: A bidirectional Mendelian randomization (MR) study was performed. Instrumental variables were obtained from the largest genome-wide association studies of serum urate (457 690 individuals) to date. We obtained summary statistics of HF from HERMES consortium (47 309 cases; 930 014 controls), the FinnGen study (13 087 cases; 195 091 controls), and the UK Biobank study (1088 cases; 360 106 controls). Inverse-variance-weighted method was applied to obtain MR estimates and other statistical methods were conducted in the sensitivity analyses. The reverse MR analysis was performed to evaluate the effect of HF on serum urate levels. Genetically determined serum urate level was associated with HF [odds ratio (OR), 1.07; 95% confidence interval (CI), 1.03-1.10; P = 8.6×10-5]. The main results kept robust in the most sensitivity analyses. The association pattern remained for the HF in FinnGen (OR, 1.10; 95% CI, 1.03-1.19; P = 0.008) and the combined results of three data sources (OR, 1.08; 95% CI, 1.04-1.13; P < 0.001). No consistent evidence was found for the causal effect of HF on serum urate levels. CONCLUSION: We provide consistent evidence for the causal effect of genetically predicted serum urate level on HF, but not the reverse effect of HF. Urate-lowering therapy may be of cardiovascular benefit in the prevention of HF.

Multiple Sclerosis and the Risk of Cardiovascular Diseases: A Mendelian Randomization Study.

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

Genetic effects of iron levels on liver injury and risk of liver diseases: A two-sample Mendelian randomization analysis.

Background and aims: Although iron homeostasis has been associated with liver function in many observational studies, the causality in this relationship remains unclear. By using Mendelian Randomization analyses, we aimed to evaluate the genetic effects of increased systemic iron levels on the risk of liver injury and various liver diseases. Moreover, in light of the sex-dependent iron regulation in human beings, we further estimated the sex-specific effect of iron levels in liver diseases. Methods: Independent single nucleotide polymorphisms associated with systemic iron status (including four indicators) at the genome-wide significance level from the Genetics of Iron Status (GIS) Consortium were selected as instrumental variables. Summary data for six liver function biomarkers and five liver diseases were obtained from the UK Biobank, the Estonian Biobank, the eMERGE network, and FinnGen consortium. Mendelian Randomization assessment of the effect of iron on liver function and liver diseases was conducted. Results: Genetically predicted iron levels were positively and significantly associated with an increased risk of different dimensions of liver injury. Furthermore, increased iron status posed hazardous effects on non-alcoholic fatty liver disease, alcoholic liver disease, and liver fibrosis/cirrhosis. Sex-stratified analyses indicated that the hepatoxic role of iron might exist in NAFLD and liver fibrosis/cirrhosis development among men. No significantly causal relationship was found between iron status and viral hepatitis. Conclusion: Our study adds to current knowledge on the genetic role of iron in the risk of liver injury and related liver diseases, which provides clinical and public health implications for liver disease prevention as iron status can be modified.

Low Intelligence Predicts Higher Risks of Coronary Artery Disease and Myocardial Infarction: Evidence From Mendelian Randomization Study.

Background: Low intelligence has been shown to be associated with a high risk of cardiovascular disease in observational studies. It remains unclear whether the association is causal. This study aimed to explore the causal association of intelligence with coronary artery disease (CAD) and myocardial infarction (MI). Methods: A two-sample Mendelian randomization study was designed to infer the causality. A total of 121 single nucleotide polymorphisms were selected as a genetic instrumental variable for intelligence. Summary data on CAD (n = 184,305) and MI (n = 171,875) were obtained from the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAM) plus The Coronary Artery Disease (C4D) Genetics (CARDIoGRAMplusC4D) consortium and the FinnGen study. Inverse variance weighting method was used to calculate the effect estimates. Sensitivity analyses including other statistical models and leave-one-out analysis were conducted to verify the robustness of results. MR-Egger test was performed to assess the pleiotropy. Results: Genetically predicted higher intelligence was significantly associated with lower risk of CAD (OR, .76; 95%CI, .69-.85; p = 1.5 × 10-7) and MI (OR, .78; 95%CI, .70-.87; p = 7.9 × 10-6). The results remained consistent in the majority of the sensitivity analyses and were repeated in the FinnGen datasets. MR-Egger test suggested no evidence of directional pleiotropy for the association with coronary artery disease (intercept = -.01, p = .19) and myocardial infarction (intercept = -.01, p = .06). Conclusion: This Mendelian randomization analysis provided genetic evidence for the causal association between low intelligence and increased risks of CAD and MI.