Chronic widespread pain (CWP) is prevalent and associated with reduced life expectancy. Cardiovascular disease is one possible mechanism for this. The purpose of this study was to examine the association of CWP with arterial stiffness and carotid plaque measured using ultrasound to determine if shared environmental or genetic factors might account for any observed association. Around 3000 participants from the TwinsUK with CWP information and measures of carotid-femoral pulse wave velocity (cfPWV), carotid intima-media thickness (cIMT), and plaque were considered. The relationship between CWP and cfPWV, cIMT, and plaque was determined. UK Biobank data were used to replicate the association. Cholesky decomposition and multivariate pathway twin models were examined. Using a 2-sample Mendelian randomisation approach, the causal association between CWP and coronary artery disease was assessed. TwinsUK participants demonstrated a significant association between CWP and increased cfPWV consistent with arterial stiffening (OR = 1.35, P -value = 0.012), as well as the presence of carotid plaque (OR = 1.45, P -value = 0.8e-5). The twin modelling showed a common latent component and pathway underlying CWP, cfPWV, and carotid plaque, with genetic factors accounting for 68% and 90% of the latent factor variation, respectively. The 2-sample MR revealed a potential causal association between CWP and coronary artery disease. This study found that those with CWP have increased the risk of arterial stiffness and atherosclerosis and suggests that CWP leads to an increased risk of cardiovascular disease through genetic factors.

Polygenic risk scores (PRS) have ushered in a new era in genetic epidemiology, offering insights into individual predispositions to a wide range of diseases. However, despite recent marked enhancements in predictive power, PRS-based models still need to overcome several hurdles before they can be broadly applied in the clinic. Chiefly, they need to achieve sufficient accuracy, easy interpretability and portability across diverse populations. Leveraging trans-ancestry genome-wide association study (GWAS) meta-analysis, we generated novel, diverse summary statistics for 30 medically-related traits and benchmarked the performance of six existing PRS algorithms using UK Biobank. We built an ensemble model using logistic regression to combine outputs of top-performing algorithms and validated it on the diverse eMERGE and PAGE MEC cohorts. It surpassed current state-of-the-art PRS models, with minimal performance drops in external cohorts, indicating good calibration. To enhance predictive accuracy for clinical application, we incorporated easily-accessible clinical characteristics such as age, gender, ancestry and risk factors, creating disease prediction models intended as prospective diagnostic tests, with easily interpretable positive or negative outcomes. After adding clinical characteristics, 12 out of 30 models surpassed 80% AUC. Further, 25 traits exceeded the diagnostic odds ratio (DOR) of five, and 19 traits exceeded DOR of 10 for all ancestry groups, indicating high predictive value. Our PRS model for coronary artery disease identified 55-80 times more true coronary events than rare pathogenic variant models, reinforcing its clinical potential. The polygenic component modulated the effect of high-risk rare variants, stressing the need to consider all genetic components in clinical settings. These findings show that newly developed PRS-based disease prediction models have sufficient accuracy and portability to warrant consideration of being used in the clinic.

Research studies of spontaneous coronary artery dissection (SCAD) have been primarily focused on European-ancestry individuals, with limited recognition and investigation in non-European-ancestry individuals. While SCAD has not been well ascertained in non-European-ancestry groups, pleiotropic associated traits identified in those of European ancestry have been assessed in individuals of other ancestries. Whether these traits are associated with the complex genetic architecture of SCAD in those of non-European ancestry has not been previously investigated.

We investigated the associations of an established SCAD polygenic score with multiple vascular diseases in ≈900 000 ancestrally diverse participants of large-scale studies. Individual-level data from the UK Biobank and the Million Veteran Program and summary statistics of publicly available databases were analyzed.

A set of associations between SCAD polygenic score and related vascular diseases were replicated in non-European samples. Notable associations with the SCAD polygenic score included (1) coronary artery disease, myocardial infarction, and migraine headache in a Hispanic group (coronary artery disease: odds ratio [OR], 0.93 [95% CI, 0.90-0.95]; P=2.35×10-7; myocardial infarction: OR, 0.88 [95% CI, 0.80-0.96]; P=5.73×10-3; migraine headache: OR, 1.03 [95% CI, 1.01-1.06]; P=1.86×10-2) of the Million Veteran Program; (2) headache in an African-ancestry group (OR, 1.22 [95% CI, 1.06-1.41]; P=6.94×10-3) and a South Asian-ancestry group (OR, 1.18 [95% CI, 1.02-1.37]; P=2.43×10-2) of the UK Biobank; and (3) coronary artery disease, myocardial infarction, and migraine headache in East Asian-ancestry cohorts (coronary artery disease: OR, 0.95 [95% CI, 0.93-0.98]; P=2.66×10-3; myocardial infarction: OR, 0.86 [95% CI, 0.83-0.89]; P=9.51×10-16; migraine headache: OR, 1.27 [95% CI, 1.10-1.47]; P=1.03×10-3).

Pleiotropic associations of SCAD polygenic risk with related vascular diseases previously identified in European-ancestry groups showed notable, largely consistent patterns in non-European-ancestry groups.

Breast cancer (BC) is the primary cause of cancer-related deaths among women worldwide, with increasing evidence pointing to the effect of metabolic factors, particularly lipid levels, in its pathogenesis. In this research, Mendelian randomization (MR) was employed to explore the causality between four plasma lipid traits-total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)-and the risk of BC. Additionally, we explored the potential mediating effects of coronary artery disease (CAD), total testosterone (TT) on these associations and possible mechanisms through bioinformatics analyses.

Data of genome-wide association study (GWAS) on lipids, CAD, TT and BC were obtained from public sources and websites as part of a genome-wide association research. The inference of causality was primarily assessed through the inverse variance weighting (IVW) approach, with supplementary tests for horizontal pleiotropy and heterogeneity. To verify the directionality of causal relationships, the MR Steiger test was applied. Additionally, reverse causality was evaluated by regarding BC as the exposure. To adjust for confounders, multivariate MR (MVMR) was performed, followed by a two-step mediation analysis to investigate the mediating roles of CAD in the lipid-BC association, and of TT in the CAD-BC relationship. The intersecting SNP (rs11556924) between causal pathways was established through a Venn diagram and its associated gene (Zinc Finger C3HC-Type Containing 1, ZC3HC1) was identified through the g:Profiler database. The expression of ZC3HC1 was further explored using the TIMER, GEPIA2 and HPA database. Finally, enrichment analyses of Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interactions (PPI) network analysis were conducted on ZC3HC1 and its related genes.

The random-effects IVW analysis yielded the following results: HDL-C on CAD (OR = 0.843, 95% CI 0.771-0.921, P < 0.001), CAD on BC (OR = 0.935, 95% CI 0.892-0.980, P = 0.005), HDL-C on BC (OR = 1.127, 95% CI 1.059-1.199, P < 0.001), CAD on TT (OR = 0.987, 95% CI 0.975-0.998, P = 0.020) and TT on BC (OR = 1.354, 95% CI 1.148-1.598, P < 0.001). The MR Steiger test results support the validity of the inferred causal direction (P < 0.001). There were no discernible causal relationships between BC and HDL-C/CAD according to reverse MR analysis (P > 0.05). Following MVMR adjustment, the causal effects of HDL-C, CAD, and TT on BC were still statistically significant (P < 0.05). Besides, the two-step mediation analysis indicated that CAD mediated 7.8% of the causal effect of HDL-C on BC, whereas TT mediated 6.1% of the causal effect between CAD and BC. The expression of ZC3HC1 showed no significant expression difference between normal and BC tissues (P > 0.05), which might indicate a carcinogenic effect independent of expression levels but driven by functional alterations induced by variants (C > T). Functional network analysis suggested that ZC3HC1 was associated with multiple signal pathways in cancers, such as PI3K-Akt and MAPK signal pathways.

From a genetic perspective, our study reveals that there is causality between HDL-C levels and BC risk, with CAD and TT acting as partial mediators in this relationship. Moreover, our study firstly establishes a potential link between CAD-associated SNP (rs11556924), the corresponding gene (ZC3HC1) functional dysregulation, and the initiation of BC. These findings shed light on the biological links between lipids and BC, potentially contributing to future prevention and treatment strategies.

Mendelian randomization (MR) leverages trait associated genetic variants as instrumental variables (IVs) to determine causal relationships in epidemiology. However, genetic IVs for complex traits are typically highly heterogeneous and, at a molecular level, exert effects on different biological processes. Exploration of the biological underpinnings of such heterogeneity can enhance our understanding of disease mechanisms and inform therapeutic strategies. Here, we introduce a new approach to instrument partitioning based on enrichment of Mendelian disease categories (pathway-partitioned) and compare it to an existing method based on genetic colocalization in contrasting tissues (tissue-partitioned).

We employed individual- and summary-level MR methodologies using SNPs grouped by pathway informed by proximity to Mendelian disease genes affecting the renal system or vasculature (for blood pressure (BP)), or mental health and metabolic disorders (for body mass index (BMI)). We compared the causal effects of pathway-partitioned SNPs on cardiometabolic outcomes with those derived using tissue-partitioned SNPs informed by colocalization with gene expression in kidney, artery (BP), or adipose and brain tissues (BMI). Additionally, we assessed the likelihood that estimates observed for partitioned exposures could emerge by chance using random SNP sampling.

Our pathway-partitioned findings suggest the causal relationship between systolic BP and heart disease is predominantly driven by vessel over renal pathways. The stronger effect attributed to kidney over artery tissue in our tissue-partitioned MR hints at a multifaceted interplay between pathways in the disease aetiology. We consistently identified a dominant role for vessel (pathway) and artery (tissue) driving the negative directional effect of diastolic BP on left ventricular stroke volume and positive directional effect of systolic BP on type 2 diabetes. We also found when dissecting the BMI pathway contribution to atrial fibrillation that metabolic-pathway and brain-tissue IVs predominantly drove the causal effects relative to mental health and adipose in pathway- and tissue-partitioned MR analyses, respectively.

This study presents a novel approach to dissecting heterogeneity in MR by integrating clinical phenotypes associated with Mendelian disease. Our findings emphasize the importance of understanding pathway-/tissue-specific contributions to complex exposures when interpreting causal relationships in MR. Importantly, we advocate caution and robust validation when interpreting pathway-partitioned effect size differences.

Mendelian randomization (MR) enables the estimation of causal effects while controlling for unmeasured confounding factors. However, traditional MR's reliance on strong parametric assumptions can introduce bias if these are violated. We describe a machine learning MR estimator named quantile instrumental variable (Quantile IV) that achieves a low estimation error in a wide range of plausible MR scenarios. Quantile IV is distinctive in its ability to estimate nonlinear and heterogeneous causal effects and offers a flexible approach for subgroup analysis. Applying quantile IV, we investigate the impact of circulating sclerostin levels on heel bone mineral density, osteoporosis, and cardiovascular outcomes. Employing various MR estimators and colocalization techniques, our analysis reveals that a genetically predicted reduction in sclerostin levels significantly increases heel bone mineral density and reduces the risk of osteoporosis while showing no discernible effect on ischemic cardiovascular diseases. As a second application, we estimated the effect of increases in low-density lipoprotein cholesterol and waist-to-hip ratio on ischemic cardiovascular diseases using this well-known association as a positive control analysis. Quantile IV contributes to the advancement of MR methodology, and the selected applications demonstrate the applicability of our estimator in various MR contexts.

It is unclear whether physical activity can benefit participants with high genetic predisposition to cardiovascular disease. We examined the joint associations of intensity-specific physical activity and genetic predisposition (based on polygenetic risk score) with incident coronary heart disease (CHD), stroke, and atrial fibrillation (AF).

This prospective cohort study included 303,950 adults (age = 56.4 ± 8.0 years, mean ± SD; 52.5% females) from the UK Biobank with physical activity and disease-related genotypes. Moderate-to-vigorous physical activity (MVPA) and intensity-specific activity was classified according to volume (e.g., MVPA was classified as none, low, medium, and high). Genetic predisposition for CHD, stroke, and AF were classified as low (Quintile 1), intermediate (Quintiles 2-4), and high (Quintile 5).

During 11.6 ± 2.1 years of follow-up: 19,865 CHD; 7907 stroke; and 16,688 AF events occurred. Compared to the no MVPA and high genetic risk group, we observed lower CHD risk for increasing levels of MVPA over and above genetic risk groupings. These associations were primarily driven by vigorous-intensity activity. For example, in the high genetic risk group, those with low vigorous-intensity activity levels (compared to none) had a hazard ratio (HR) of 0.78 (95% confidence interval (95% CI):0.72-0.86) compared to an HR of 0.90 (95% CI: 0.83-0.98) for low moderate-intensity activity levels. For stroke incidence, we observed a protective association for MVPA across genetic risk groups that was mostly driven by moderate-intensity activity volume. Among the high genetic risk group, low moderate-intensity had an HR of 0.77 (95% CI:0.66-0.90), whereas low vigorous-intensity had no association (HR = 0.95, 95% CI:0.82-1.09). We did not observe a consistent joint association of MVPA and AF genetic predisposition.

We observed lower CHD and stroke risk for low to high MVPA among participants with high genetic predisposition. The associations of moderate- and vigorous-intensity activity volume differed considerably across cardiovascular disease sub-types. Overall, our findings suggest vigorous intensity activity may mitigate genetic predisposition for CHD while moderate intensity activity may be associated with similar effects for stroke. Joint associations were less consistent across AF genetic predisposition groups. Our results inform precision medicine approaches and future lifestyle modification interventions by quantifying the potential benefits of physical activity among at-risk individuals.

Emerging antihypertensive drug classes offer new opportunities to manage hypertension; however, their long-term effects on cardiovascular, kidney, and metabolic (CKM) outcomes remain to be elucidated. This study aims to explore the effects of phosphodiesterase type 5 inhibitors (PDE5i), soluble guanylate cyclase stimulators (sGCs), endothelin receptor antagonists (ERAs), and angiotensinogen inhibitors (AGTis) on a range of CKM outcomes.

Mendelian randomization (MR), summary-based MR (SMR), and colocalization analyses were applied to assess the drug effect on coronary artery disease (CAD), myocardial infarction (MI), ischaemic stroke, atrial fibrillation (AF), heart failure (HF), type 2 diabetes (T2D), and chronic kidney disease (CKD). Genetic association and gene expression summary data were obtained from the largest European-ancestry genome-wide association studies (GWAS) and the genotype-tissue expression version 8 for 29 tissues relevant to the outcomes' pathophysiology.Genetically predicted systolic blood pressure (SBP) reduction was associated with reduced risks of all outcomes. PDE5i was associated with reduced risks of CAD (OR per 10-mmHg decrease in SBP: 0.348[95% confidence interval (CI): 0.199-0.607]) and ischaemic stroke (0.588[0.453-0.763]). sGCs showed protective effects against CAD (0.332[0.236-0.469]), MI (0.238[0.168-0.337]), and CKD (0.55[0.398-0.761]). ERA and AGTi showed protective effects against CAD and ischaemic stroke. SMR and colocalization supported the association of gene expression levels of GUCY1A3 and PDE5A with CAD and MI risk.

Our study highlights the potential of PDE5i, sGCs, ERA, and AGTi in reducing cardiovascular and renal risks. These findings underscore the necessity for targeted clinical trials to validate the efficacy and safety of these therapies.

Understanding the etiological risk factors for retinal vascular occlusion (RVO) is critical for prevention and treatment. While the effects of cardiovascular events, hypertension, glaucoma, obesity and glycemic risk factors on RVO are still controversial. This study employed two-sample Mendelian randomization (MR) analysis to investigate these causal risk factors. Single-nucleotide polymorphisms (SNPs) were used as instrumental variables (IVs). Genetic instruments for hypertension, glaucoma, obesity, cardiovascular events and glycemic risk factors were obtained from published genome-wide association studies (GWASs). Summary-level data for RVO and hypertension were obtained from the FinnGen consortium. MR analysis primarily utilized the inverse variance weighted (IVW) method, with MR-Egger and weighted median as supplementary approaches. Multivariable MR (MVMR) adjusting for hypertension or glaucoma of RVO were conducted. Heterogeneity was assessed using Cochrane's Q test and I2, while MR-Egger intercept and MR-PRESSO tested horizontal pleiotropy. All MR analyses were performed within R software (4.1.3) using the R packages "TwoSampleMR" and "MR-PRESSO." Genetic instruments for hypertension and glaucoma were significantly associated with RVO risk. A one-standard deviation (SD) increase in hypertension was associated with a higher risk of RVO [OR = 1.577, 95% CI = (1.342, 1.854), P < .001], while a one-SD increase in the log odds of genetically predicted glaucoma was associated with a higher risk of RVO [OR = 1.24, 95% CI = (1.115, 1.379), P < .001]. Meanwhile, hypertension and glaucoma were still significant in multivariable MR. There was not sufficient evidence to suggest cardiovascular events and obesity were associated with RVO risk. This MR study provided genetic evidence supporting that hypertension and glaucoma were causally associated with the risk of RVO. It may help guide clinical decisions in the management of RVO patients with hypertension and glaucoma.

The burden of cardiovascular disease is rising in the Asia-Pacific region, in contrast to falling cardiovascular disease mortality rates in Europe and North America. Here we perform quantification of 883 metabolites by untargeted mass spectroscopy in 8,124 Asian adults and investigate their relationships with carotid intima media thickness, a marker of atherosclerosis. Plasma concentrations of 3beta-hydroxy-5-cholestenoate (3BH5C), a cholesterol metabolite, were inversely associated with carotid intima media thickness, and Mendelian randomization studies supported a causal relationship between 3BH5C and coronary artery disease. The observed effect size was 5- to 6-fold higher in Asians than Europeans. Colocalization analyses indicated the presence of a shared causal variant between 3BH5C plasma levels and messenger RNA and protein expression of ferredoxin-1 (FDX1), a protein that is essential for sterol and bile acid synthesis. We validated FDX1 as a regulator of 3BH5C synthesis in hepatocytes and macrophages and demonstrated its role in cholesterol efflux in macrophages and aortic smooth muscle cells, using knockout and overexpression models.

Mendelian randomization (MR) is a widely used tool to uncover causal relationships between exposures and outcomes. However, existing MR methods can suffer from inflated type I error rates and biased causal effects in the presence of invalid instruments. Our proposed method enhances MR analysis by augmenting latent phenotypes of the outcome, explicitly disentangling horizontal and vertical pleiotropy effects. This allows for explicit assessment of the exclusion restriction assumption and iteratively refines causal estimates through the expectation-maximization algorithm. This approach offers a unique and potentially more precise framework compared to existing MR methods. We rigorously evaluate our method against established MR approaches across diverse simulation scenarios, including balanced and directional pleiotropy, as well as violations of the Instrument Strength Independent of Direct Effect (InSIDE) assumption. Our findings consistently demonstrate superior performance of our method in terms of controlling type I error rates, bias, and robustness to genetic confounding, regardless of whether individual-level or summary data is used. Additionally, our method facilitates testing for directional horizontal pleiotropy and outperforms MR-Egger in this regard, while also effectively testing for violations of the InSIDE assumption. We apply our method to real data, demonstrating its effectiveness compared to traditional MR methods. This analysis reveals the causal effects of body mass index (BMI) on metabolic syndrome (MetS) and a composite MetS score calculated by the weighted sum of its component factors. While the causal relationship is consistent across most methods, our proposed method shows fewer violations of the exclusion restriction assumption, especially for MetS scores where horizontal pleiotropy persists and other methods suffer from inflation.

Patients with benign paroxysmal positional vertigo (BPPV) may be at increased risk for hypertension.

To examine the causal relationship between hypertensive disorders and benign paroxysmal vertigo (BPV).

A bidirectional two-sample Mendelian randomization (MR) study was conducted to assess the causal relationship between hypertension and BPV. Summary statistics for BPV and hypertension were obtained from the FinnGen biobank to support the primary MR analysis. Five complementary methods - inverse variance weighted, weighted median, MR-Egger, simple mode, and weighted mode - were applied to obtain MR estimates. Furthermore, a multivariable MR (MVMR) analysis was conducted to examine whether hypertension independently influences BPV.

The MR analysis indicated a significant causal effect of hypertension on BPV, with an odds ratio (OR) of 1.11 (95% CI: 1.02-1.22, p = .019), indicating an increased risk of BPV associated with hypertension. MVMR analysis further indicated that the causal effect of hypertension on BPV remained significant even after adjusting for menopausal disorders and ischemic stroke (OR: 1.108, 95% CI: 1.003-1.225, p = .043).

This MR study provided evidence supporting a causal effect of hypertension on BPV.

To evaluate the survival outcomes of stereotactic body radiotherapy (SBRT) versus surgical resection in elderly patients (≥ 70 years old) with early-stage non-small-cell lung cancer (NSCLC).

A systematic search was conducted across databases such as PubMed, Web of Science, EMBASE, Cochrane Library, CNKI, VIP, and Wanfang to collect comparative studies on the survival outcomes of SBRT versus surgery for early-stage NSCLC in elderly patients, with searches up to December 2023 and statistical analysis performed using Stata software. This meta-analysis included 10 comparative studies, encompassing 9410 elderly patients with early-stage NSCLC.

The results indicated that the SBRT group had worse outcomes compared to the surgery group in terms of 3-year overall survival (OS) [HR = 1.31, 95% CI (1.02-1.70), p < 0.05], 5-year OS [HR = 1.37, 95% CI (1.06-1.77), p < 0.05], 1-year cancer-specific survival (CSS) [HR = 1.32, 95% CI (1.03-1.68), p < 0.05], 3-year CSS [HR = 1.89, 95% CI (1.70-2.11), p < 0.01], and 5-year CSS [HR = 1.92, 95% CI (1.75-2.10), p < 0.01]. There were no statistically significant differences between the two groups in terms of 1-year OS, 1-year, 3-year, and 5-year progression-free survival (PFS), and locoregional control (LC) rates (p > 0.05).

For elderly early-stage NSCLC patients with acceptable risk, surgery remains the more appropriate treatment method. For patients unable to undergo surgery or who refuse it, SBRT serves as a viable alternative treatment option.

Genome-wide association studies have identified common genetic variants at ≈300 human genomic loci linked to coronary artery disease susceptibility. Among these genomic regions, the most impactful is the 9p21.3 coronary artery disease risk locus, which spans a 60-kb gene desert and encompasses ≈80 SNPs (single nucleotide polymorphism) in high linkage disequilibrium. Despite ≈2 decades since its discovery, the role of the 9p21.3 locus in cells of the vasculature remains incompletely resolved.

We differentiated induced pluripotent stem cells (iPSCs) from risk, nonrisk donors at 9p21.3, and isogenic knockouts into vascular smooth muscle cells (VSMCs). We performed single-cell transcriptomic profiling, including coembedding and comparison with publicly available human arterial data sets. We conducted functional characterization using migration and calcification assays and confirmed our findings on iPSC-VSMCs derived from additional donors. Finally, we used overexpression of ANRIL followed by gene expression analysis.

We demonstrated that iPSC-VSMCs harboring the 9p21.3 risk haplotype preferentially adopt an osteochondrogenic state and show remarkable similarity to fibrochondrocytes from human artery tissue. The transcriptional profile and functional assessment of migration and calcification capacity across iPSC-VSMC lines from multiple donors concordantly resemble an osteochondrogenic state. Importantly, we identified numerous transcription factors driving different VSMC state trajectories. Additionally, we prioritized LIMCH1 and CRABP1 as signature genes critical for defining the risk transcriptional program. Finally, overexpression of a short isoform of ANRIL in 9p21.3 knockout cells was sufficient to induce the osteochondrogenic transcriptional signature.

Our study provides new insights into the mechanism of the 9p21.3 risk locus and defines its previously undescribed role in driving a disease-prone transcriptional and functional state in VSMCs concordant with an osteochondrogenic-like state. Our data suggest that the 9p21.3 risk haplotype likely promotes arterial calcification, through altered expression of ANRIL, in a cell type-specific and cell-autonomous manner, providing insight into potential risk assessment and treatment for carriers.

The relationship between high-density lipoprotein (HDL) and atherosclerotic risk remains incompletely elucidated, potentially due to the inherent heterogeneity of HDL particles. Hypertriglyceridemia is associated with alterations in HDL composition. This study investigated the impact of elevated triglycerides (TG) on HDL and its association with coronary artery disease (CAD) risk using a large prospective cohort study and Mendelian randomization (MR). We found that elevated TG was associated with reduced HDL particle size, decreased concentrations of HDL components, and increased triglycerides in HDL (HDL-TG) (all P for trend < 0.001). The protective effects of HDL particle concentration and HDL cholesterol on CAD are attenuated with increasing serum TG levels. An independent and positive association between HDL-TG levels and incident CAD events (hazard ratio [HR] per 1 standard deviation increase: 1.066, 95% CI: 1.052-1.080, P < 0.001) was confirmed even after adjustment for established cardiovascular disease risk factors. MR analyses supported a causal role for HDL-TG in CAD development (inverse-variance weighted [IVW] method: odds ratios [ORs] of 1.120 (95% CI: 1.053-1.192, P < 0.001) and 1.141 (95% CI: 1.032-1.263, P = 0.010) for dataset groups 1 and 2, respectively). Drug-target MR analyses suggested a potential association between omega-3 fatty acids (OM3-FA) and lower HDL-TG levels, with LPL and DGAT2 as key pharmacological targets. Our findings suggest that elevated TG contributes to adverse alterations in HDL, elevating CAD risk. HDL-TG is an independent positive risk factor for CAD and a potential causal contributor to CAD development. OM3-FA supplementation may offer a therapeutic strategy for mitigating the CAD risk associated with elevated HDL-TG.

Growth differentiation factor 15 (GDF15) is a key regulator of food intake and energy metabolism. GDF15 mimetic drugs for the treatment of metabolic syndrome and obesity are under clinical development. While GDF15 presents a promising target for weight management, its potential cardiovascular actions remain elusive. In this study we investigated the role of GDF15 in macrophage function and atherosclerosis pathogenesis and whether GDF15 acts both as a biomarker and mediator of atherosclerosis severity. ApoE-/- mice were fed a high-cholesterol diet (HCD, 1.25% cholesterol) for 6, 12 or 18 weeks to establish atherosclerotic models. We showed that serum levels of GDF15 were elevated in ApoE-/- mice with atheroprogression; increased serum levels of GDF15 were also observed in patients with coronary artery disease. Enlightened by this finding, we established atherosclerotic model in Gdf15-/- mice by injecting with AAV8-PCSK9D377Y virus and feeding HCD for 12 or 16 weeks. We showed that global Gdf15 knockout, whether in male or female mice, did not alter plaque size in en face aorta, lesion in aortic sinus, size of necrotic core or plaque composition. In macrophage-derived foam cells isolated from atherosclerotic mice, neither Gdf15 deletion nor the treatment with recombinant GDF15 protein (1, 10, 100 ng/mL) affected lipid deposition or macrophage polarization. To translate this finding into a clinically relevant scenario, we performed Mendelian randomization (MR) analysis, and found no significant causal association between circulating GDF15 levels and the incidence of cardiovascular diseases. Furthermore, MR studies suggest that genetic associations between GDF15 and factors such as BMI, ApoB, LDL and HDL were not significant in plasma data from the UK Biobank and the deCODE cohort. In summary, this study demonstrates that global Gdf15 deficiency does not affect the development of atherosclerosis in male or female mice despite the positive association between circulating GDF15 levels and disease progression in mice and human. Thus, GDF15 in circulation is a potential biomarker, but not a causal mediator, of atherosclerosis. Long-term cardiovascular safety of GDF15-targeted therapies warrants further investigation.

Both genetic and lifestyle factors contribute to myocardial infarction (MI) and stroke, including ischaemic stroke (IS) and intracerebral haemorrhage (ICH). We explored how and the extent to which a healthy lifestyle, by considering a comprehensive list, could counteract the genetic risk of those diseases, respectively.

315 044 participants free of stroke and MI at baseline were identified from the UK Biobank. Genetic risk scores (GRS) for those diseases were constructed separately and categorised as low, intermediate and high by tertile. Lifestyle risk scores (LRS) were constructed separately using smoking, alcohol intake, physical activity, dietary patterns and sleep patterns. Similarly, participants were categorised into low, intermediate and high LRS. The data were analysed using Cox proportional hazard models.

Over a median follow-up of 12.8 years, 4642, 1046 and 9485 participants developed IS, ICH and MI, respectively. Compared with participants with low levels of GRS and LRS, the HRs of those with high levels of GRS and LRS were 3.45 (95% CI 2.71 to 4.41), 2.32 (95% CI 1.40 to 3.85) and 4.89 (95% CI 4.16 to 5.75) for IS, ICH and MI, respectively. Moreover, among participants with high GRS, the standardised 14-year rates of IS events were 4.40% (95% CI 3.45% to 5.36%) among those with high LRS. In contrast, it is only 1.78% (95% CI 1.63% to 1.94%) among those with low LRS. Similarly for MI, the high LRS group had standardised rates of 8.60% (95% CI 7.38% to 9.81%), compared with 3.34% (95% CI 3.12% to 3.56%) in low LRS. Among the high genetic risk group of ICH, the rate is reduced by about half compared low LRS to high LRS, although the rate was low for both (0.36% (95% CI 0.31% to 0.42%) and 0.71% (95% CI 0.36% to 1.05%), respectively).

Healthy lifestyles were substantially associated with a reduction in the risk of IS, ICH and MI and attenuated the genetic risk of IS, ICH and MI by at least half, respectively.

Cardiovascular diseases, such as atrial fibrillation, coronary artery disease, heart failure (HF) and ischaemic stroke, are leading causes of death globally and exert major global health burden. Recent studies suggest that glucagon-like peptide-1 receptor agonists (GLP1Ra), a novel class of antidiabetic drugs, may not only help manage blood glucose but also reduce the risks of cardiovascular diseases. However, the mechanisms through which GLP1Ra protects against cardiovascular diseases, remain incompletely understood.

Genome-wide association study dates were used to investigate the impact of GLP1Ra on cardiovascular diseases, including atrial fibrillation (1,202,168 European and 28,612 East Asian), coronary artery disease (501,756 European and 183,134 East Asian), heart failure (HF) (1,350,497 European and 203,040 East Asian) and ischaemic stroke (689,168 European and 192,383 East Asian). Genetic instruments were selected from the GLP1R gene region, and two-sample Mendelian randomization (MR) analyses were conducted to assess the causal effects of GLP1Ra on cardiovascular diseases in European and East Asian populations. Summary-data-based MR analyses were performed for further validation using expression quantitative trait loci data. Mediation analysis evaluates the role of circulating inflammatory proteins and metabolites in mediating the effects of GLP1Ra. Meantime, we performed a series of sensitivity analyses to confirm the robustness of the results. The result demonstrated significant causal association between GLP1Ra and HF in European populations (odds ratio: 0.60, 95% CI 0.51-0.72, P = 2.76 × 10-8), and this result was confirmed by SMR analyses. No significant associations were found for atrial fibrillation, coronary artery disease, ischaemic stroke in European populations or all cardiovascular diseases in East Asian populations. GLP1Ra was found to influence 27 circulating inflammatory proteins and 146 circulating metabolites. Among them, 4 inflammatory proteins and 17 metabolites are associated with HF. Mediation analysis indicated that the protective effect of GLP1Ra on HF was mediated by circulating fibroblast growth factor 5 (FGF5) and N-acetylglycine (NAC), with a mediated proportion of 4.37% and 8% of the total effect, respectively.

This study provides multiomics insight into the role of GLP1Ra in cardiovascular diseases, especially in HF and the underlying pathway. The results suggest that GLP1Ra may exert anti-HF effects by reducing the concentration of circulating FGF5 and increasing the levels of circulating NAC, and enriches the potential mechanisms through which GLP1Ra alleviates HF.

The influence of gut microbes on aging has been reported in several studies, but the mediating pathways of gut microbiota, whether there is a causal relationship between the two, and biomarker screening and validation have not been fully discussed. In this study, Mendelian Randomization (MR) and Linkage Disequilibrium Score Regression (LDSC) are used to systematically investigate the associations between gut microbiota, three aging indicators, and 14 age-related diseases. Additionally, this study integrates machine learning algorithms to explore the potential of MR and LDSC methods for biomarker screening. Gut microbiota is found to be a potential risk factor for 14 age-related diseases. The causal effects of gut microbiota on chronic kidney disease, cirrhosis, and heart failure are partially mediated by aging indicators. Additionally, gut microbiota identified through MR and LDSC methods exhibit biomarker properties for disease prediction (average AUC = 0.731). These methods can serve as auxiliary tools for conventional biomarker screening, effectively enhancing the performance of disease models (average AUC increased from 0.808 to 0.832). This study provides evidence that supports the association between the gut microbiota and aging and highlights the potential of genetic correlation and causal relationship analysis in biomarker discovery. These findings may help to develop new approaches for healthy aging detection and intervention.

Sudden cardiac death (SCD) is a major cause of mortality among patients with coronary artery disease (CAD). This study aimed to identify risk factors for CAD-related SCD (SCDCAD) through autopsy data and genetic screening with a particular emphasis on rare variants (minor allele frequency < 0.01). We included 241 SCDCAD cases (mean age 54.6 ± 12.8 years, 74.7% male) verified by medico-legal examination and 241 silent CAD controls (mean age 53.6 ± 15.2 years, 25.3% female) who died from severe craniocerebral trauma. Information about death characteristics was obtained from questionnaires, police reports and autopsy data. Whole-exome sequencing was performed on myocardial tissue samples. Polygenic risk score (PRS) from a previously validated model was applied and rare variant pathogenicity was predicted using in silico tools. SCDCAD victims predominantly died at night and showed higher mortality rates during summer and winter months, with more complex coronary disease. Nocturnal time (adjusted odds ratio [AOR] = 3.53, 95% CI: 2.37-5.25, p < 0.001), winter (AOR = 2.06, 95% CI: 1.33-3.20, p = 0.001), multiple vessel occlusion (AOR = 1.79, 95% CI: 1.16-2.77, p = 0.009), right coronary artery stenosis (AOR = 2.38, 95% CI: 1.54-3.68, p < 0.001) and unstable plaque (AOR = 2.17, 95% CI: 1.46-3.23, p < 0.001) were identified as risk factors of SCDCAD. The PRS score was associated with a 60% increased risk of SCDCAD (OR = 1.632 per SD, 95%CI: 1.631-1.633, p < 0.001). Genetic analysis identified MUC19 and CGN as being associated with SCDCAD. We identified both hereditary and acquired risk factors that may contribute to cardiac dysfunction and precipitate SCD in CAD patients, thereby facilitating the prevention and early recognition of high-risk individuals.

ObjectiveObservational studies on glucosamine supplementation and type 2 diabetes risk have shown inconsistent results, necessitating the use of Mendelian randomization to clarify the true causal relationship.MethodsThe glucosamine supplementation-related genome-wide association study dataset was obtained from the MRC Integrative Epidemiology Unit consortium, whereas type 2 diabetes-related genome-wide association study datasets were obtained from the FinnGen consortium (discovery) and Xue et al.'s meta-analysis (validation). Two-sample Mendelian randomization analyses were performed separately in the discovery and validation datasets, followed by meta-analysis and multivariable Mendelian randomization analyses to verify the robustness of the results of two-sample Mendelian randomization. The estimation of the causal relationship was conducted through the inverse variance weighted method.ResultsGlucosamine supplementation exhibited a significant protective effect against type 2 diabetes, as identified by two-sample Mendelian randomization analysis in the FinnGen consortium (odds ratio: 0.13, 95% confidence interval: 0.02-0.89) and validated in Xue et al.'s meta-analysis (odds ratio: 0.06, 95%; confidence interval: 0.01-0.29). A combined meta-analysis (odds ratio: 0.08, 95%; confidence interval: 0.02-0.27) of the results of two-sample Mendelian randomization confirmed the robustness of these findings. Additionally, multivariable Mendelian randomization analysis (odds ratio: 0.12, 95%; confidence interval: 0.02-0.94), after adjusting for confounding factors, supported the results of two-sample Mendelian randomization. No evidence of heterogeneity or pleiotropy was observed.ConclusionOverall, our results revealed that genetically predicted glucosamine supplementation was inversely associated with the risk of type 2 diabetes, highlighting the potential importance of glucosamine supplementation in preventing type 2 diabetes.

Vascular calcification (VC) significantly increases the incidence and mortality of many diseases. The causal relationships of dyslipidaemia and lipid-lowering drug use with VC severity remain unclear. This study explores the genetic causal associations of different circulating lipids and lipid-lowering drug targets with coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC).

We obtained single-nucleotide polymorphisms (SNPs) and expression quantitative trait loci (eQTLs) associated with seven circulating lipids and 13 lipid-lowering drug targets from publicly available genome-wide association studies and eQTL databases. Causal associations were investigated by univariable, multivariable, drug-target, and summary data-based Mendelian randomization (MR) analyses. Potential mediation effects of metabolic risk factors were evaluated.

MR analysis revealed that genetic proxies for low-density lipoprotein cholesterol (LDL-C), triglycerides (TC) and Lipoprotein (a) (Lp(a)) were causally associated with CAC severity, and apolipoprotein B (apoB) level was causally associated with AAC severity. A significant association was detected between hepatic Lipoprotein(A) (LPA) gene expression and CAC severity. Colocalisation analysis supported the hypothesis that the association between LPA expression and CAC quantity is driven by different causal variant sites within the ±1 Mb flanking region of LPA. Serum calcium and phosphorus had causal associations with CAC severity.

Inhibitors targeting LPA might represent CAC drug candidates. Moreover, T2DM, hypercalcemia, and hyperphosphatemia are positively causally associated with CAC severity, while chronic kidney disease and estimated glomerular filtration rate are not.

The mechanism by which ibrutinib, a Bruton's tyrosine kinase inhibitor, can elevate the risk of arrhythmias is not fully elucidated. In this study, we explored how inhibition of off-target kinases can contribute to this phenomenon.

We performed a Mendelian randomization analysis to examine the causal associations between genetically proxied inhibition of six putative ibrutinib drug targets (ErbB2/HER2, CSK, JAK3, TEC, BLK, and PLCG2) and the atrial fibrillation (AF) risk, proarrhythmic ECG indices, and cardiometabolic traits and diseases. Inverse-variance weighted random-effects models and Wald ratio were used to examine the associations between genetically proxied inhibition of these drug targets and the risk of outcomes. Colocalization analyses were employed to examine the robustness of the causally significant findings. ELISAs were used to measure ErbB2 levels in intracardiac plasma samples.

Genetically proxied ErbB2 inhibition was associated with an increased AF risk, higher P wave terminal force, and prolonged QTc interval. Patients with AF had significantly higher intracardiac ErbB2 levels compared with patients with paroxysmal supraventricular tachycardia. CSK inhibition prolonged the QRS duration, decreased the QTc interval, and was potentially linked to conduction blocks. PLCG2 inhibition led to decreased P wave terminal force, shorter QTc interval, and increased risk of left bundle branch block. BLK inhibition shortened the QTc interval and was also associated with atrioventricular block.

The off-target effects and downstream targets of ibrutinib, including CSK, PLCG2, ERBB2, TEC, and BLK, may lead to cardiac electrical homeostasis imbalances and lethal cardiovascular diseases. Using drugs that inhibit these targets should be given extra caution.

Genome-wide association studies have revealed numerous loci associated with coronary artery disease (CAD). However, some potential causal/risk genes remain unidentified, and causal therapies are lacking.

We integrated multi-omics data from gene methylation, expression, and protein levels using summary data-based Mendelian randomization and colocalization analysis. Candidate genes were prioritized based on protein-level associations, colocalization probability, and links to methylation and expression. Single-cell RNA sequencing data were used to assess differential expression in the coronary arteries of patients with CAD. TAGLN2 (Transgelin 2), APOB (Apolipoprotein B), and GIP (Glucose-dependent insulinotropic polypeptide) were identified as the genes most strongly associated with CAD, with TAGLN2 exhibiting the most significant association. Higher methylation levels of TAGLN2 at specific Cytosine-phosphate-Guanine sites were negatively correlated with its gene expression and associated with a lower risk of CAD, whereas higher circulating TAGLN2 protein levels were positively associated with CAD risk (odds ratio,1.66 [95% CI, 1.32-2.08). These results suggest distinct regulatory mechanisms for TAGLN2. In contrast, APOB and GIP showed positive associations with CAD risk, whereas DHX58 (DExH-box helicase 58) and SWAP70 (Switch-associated protein 70) were associated with decreased risk.

Our findings provide multi-omics evidence suggesting that TAGLN2, APOB, GIP, DHX58, and SWAP70 genes are associated with CAD risk. This work provides novel insights into the molecular mechanisms of CAD and highlights the potential of integrating multi-omics data to uncover potential causal relationships that cannot be fully captured by traditional genome-wide association studies.

Circulating lipids play a crucial role in the development of coronary artery disease (CAD). However, it is unclear whether the genetic susceptibility to hyperlipidemia may interact with lifestyle factors in CAD risk. Using UK Biobank data from 328,606 participants, we evaluated combined effects of genetic susceptibility to hyperlipidemia and lifestyle factors with risk of CAD. We found that both blood lipid-related polygenic score (PGS) and healthy lifestyle score (HLS) are independently associated with CAD risk, and individuals with the highest-risk lipid-related PGS and the least healthy HLS had the highest CAD risk. This association was stronger in younger (< 60 years, hazard ratio: 4.46, 95% confidence interval: 3.44-5.78) than older adults (2.54, 2.13-3.03). Our study suggests that individuals, particularly younger adults, with higher-risk PGSs of blood lipid traits would benefit more substantially by adherence to a healthy lifestyle than those with lower PGSs.

An elevated level of lipoprotein(a), or Lp(a), in the bloodstream has been causally linked to the development of atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Steady state levels of circulating lipoproteins are modulated by their rate of clearance, but the identity of the Lp(a) uptake receptor(s) has been controversial.

We performed a genome-scale CRISPR screen to functionally interrogate all potential Lp(a) uptake regulators in HuH7 cells. Screen validation was performed by single gene disruption and overexpression. Direct binding between purified lipoproteins and recombinant protein was tested using biolayer interferometry. An association between human genetic variants and circulating Lp(a) levels was analyzed in the UK Biobank cohort.

The top positive and negative regulators of Lp(a) uptake in our screen were LDLR and MYLIP, encoding the LDL receptor and its ubiquitin ligase IDOL, respectively. We also found a significant correlation for other genes with established roles in LDLR regulation. No other gene products, including those previously proposed as Lp(a) receptors, exhibited a significant effect on Lp(a) uptake in our screen. We validated the functional influence of LDLR expression on HuH7 Lp(a) uptake, confirmed in vitro binding between the LDLR extracellular domain and purified Lp(a), and detected an association between loss-of-function LDLR variants and increased circulating Lp(a) levels in the UK Biobank cohort.

Our findings support a central role for the LDL receptor in mediating Lp(a) uptake by hepatocytes.

Plasma 1H-NMR metabolomic measures have yielded significant insight into the pathophysiology of cardiometabolic disease, but their inter-related nature complicates causal inference and clinical interpretation. This study aimed to investigate the associations of unrelated 1H-NMR metabolomic profiles with coronary artery disease (CAD) and ischemic stroke (IS). Principal component (PC) analysis was performed on 168 1H-NMR metabolomic measures in 56,712 unrelated European participants from UK Biobank to retrieve uncorrelated PCs, which were used in Cox-proportional hazard models. For each outcome, two-sample Mendelian randomization analyses were then conducted based on three nonoverlapping databases, followed by a meta-analysis. The first six PCs collectively explaining 88% of the total variance were identified. For CAD, results from Cox and Mendelian randomization analyses were generally directionally consistent. The pooled odds ratios (95% CI) for CAD per one-SD increase in genetically influenced PC1 and PC3 (both characterized by distinct apolipoprotein B [ApoB]-associated lipoprotein profiles) were 1.04 (1.03, 1.05) and 0.94 (0.93, 0.96), respectively. Besides, the pooled odds ratio (95% CI) for CAD per one-SD increase in genetically influenced PC4, characterized by simultaneously decreased small HDL and increased large HDL, and independent of ApoB, was 1.05 (1.03, 1.07). For IS, increases of PC3 and PC5 (characterized by increased amino acids) were associated with a lower risk and a higher risk, respectively. This study confirms associations of ApoB-associated lipoprotein profiles with CAD and IS, and highlights the possible existence of an ApoB-independent lipoprotein profile, characterized by a distinctive HDL subparticle distribution, driving CAD.

Imaging-defined atherosclerosis represents an intermediate phenotype of atherosclerotic cardiovascular disease (ASCVD). Genome-wide association studies (GWAS) on directly measured coronary plaques using coronary computed tomography angiography (CCTA) are scarce. In the so far largest population-based cohort with CCTA data, we performed a GWAS on coronary plaque burden as determined by the segment involvement score (SIS) in 24,811 European individuals. We identified 20 significant independent genetic markers for SIS, three of which were found in loci not implicated in ASCVD before. Further GWAS on coronary artery calcification showed similar results to that of SIS, whereas a GWAS on ultrasound-assessed carotid plaques identified both shared and non-shared loci with SIS. In two-sample Mendelian randomization studies using SIS-associated markers in UK Biobank and CARDIoGRAMplusC4D, one extra coronary segment with atherosclerosis corresponded to 1.8-fold increased odds of myocardial infarction. This GWAS data can aid future studies of causal pathways in ASCVD.

The pathogenesis of hepatocellular carcinoma (HCC) involves a variety of environmental risk factors, some of which have yet to be fully clarified. Using the Mendelian randomization (MR) approach, this study comprehensively investigates the causal effect of genetically predicted modifiable risk factors on HCC.

Genetic variants related to the 50 risk factors that had been identified in previous research were derived from genome-wide association studies. Summary statistics for the discovery cohort and validation cohort of HCC were sourced from the FinnGen consortium and the UK Biobank, respectively. Bidirectional MR analysis and sensitivity analysis were performed to establish causative risk factors for HCC.

Through the inverse variance weighted method, the results of the discovery cohort indicated that waist circumference, nonalcoholic fatty liver disease (NAFLD), alanine aminotransferase (ALT) levels, and aspartate aminotransferase (AST) levels were significantly linked to HCC occurrence risk. Furthermore, body fat percentage, glycated hemoglobin (HbA1c), obesity class 1-3, waist-to-hip ratio, iron, ferritin, transferrin saturation, and urate had suggestive associations with HCC. The validation cohort further confirmed that NAFLD and ALT levels were strongly related to HCC. Reverse MR indicated that genetic susceptibility to HCC was connected to NAFLD and transferrin saturation. Sensitivity analyses showed that most of the findings were robust.

This MR study delivers evidence of the complex causal relationship between modifiable risk factors and HCC. These findings offer new insights into potential prevention and treatment strategies for HCC.

Polygenic Scores (PGSs) summarize an individual's genetic propensity for a given trait in a single value based on SNP effect sizes derived from Genome-Wide Association Study (GWAS) results. Methods have been developed that apply Bayesian approaches to improve the prediction accuracy of PGSs through optimization of estimated effect sizes. While these methods are generally well-calibrated for continuous traits (implying the predicted values are, on average, equal to the true trait values), they are not well-calibrated for binary disorder traits in ascertained samles. This is a problem because well-calibrated PGSs are needed to reliably compute the absolute disorder probability for an individual to facilitate future clinical implementation. Here, we introduce the Bayesian polygenic score Probability Conversion (BPC) approach, which computes an individual's predicted disorder probability using GWAS summary statistics, an existing Bayesian PGS method (e.g., PRScs, SBayesR), the individual's genotype data, and a prior disorder probability (which can be specified flexibly, based on e.g., literature, small reference samples, or prior elicitation). The BPC approach transforms the PGS to its underlying liability scale, computes the variances of the PGS in cases and controls, and applies Bayes' Theorem to compute the absolute disorder probability; it is practical in its application as it does not require a tuning sample with both genotype and phenotype data. We applied the BPC approach to extensive simulated data and empirical data of nine disorders. The BPC approach yielded well-calibrated results that were consistently better than the results of another recently published approach.

Coronary artery disease (CAD) is the leading cause of death around the world, with epidemiological sex and gender differences in prevalence, pathophysiology and outcomes. It has been hypothesized that sex steroids, like estrogen, may contribute to these sex differences. There is a relatively large genetic component to developing CAD, with heritability estimates ranging between 40%-60%. In the last two decades, genome-wide association studies (GWAS) have contributed substantially to advancing the understanding of genetic candidates contributing to CAD. The aim of this study was to determine if genes discovered in CAD GWASs are affected by estrogen via direct modulation or indirect down-stream targets.

A scoping review was conducted using MEDLINE and EMBASE for studies of atherosclerotic coronary artery disease and a genome-wide association study (GWAS) design. Analysis was limited to candidate genes with corresponding single nucleotide polymorphisms (SNPs) surpassing genome-wide significance and had been mapped to genes by study authors. The number of studies that conducted sex-stratified analyses with significant genes were quantified. A literature search of the final gene lists was done to examine any evidence suggesting estrogen may modulate the genes and/or gene products.

There were 60 eligible CAD GWASs meeting inclusion criteria for data extraction. Of these 60, only 36 had genome-wide significant SNPs reported, and only 3 of these had significant SNPs from sex-stratified analyses mapped to genes. From these 36 studies, a total of 61 genes were curated, of which 26 genes (43%) were found to have modulation by estrogen. All 26 were discovered in studies that adjusted for sex. 12/26 genes were also discovered in studies that conducted sex-stratified analyses. 12/26 genes were classified as having a role in lipid synthesis, metabolism and/or lipoprotein mechanisms, while 11/26 were classified as having a role in vascular integrity, and 3/26 were classified as having a role in thrombosis.

This study provides further evidence of the relationship between estrogen, genetic risk and the development of CAD. More sex-stratified research will need to be conducted to further characterize estrogen's relation to sex differences in the pathology and progression of CAD.

Although several preclinical and epidemiological studies have shown that blood lipids and lipid-lowering drugs can reduce the risk of breast cancer, this finding remains controversial. This study aimed to explore the causal relationship between dyslipidemia,lipid-lowering drugs, and breast cancer. We also aimed to evaluate the potential impact of lipid-lowering drug targets on breast cancer.

Data of 431 lipid- and lipid-related phenotypes were obtained from genome-wide association study (GWAS), and mendelian randomization (MR) analyses were performed using two independent breast cancer datasets as endpoints. Genetic variants associated with genes encoding lipid-lowering drug targets were extracted from the Global Lipid Genetics Consortium. Expression quantitative trait loci data in relevant tissues were used to further validate lipid-lowering drug targets that reached significance and combined with bioinformatics approaches for molecular expression and prognostic exploration. Further mediation analyses were performed to explore potential mediators.

In two independent datasets, phosphatidylcholine (18:1_0:0 levels) was associated with breast cancer risk (discovery: odds ratio (OR) = 1.255 [95% confidence interval (CI) 1.120-1.406]; p = 8.936 × 10-5, replication: OR = 1.016 [95% CI, 1.003-1.030]; p = 0.017), HMG- CoA reductase (HMGCR) inhibition was genetically modeled and associated with a reduced risk of breast cancer (discovery: OR = 0.833 [95% CI 0.752-0.923], p = 5.12 × 10-4; replication: OR = 0.975 [95% CI 0.960-0.990], p = 1.65 × 10-3). There was a significant MR correlation between HMGCR expression in whole blood and breast cancer (OR = 1.11 [95% 1.01-1.22] p = 0.04). Bioinformatics analysis revealed that HMGCR expression higher in breast cancer tissues than in normal tissues, along with poor overall survival and relapse-free survival, and was associated with multiple immune cell infiltration. Finally, the mediation analysis showed that HMGCR inhibitors affected breast cancer through different immune cell phenotypes and C-reactive protein levels.

In this study, we found for the first time that phosphatidylcholine (18:1_0:0) levels are associated with breast cancer risk. We found that HMGCR inhibitors are associated with a reduced risk of breast cancer, and part of their action may be through pathways other than lipid-lowering, including modulation of immune function and reduction of inflammation represented by C-reactive protein levels.

Dyslipidemia or hypercholesterolemia are among the main risk factors for cardiovascular diseases. Unraveling the molecular basis of lipid or cholesterol homeostasis would help to identify novel drug targets and develop effective therapeutics.

Here, we adopt a systematic approach to catalog the genes underlying lipid and cholesterol homeostasis by combinatorial use of high-throughput CRISPR screening, RNA sequencing, human genetic variant association analysis, and proteomic and metabolomic profiling. Such integrative multi-omics efforts identify gamma-glutamyltransferase GGT7 as an intriguing potential cholesterol and lipid regulator. As a SREBP2-dependent target, GGT7 positively regulates cellular cholesterol levels and affects the expression of several cholesterol metabolism genes. Furthermore, GGT7 interacts with actin-dependent motor protein MYH10 to control low-density lipoprotein cholesterol (LDL-C) uptake into the cells. Genetic ablation of Ggt7 in mice leads to reduced serum cholesterol levels, supporting an in vivo role of Ggt7 during cholesterol homeostasis.

Our study not only provides a repertoire of lipid or cholesterol regulatory genes from multiple angles but also reveals a causal link between a gamma-glutamyltransferase and cholesterol metabolism.

Observational studies have reported that sleep is associated with the risk of major depressive disorder (MDD) and cardiovascular diseases (CVDs). However, the causal relationships among various sleep traits remain contentious, and whether MDD mediates the impact of specific sleep traits on CVDs is unclear.

We performed two-sample Mendelian randomisation analyses to explore whether insomnia, sleep time, daytime napping, daytime sleepiness, chronotype, snoring or obstructive sleep apnoea were causally associated with the risk of five CVDs, including coronary artery disease (CAD), myocardial infarction (MI), heart failure (HF), atrial fibrillation and stroke. Mediation analyses were performed to assess the proportion mediated by MDD.

Genetically predicted insomnia, short sleep, daytime napping and daytime sleepiness increased the risk of CVDs, with the OR ranging from 1.24 (95% CI 1.06 to 1.45) for insomnia on stroke to 1.55 (95% CI 1.28 to 1.89) for insomnia on MI. In contrast to short sleep, genetically predicted sleep duration decreased the risk of CAD (OR 0.88 (95% CI 0.80 to 0.97)), MI (OR 0.89 (95% CI 0.80 to 0.99)) and HF (OR 0.90 (95% CI 0.83 to 0.98)). However, we found no significant associations of long sleep, chronotype, snoring and obstructive sleep apnoea with increased risk for any CVD subtype. Additionally, the effect of insomnia was partially mediated by MDD for the risk of CAD (proportion mediated: 8.81% (95% CI 1.20% to 16.43%)), MI (9.17% (95% CI 1.71% to 16.63%)) and HF (14.46% (95% CI 3.48% to 25.45%)). Similarly, the effect of short sleep was partially mediated by MDD for the risk of CAD (8.92% (95% CI 0.87% to 16.97%)), MI (11.43% (95% CI 0.28% to 22.57%)) and HF (12.65% (95% CI 1.35% to 23.96%)). MDD also partially mediated the causal effects of insomnia on stroke, sleep duration on CAD, MI and HF, daytime napping on HF and daytime sleepiness on CAD.

Our study provides evidence that genetically predicted insomnia, short sleep, frequent daytime napping and sleepiness are associated with a higher risk of certain CVD subtypes, partly mediated by MDD.