Comprehensive mendelian randomization reveals atrial fibrillation-breast cancer relationship and explores common druggable targets

BackgroundAtrial fibrillation (AF) and breast cancer pose significant risks to human health. The reasons behind the concurrent occurrence of AF and breast cancer remain unclear, leading to complex treatment approaches. Mendelian Randomization (MR) analyses aim to offer genetic evidence supporting the causation of AF and breast cancer and to investigate common druggable genes associated with both conditions.MethodsWe used two-samples of MR to sequentially explore the causal relationship between atrial fibrillation and breast cancer, and between atrial fibrillation and breast cancer therapeutic drugs, and verified the stability of the results through colocalization analysis. We utilized the Connectivity map database to infer the direction of drug effects on disease. Finally, we explored druggable genes that play a role in AF and breast cancer and performed a Phenome-wide MR analysis to analyze the potential side effects of drug targets.ResultsWe found 15 breast cancer therapeutic drugs that significantly support a causal association between AF and breast cancer through expression in blood and/or atrial appendage tissue. Among these, activation of ANXA5 by Docetaxel, inhibition of EIF5A by Fulvestrant, and inhibition of GNA12 by Tamoxifen increased the risk of AF, while inhibition of ANXA5 by Gemcitabine and Vinorebine and inhibition of PCGF6 by Paclitaxel reduced the risk of AF. Inhibition of MSH6 and SF3B1 by Cyclophosphamide, as well as inhibition of SMAD4 and PSMD2 and activation of ASAH1 and MLST8 by Doxorubicin can have bidirectional effects on AF occurrence. XBP1 can be used as a common druggable gene for AF and breast cancer, and there are no potential side effects of treatment against this target.ConclusionThis study did not find a direct disease causality between AF and breast cancer but identified 40 target genes for 15 breast cancer therapeutic drugs associated with AF, clarified the direction of action of 8 breast cancer therapeutic drugs on AF, and finally identified one common druggable target for AF and breast cancer

S1-S12 Tables are included in the file.

BackgroundNumerous observational studies have investigated on the correlation of whole, semi-skimmed, and skimmed milk with coronary artery disease (CAD) and myocardial infarction (MI) risk; However, no consensus has been reached and evidence on any causal links between these exposures and outcomes remains unclear. This study aimed to conduct univariate and multivariate Mendelian randomization (MR) analyses, using publicly released genome-wide association study summary statistics (GWAS) from the IEU GWAS database, to ascertain the causal association of milk with various fat content with CAD and MI risk.MethodsFor the exposure data, 29, 15, and 30 single-nucleotide polymorphisms for whole milk, semi-skimmed milk, and skimmed milk, respectively, obtained from 360,806 Europeans, were used as instrumental variables. CAD and MI comprised 141,217 and 395,795 samples, respectively. We used inverse variance weighted (IVW), weighted median, MR-Egger regression, and MR Pleiotropy Residual Sum and Outlier analyses to determine whether pleiotropy and heterogeneity could skew the MR results. Sensitivity tests were conducted to verify the robustness of the results.ResultsAfter adjusting for false discovery rates (FDR), we discovered proof that skimmed milk intake is a genetically predicted risk factor for CAD (odds ratio [OR] = 5.302; 95% confidence interval [CI] 2.261–12.432; P P P = 0.010; FDR-corrected P = 0.009). Most sensitivity assessments yielded valid results. Multivariable MR for CAD and MI produced results consistent with those obtained using the IVW method. There was no causal relationship between whole or semi-skimmed milk, and CAD or MI.ConclusionOur findings indicate that the consumption of skimmed milk may increase the risk of CAD and MI. This evidence may help inform dietary recommendations for preventing cardiovascular disease. Further studies are required to elucidate the underlying mechanisms.</div

S1-S18 Figs are included in the file.

BackgroundNumerous observational studies have investigated on the correlation of whole, semi-skimmed, and skimmed milk with coronary artery disease (CAD) and myocardial infarction (MI) risk; However, no consensus has been reached and evidence on any causal links between these exposures and outcomes remains unclear. This study aimed to conduct univariate and multivariate Mendelian randomization (MR) analyses, using publicly released genome-wide association study summary statistics (GWAS) from the IEU GWAS database, to ascertain the causal association of milk with various fat content with CAD and MI risk.MethodsFor the exposure data, 29, 15, and 30 single-nucleotide polymorphisms for whole milk, semi-skimmed milk, and skimmed milk, respectively, obtained from 360,806 Europeans, were used as instrumental variables. CAD and MI comprised 141,217 and 395,795 samples, respectively. We used inverse variance weighted (IVW), weighted median, MR-Egger regression, and MR Pleiotropy Residual Sum and Outlier analyses to determine whether pleiotropy and heterogeneity could skew the MR results. Sensitivity tests were conducted to verify the robustness of the results.ResultsAfter adjusting for false discovery rates (FDR), we discovered proof that skimmed milk intake is a genetically predicted risk factor for CAD (odds ratio [OR] = 5.302; 95% confidence interval [CI] 2.261–12.432; P P P = 0.010; FDR-corrected P = 0.009). Most sensitivity assessments yielded valid results. Multivariable MR for CAD and MI produced results consistent with those obtained using the IVW method. There was no causal relationship between whole or semi-skimmed milk, and CAD or MI.ConclusionOur findings indicate that the consumption of skimmed milk may increase the risk of CAD and MI. This evidence may help inform dietary recommendations for preventing cardiovascular disease. Further studies are required to elucidate the underlying mechanisms.</div

Associations of whole, semi-skimmed, and skimmed milk with coronary artery disease and myocardial infarction.

CI, confidence interval; OR, odds ratio; SNP, single-nucleotide polymorphism; P-adjusted, FDR-corrected P.</p

Study design of MR.

Three core assumptions were as follows: (1) Relevance assumption, the genetic variants must be associated with exposure (milk with different fat content); (2) Independence assumption, the genetic variants should not be associated with confounders; (3) Exclusion restriction, the genetic variants must influence outcome (coronary artery disease and myocardial infarction) only via exposure.</p

Preferred spin excitations in the bilayer iron-based superconductor CaK ( Fe0.96_{0.96}Ni0.04_{0.04})4_4As4_4 with spin-vortex crystal order

International audienceSpin-orbit coupling (SOC) is a key to understand the magnetically driven superconductivity in iron-based superconductors, where both local and itinerant electrons are present and the orbital angular momentum is not completely quenched. Here, we report a neutron scattering study on the bilayer compound CaK Fe$_{0.96}$Ni$_{0.04}$$_4$As$_4$ with superconductivity coexisting with a noncollinear spin-vortex crystal magnetic order that preserves the tetragonal symmetry of the Fe-Fe plane. In the superconducting state, two spin resonance modes with odd and even L symmetries due to the bilayer coupling are found similar to the undoped compound CaKFe$_4$As$_4$ but at lower energies. Polarization analysis reveals that the odd mode is c-axis polarized, and the low-energy spin anisotropy can persist to the paramagnetic phase at high temperature, which closely resembles other systems with in-plane collinear and c-axis biaxial magnetic orders. These results provide the missing piece of the puzzle on the SOC effect in iron-pnictide superconductors, and also establish a common picture of c-axis preferred magnetic excitations below Tc regardless of the details of magnetic pattern or lattice symmetry

Lower rate of mpox vaccination hesitancy and medical consultation among Chinese men who have sex with men living with HIV in comparison with those living without HIV: A national observational study

ABSTRACTThis anonymous cross-sectional study aimed to investigate the relationships between HIV infection and mpox-related focus issues among Chinese men who have sex with men (MSM). This study involved in 27 MSM social organizations and was conducted from July 31 to August 4, 2023. Mpox vaccination hesitancy was defined as the proportion of participants who expressed unwillingness to receive self-funded and free vaccines. Logistic regression models were employed to estimate odds ratios (OR) and 95% confidence interval (95%CI). Of 7196 MSMs, the prevalence of mpox differed between people living with HIV (PLWH) (1.04%, 20/1920) and people living without HIV (PLWoH) (0.55%, 29/5276) (P = .037). However, after adjusting for all covariates, there was no significant association between HIV status and mpox (aOR = 1.17; 95%CI = 0.58, 2.39; P = .658). Furthermore, the crude rates of vaccination hesitation (PLWoH: 5.91%, PLWH: 4.11%; P = .004) and consultation hesitation (PLWoH: 16.22%, PLWH: 10.78%; P < .001) were both lower in the PLWH. Compared with PLWoH, PLWH had lower odds ratios of vaccination hesitation (aOR = 0.70; 95%CI = 0.53, 0.92; P = .011) and consultation hesitation (aOR = 0.74; 95%CI = 0.60, 0.90; P = .003) among MSM. The estimate of association between HIV status and consultation hesitation was even smaller among MSM who reported hepatitis C infection or uncertainty (aOR = 0.30; 95%CI = 0.15, 0.56), compared with those without hepatitis C (aOR = 0.73; 95%CI = 0.60, 0.89) (P for interaction = .037). MSM living with HIV in China demonstrated a greater willingness to accept mpox vaccination and medical consultation. In the future, it is recommended that medical institutions establish good medical environment to control the mpox epidemic, especially for PLWH

Mpox Vaccination Hesitancy and Its Associated Factors among Men Who Have Sex with Men in China: A National Observational Study

More than 400 confirmed mpox cases have been reported in China. The mpox vaccination is crucial to mitigate mpox transmission, especially for at-risk populations. This study aimed to determine mpox vaccination hesitancy and its associated factors in Chinese men who have sex with men (MSM). This nationwide cross-sectional study was conducted among 7538 Chinese MSM in 27 MSM social organizations from 21 provinces, municipalities, and autonomous regions of China from 31 July to 4 August 2023. Of them, the rate of mpox vaccination hesitancy was 5.59% (421/7538). The most common reason for mpox vaccination hesitation was concerns of safety and side effects (62.71%, 264/421), followed by concerns of privacy (38.24%, 161/421), thoughts of impossible infection (37.53%, 158/421), no effectiveness in preventing reinfection (30.88%, 130/421), and no worry about infection (12.35%, 52/421). Regarding the concerning characteristics of the vaccines, concerns of vaccine safety ranked first (71.74%, 5408/7538), followed by vaccine effectiveness (14.05%, 1059/7538), vaccine costs (7.35%, 554/7538), and the continuity of vaccine effectiveness (3.91%, 295/7538). The highest odds ratio of mpox vaccination hesitation was seen in MSM who were infected with mpox virus (aOR = 2.38; 95%CI = 1.08, 5.23), followed by those aged ≥60 years (aOR = 2.25; 95%CI = 1.31, 3.88), those who were unemployed (aOR = 1.66; 95%CI = 1.25, 2.19), and those who had an education level of postgraduate and above (aOR = 1.55; 95%CI = 1.01, 2.37). However, MSM who had a higher level of mpox-related knowledge (moderate: aOR = 0.53; 95%CI = 0.36, 0.77; high: aOR = 0.30; 95%CI = 0.23, 0.40) had a lower odds ratio of mpox vaccination hesitation. MSM in China had low hesitancy toward mpox vaccination. The safety and effectiveness of the vaccine and privacy were important aspects of hesitancy. Health education on mpox-related knowledge should be encouraged to promote future vaccination plans