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Two researchers independently assessed studies published up to February 5, 2023, across PubMed, Web of Science, Embase, and Cochrane Library, to investigate the associations of sleep traits with cardiometabolic risk factors, as well as with cardiovascular diseases. Fourteen systematic reviews consisting of 23 meta-analyses, and 11 Mendelian randomization (MR) studies were included in this study. Short sleep duration was associated with a higher risk of obesity, type 2 diabetes (T2D), hypertension, stroke, and coronary heart disease (CHD) in observational studies, while a causal role was only demonstrated in obesity, hypertension, and CHD by MR. Similarly, long sleep duration showed connections with a higher risk of obesity, T2D, hypertension, stroke, and CHD in observational studies, none was supported by MR analysis. Both observational and MR studies indicated heightened risks of hypertension, stroke, and CHD in relation to insomnia. Napping was linked to elevated risks of T2D and CHD in observational studies, with MR analysis confirming a causal role in T2D. Additionally, snoring was correlated with increased risks of stroke and CHD in both observational and MR studies. This work consolidates existing evidence on a causal relationship between sleep characteristics and cardiometabolic risk factors, as well as cardiovascular diseases.
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BACKGROUND: Several studies reported that exposure to higher levels of fine particulate matter (PM2.5) was associated with deteriorated lipid profiles in children and adolescents. However, whether a sodium-rich diet could modify the associations remains unknown. We aimed to examine the associations of long-term exposure to PM2.5 with blood lipids in children and adolescents, and further examine the effect modification by dietary and urinary sodium levels based on a multi-community population in China. METHODS: The 3711 study participants were from a cross-sectional study, which interviewed children and adolescents aged 6 to 17 years across Sichuan Province, China between 2015 and 2017. Blood lipid outcomes including blood total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were assessed. Information on daily dietary sodium consumption was estimated with a semi-quantitative food frequency questionnaire (FFQ), and urinary sodium was used as an internal exposure biomarker. A linear regression model was applied to estimate the associations of prior 2-years' average exposure to ambient PM2.5 with blood lipids. The effect modification by dietary and urinary sodium was examined by stratified analyses. RESULTS: The participants from rural areas had higher levels of daily sodium consumptions. The results of multivariable regression analysis indicated that per 10 µg/m3 incremental change in PM2.5 was associated with a 1.56% (95% confidence interval 0.90%-2.23%) and a 2.26% (1.15%-3.38%) higher blood TC and LDL-C levels, respectively. Among the study participants with higher levels of dietary sodium or urinary sodium, exposure to higher levels of PM2.5 was significantly associated with deteriorated lipid profiles. For example, each 10 µg/m3 incremental change in exposure to PM2.5 was correlated with a 2.83 (-4.65 to -0.97) lower percentage decrease in blood HDL-C levels among the participants who were from the highest quartile of urinary sodium levels. While, these associations changed to be nonsignificant in the participants who were from the lowest quartile of dietary sodium levels. CONCLUSION: Exposure to higher levels of PM2.5 was associated with deteriorated blood lipid levels in children and adolescents. It is noteworthy that these associations might be ameliorated through the adoption of a low-sodium dietary regimen.
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Exposición a Riesgos Ambientales , Lípidos , Material Particulado , Sodio en la Dieta , Humanos , Adolescente , Material Particulado/efectos adversos , Material Particulado/análisis , Niño , Masculino , Femenino , Estudios Transversales , China , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Lípidos/sangre , Sodio/sangre , Sodio/orina , DietaRESUMEN
While carotid intima-media thickness (cIMT) as a noninvasive surrogate measure of atherosclerosis is widely considered a risk factor for stroke, the intrinsic link underlying cIMT and stroke has not been fully understood. We aimed to evaluate the clinical value of cIMT in stroke through the investigation of phenotypic and genetic relationships between cIMT and stroke. We evaluated phenotypic associations using observational data from UK Biobank (N = 21,526). We then investigated genetic relationships leveraging genomic data conducted in predominantly European ancestry for cIMT (N = 45,185) and any stroke (AS, Ncase/Ncontrol=40,585/406,111). Observational analyses suggested an increased hazard of stroke per one standard deviation increase in cIMT (cIMTmax-AS: hazard ratio (HR) = 1.39, 95%CI = 1.09-1.79; cIMTmean-AS: HR = 1.39, 95%CI = 1.09-1.78; cIMTmin-AS: HR = 1.32, 95%CI = 1.04-1.68). A positive global genetic correlation was observed (cIMTmax-AS: [Formula: see text]=0.23, P=9.44 × 10-5; cIMTmean-AS: [Formula: see text]=0.21, P=3.00 × 10-4; cIMTmin-AS: [Formula: see text]=0.16, P=6.30 × 10-3). This was further substantiated by five shared independent loci and 15 shared expression-trait associations. Mendelian randomization analyses suggested no causal effect of cIMT on stroke (cIMTmax-AS: odds ratio (OR)=1.12, 95%CI=0.97-1.28; cIMTmean-AS: OR=1.09, 95%CI=0.93-1.26; cIMTmin-AS: OR=1.03, 95%CI = 0.90-1.17). A putative association was observed for genetically predicted stroke on cIMT (AS-cIMTmax: beta=0.07, 95%CI = 0.01-0.13; AS-cIMTmean: beta=0.08, 95%CI = 0.01-0.15; AS-cIMTmin: beta = 0.08, 95%CI = 0.01-0.16) in the reverse direction MR, which attenuated to non-significant in sensitivity analysis. Our work does not find evidence supporting causal associations between cIMT and stroke. The pronounced cIMT-stroke association is intrinsic, and mostly attributed to shared genetic components. The clinical value of cIMT as a surrogate marker for stroke risk in the general population is likely limited.
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BACKGROUND: The incidence of prostate cancer is increasing in older males globally. Age, ethnicity, and family history are identified as the well-known risk factors for prostate cancer, but few modifiable factors have been firmly established. The objective of this study was to identify and evaluate various factors modifying the risk of prostate cancer reported in meta-analyses of prospective observational studies and mendelian randomization (MR) analyses. METHODS AND FINDINGS: We searched PubMed, Embase, and Web of Science from the inception to January 10, 2022, updated on September 9, 2023, to identify meta-analyses and MR studies on prostate cancer. Eligibility criteria for meta-analyses were (1) meta-analyses including prospective observational studies or studies that declared outcome-free at baseline; (2) evaluating the factors of any category associated with prostate cancer incidence; and (3) providing effect estimates for further data synthesis. Similar criteria were applied to MR studies. Meta-analysis was repeated using the random-effects inverse-variance model with DerSimonian-Laird method. Quality assessment was then conducted for included meta-analyses using AMSTAR-2 tool and for MR studies using STROBE-MR and assumption evaluation. Subsequent evidence grading criteria for significant associations in meta-analyses contained sample size, P values and 95% confidence intervals, 95% prediction intervals, heterogeneity, and publication bias, assigning 4 evidence grades (convincing, highly suggestive, suggestive, or weak). Significant associations in MR studies were graded as robust, probable, suggestive, or insufficient considering P values and concordance of effect directions. Finally, 92 selected from 411 meta-analyses and 64 selected from 118 MR studies were included after excluding the overlapping and outdated studies which were published earlier and contained fewer participants or fewer instrument variables for the same exposure. In total, 123 observational associations (45 significant and 78 null) and 145 causal associations (55 significant and 90 null) were categorized into lifestyle; diet and nutrition; anthropometric indices; biomarkers; clinical variables, diseases, and treatments; and environmental factors. Concerning evidence grading on significant associations, there were 5 highly suggestive, 36 suggestive, and 4 weak associations in meta-analyses, and 10 robust, 24 probable, 4 suggestive, and 17 insufficient causal associations in MR studies. Twenty-six overlapping factors between meta-analyses and MR studies were identified, with consistent significant effects found for physical activity (PA) (occupational PA in meta: OR = 0.87, 95% CI: 0.80, 0.94; accelerator-measured PA in MR: OR = 0.49, 95% CI: 0.33, 0.72), height (meta: OR = 1.09, 95% CI: 1.06, 1.12; MR: OR = 1.07, 95% CI: 1.01, 1.15, for aggressive prostate cancer), and smoking (current smoking in meta: OR = 0.74, 95% CI: 0.68, 0.80; smoking initiation in MR: OR = 0.91, 95% CI: 0.86, 0.97). Methodological limitation is that the evidence grading criteria could be expanded by considering more indices. CONCLUSIONS: In this large-scale study, we summarized the associations of various factors with prostate cancer risk and provided comparisons between observational associations by meta-analysis and genetically estimated causality by MR analyses. In the absence of convincing overlapping evidence based on the existing literature, no robust associations were identified, but some effects were observed for height, physical activity, and smoking.
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Análisis de la Aleatorización Mendeliana , Neoplasias de la Próstata , Masculino , Humanos , Anciano , Factores de Riesgo , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/genética , Fumar/efectos adversos , Fumar Tabaco , Estudios Observacionales como AsuntoAsunto(s)
Tamizaje Masivo , Humanos , Tamizaje Masivo/métodos , Femenino , Masculino , Análisis por ConglomeradosRESUMEN
BACKGROUND: Emerging evidence suggests that exposure to outdoor artificial light at night (ALAN) may be associated with diabetes. However, limited research explores the relationship between outdoor ALAN and gestational diabetes mellitus (GDM). METHODS: We utilized data from a multilevel infant and early life cohort study conducted in Sichuan Province, China, between February 2018 and April 2021. A total of 9,120 participants were included in the final analysis. Outdoor ALAN exposure at participants' residential locations was estimated using time-varying satellite data, focusing on persistent night-time illumination at a scale of approximately 500x500m. The information about GDM was obtained from medical records. After adjusting for potential confounders, multivariable logistic regression models and restricted cubic splines were employed to estimate the association between ALAN exposure during pregnancy and GDM. RESULTS: Among the total recruitments, 1,484 (16.27%) women were diagnosed with GDM. Compared to women without GDM, those with GDM had a significantly higher mean outdoor ALAN exposure during pregnancy (18.98 nW/cm2/sr1 vs 24.28 nW/cm2/sr1, P < 0.001). Results from multivariable logistic models showed that higher outdoor ALAN exposure during pregnancy could increase the risk of GDM (OR (95% CI) 1st+2nd trimesters ALAN = 1.253 (1.157-1.356)). Meanwhile, results from the restricted cubic spline further indicated a non-linear association between outdoor ALAN exposure during pregnancy and GDM. Generally, with the radiance of the first two trimesters of ALAN increasing to about 17.9 nW/cm2/sr1, outdoor ALAN exposure became a risk factor for GDM. However, when the radiance of ALAN reached about 40.7 nW/cm2/sr1, the continued increasing OR estimation (OR (95% CI) = 1.489 (1.223-1.814)) of outdoor ALAN changed to steady. CONCLUSION: Our findings suggested that high levels of outdoor ALAN exposure during pregnancy can be associated with an increased risk of GDM, and a non-linear relationship pattern might exist. These findings substantially augment existing evidence, positing outdoor ALAN as an emergent, modifiable risk factor for GDM.
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Diabetes Gestacional , Embarazo , Humanos , Femenino , Masculino , Diabetes Gestacional/epidemiología , Estudios de Cohortes , Estudios Prospectivos , Contaminación Lumínica , China/epidemiologíaRESUMEN
BACKGROUND AND HYPOTHESIS: While the phenotypic association between schizophrenia and breast cancer has been observed, the underlying intrinsic link is not adequately understood. We aim to conduct a comprehensive interrogation on both phenotypic and genetic relationships between schizophrenia and breast cancer. STUDY DESIGN: We first used data from UK Biobank to evaluate a phenotypic association and performed an updated meta-analysis incorporating existing cohort studies. We then leveraged genomic data to explore the shared genetic architecture through a genome-wide cross-trait design. STUDY RESULTS: Incorporating results of our observational analysis, meta-analysis of cohort studies suggested a significantly increased incidence of breast cancer among women with schizophrenia (RR = 1.30, 95% CIs = 1.14-1.48). A positive genomic correlation between schizophrenia and overall breast cancer was observed (rg = 0.12, P = 1.80 × 10-10), consistent across ER+ (rg = 0.10, P = 5.74 × 10-7) and ER- subtypes (rg = 0.09, P = .003). This was further corroborated by four local signals. Cross-trait meta-analysis identified 23 pleiotropic loci between schizophrenia and breast cancer, including five novel loci. Gene-based analysis revealed 27 shared genes. Mendelian randomization demonstrated a significantly increased risk of overall breast cancer (OR = 1.07, P = 4.81 × 10-10) for genetically predisposed schizophrenia, which remained robust in subgroup analysis (ER+: OR = 1.10, P = 7.26 × 10-12; ER-: OR = 1.08, P = 3.50 × 10-6). No mediation effect and reverse causality was found. CONCLUSIONS: Our study demonstrates an intrinsic link underlying schizophrenia and breast cancer, which may inform tailored screening and management of breast cancer in schizophrenia.
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Neoplasias de la Mama , Esquizofrenia , Humanos , Femenino , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Esquizofrenia/epidemiología , Esquizofrenia/genética , Esquizofrenia/diagnóstico , Predisposición Genética a la Enfermedad , Incidencia , Polimorfismo de Nucleótido Simple , Análisis de la Aleatorización Mendeliana , Estudio de Asociación del Genoma Completo , Estudios Observacionales como AsuntoRESUMEN
Due to the worldwide increased rate of infertility among reproductive-age couples, there is a growing interest in the relationship between environmental stimuli and human sperm quality. While animal studies have demonstrated the detrimental effects of outdoor artificial light at night (ALAN) on sperm quality, investigations based on human data are lacking. Therefore, we conducted a retrospective cohort study involving 1991 sperm donor candidates and employed multivariate linear regression and restricted cubic spline models to quantify the association between outdoor ALAN and sperm quality. The aim was to determine whether there exists an association between exposure to outdoor ALAN and sperm quality. The study included 1991 sperm donor candidates with the following characteristics: mean [SD] age, 24.98 [4.78] years; mean [SD] BMI, 22.13 [2.60] kg/m2; mean [SD] sleep duration, 7.66 [1.07] hours/day. Outdoor ALAN exposure of study participants ranged from 0 to 100 nW/cm2/sr. Multiple regression analysis on chronic exposure (0-90 days before sperm donation) and human sperm quality revealed the following associations: for CASA primary motion parameters, every 100-unit (nW/cm2/sr) increase in chronic outdoor ALAN was associated with a change of -0.043 [95%CI: 0.073, -0.014] in Linearity (LIN), and -5.523 [95%CI: 9.100, -1.946] in Curvilinear velocity (VCL). For CASA secondary motion parameters, every 100-unit (nW/cm2/sr) increase in chronic outdoor ALAN was associated with a change of -3.873 [95%CI: 4.926, -2.748] in non-progressive motility rate (NP). Furthermore, the primary sperm quality parameter exhibited a decline of -4.740 [95%CI: 8.853, -0.628] in sperm motility rate per 100-unit (nW/cm2/sr) increase in chronic outdoor ALAN. Similar associations were also observed for acute exposure (0-9 days before sperm donation). This retrospective study suggests that poorer sperm quality is more prevalent among adult males residing in areas with higher levels of outdoor ALAN, with a particularly pronounced impact observed in males below the age of 25 years.
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Contaminación Lumínica , Semen , Adulto , Animales , Humanos , Masculino , Adulto Joven , Estudios Retrospectivos , Motilidad Espermática , Espermatozoides , LuzRESUMEN
BACKGROUND: While type 2 diabetes mellitus (T2DM) is considered a putative causal risk factor for coronary artery disease (CAD), the intrinsic link underlying T2DM and CAD is not fully understood. We aimed to highlight the importance of integrated care targeting both diseases by investigating the phenotypic and genetic relationships between T2DM and CAD. METHODS: We evaluated phenotypic associations using data from the United Kingdom Biobank ( N = 472,050). We investigated genetic relationships by leveraging genomic data conducted in European ancestry for T2DM, with and without adjustment for body mass index (BMI) (T2DM: Ncase / Ncontrol = 74,124/824,006; T2DM adjusted for BMI [T2DM adj BMI]: Ncase / Ncontrol = 50,409/523,897) and for CAD ( Ncase / Ncontrol = 181,522/984,168). We performed additional analyses using genomic data conducted in multiancestry individuals for T2DM ( Ncase / Ncontrol = 180,834/1,159,055). RESULTS: Observational analysis suggested a bidirectional relationship between T2DM and CAD (T2DMâCAD: hazard ratio [HR] = 2.12, 95% confidence interval [CI]: 2.01-2.24; CADâT2DM: HR = 1.72, 95% CI: 1.63-1.81). A positive overall genetic correlation between T2DM and CAD was observed ( rg = 0.39, P = 1.43 × 10 -75 ), which was largely independent of BMI (T2DM adj BMI-CAD: rg = 0.31, P = 1.20 × 10 -36 ). This was corroborated by six local signals, among which 9p21.3 showed the strongest genetic correlation. Cross-trait meta-analysis replicated 101 previously reported loci and discovered six novel pleiotropic loci. Mendelian randomization analysis supported a bidirectional causal relationship (T2DMâCAD: odds ratio [OR] = 1.13, 95% CI: 1.11-1.16; CADâT2DM: OR = 1.12, 95% CI: 1.07-1.18), which was confirmed in multiancestry individuals (T2DMâCAD: OR = 1.13, 95% CI: 1.10-1.16; CADâT2DM: OR = 1.08, 95% CI: 1.04-1.13). This bidirectional relationship was significantly mediated by systolic blood pressure and intake of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, with mediation proportions of 54.1% (95% CI: 24.9-83.4%) and 90.4% (95% CI: 29.3-151.5%), respectively. CONCLUSION: Our observational and genetic analyses demonstrated an intrinsic bidirectional relationship between T2DM and CAD and clarified the biological mechanisms underlying this relationship.
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Enfermedad de la Arteria Coronaria , Diabetes Mellitus Tipo 2 , Humanos , Enfermedad de la Arteria Coronaria/genética , Diabetes Mellitus Tipo 2/genética , Estudios Prospectivos , Factores de Riesgo , Fenotipo , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND: While the association between depression and hypertension has been extensively investigated, the pattern and nature of such association remain inconclusive. We sought to investigate the bidirectional relationship between depression and hypertension and its causal. METHODS: We first performed observational analyses using longitudinal data from the UK Biobank. We then performed genetic analyses leveraging summary statistics from large-scale genome-wide association studies (GWASs) conducted in European ancestry for depression and hypertension. RESULTS: Observational analysis suggested a significant bidirectional phenotypic association between depression and hypertension (Depression â Hypertension: HR = 1.27, 95 % CI: 1.19, 1.36; Hypertension â Depression: HR = 1.65, 95 % CI: 1.58, 1.72). Linkage disequilibrium score regression demonstrated a positive genetic correlation between the two conditions (rg=0.15, P = 5.75 × 10-10). Bidirectional two-sample Mendelian randomization (MR) suggested that genetic liability to depression was significantly associated with an increased risk of hypertension (OR = 1.27, 95 % CI: 1.12, 1.43), while the genetic liability to hypertension was not associated with the risk of depression (OR = 1.01, 95 % CI: 0.99, 1.03). Multivariate MR, after adjusting for smoking, drinking, and body mass index, further supported an independent causal effect of genetic liability to depression on hypertension risk (OR = 1.10, 95 % CI: 1.02, 1.18). LIMITATIONS: (1) interference of confounders, (2) absence of adequate statistical power, and (3) limitation to European populations. CONCLUSION: Our study indicates depression is a causal risk factor for hypertension, whereas the reverse maybe not. Findings support that prevention of depression might help in decreasing hypertension incidence.
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Depresión , Hipertensión , Humanos , Depresión/epidemiología , Depresión/genética , Estudio de Asociación del Genoma Completo , Índice de Masa Corporal , Hipertensión/epidemiología , Hipertensión/genética , Desequilibrio de Ligamiento , Análisis de la Aleatorización MendelianaRESUMEN
Importance: Fetal growth in the critical rapid growth stage (CRGS) before delivery, approximately between 30 to 37 gestational weeks, carries significant implications for subsequent overweight, obesity, and arterial health. Previous evidence has demonstrated the association between maternal depressive symptoms and fetal growth trajectories from early to late pregnancy, but there remains limited understanding of the association of these symptoms with the longitudinal fetal growth change within the CRGS. Objective: To investigate the association between maternal depressive symptoms and fetal growth during the CRGS before delivery. Design, Setting, and Participants: This prospective birth cohort study was conducted from January 2018 to December 2020. Volunteer pregnant women were enrolled in their first trimester of prenatal visits. Women with severe disease before pregnancy and multiple births, fetuses with congenital anomalies, and preterm or postterm births were excluded. This multicenter study was based in 13 hospitals covering 81 counties across 12 cities in Sichuan Province, China. Follow-up visits were performed at the second trimester, the third trimester, and 24 hours after delivery. The analysis was conducted from January to May 2023. Exposures: Maternal depressive symptoms, as a continuous variable, measured by the Edinburgh Postpartum Depression Scale (EPDS) at a median gestational week of 24 (range, 14 to 27) weeks of gestation. A higher score on the EPDS indicates worse depressive symptoms. Main Outcomes and Measures: The main outcomes included ultrasonography-measured biparietal diameter (BPD), femur length (FL), and abdominal circumference (AC), along with calculated estimated fetal weight (EFW). These parameters were evaluated longitudinally at a median gestational week of 30 (range, 28 to 32) and 37 (range, 35 to 39) weeks. Linear mixed models were used to estimate the associations between maternal depressive symptoms and fetal growth parameters. Results: A total of 2676 mother-offspring dyads were included, in which the mean (SD) age of mothers was 28.0 (4.4) years, and 1294 (48.4%) of the offspring were female. The median (IQR) maternal EPDS score was 5.0 (4.0 to 9.0). After adjustment for confounders, a significant correlation was found between a higher score of depressive symptoms in mothers and a slower rate of fetal growth across FL (ß = -0.40; 95% CI, -0.58 to -0.22), AC (ß = -1.97; 95% CI, -2.90 to -1.03), and EFW (ß = -50.11; 95% CI, -68.46 to -31.75). These associations were stronger in female fetuses or those with better family socioeconomic conditions. Conclusions and Relevance: In this prospective cohort study, maternal depressive symptoms were associated with slower fetal growth rate in the CRGS before delivery. Early screening for depressive disorders in pregnant women appears to be essential for fetal growth and later health.
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Depresión , Desarrollo Fetal , Recién Nacido , Embarazo , Femenino , Humanos , Adulto , Masculino , Estudios Prospectivos , Estudios de Cohortes , Depresión/epidemiología , Peso Fetal , MadresRESUMEN
BACKGROUND: This study aims to comprehensively investigate the phenotypic and genetic relationships between four common lipids (high-density lipoprotein cholesterol, HDL-C; low-density lipoprotein cholesterol, LDL-C; total cholesterol, TC; and triglycerides, TG), chronic kidney disease (CKD), and estimated glomerular filtration rate (eGFR). METHODS: We first investigated the observational association of lipids (exposures) with CKD (primary outcome) and eGFR (secondary outcome) using data from UK Biobank. We then explored the genetic relationship using summary statistics from the largest genome-wide association study of four lipids (N = 1,320,016), CKD (Ncase = 41,395, Ncontrol = 439,303), and eGFR(N = 567,460). RESULTS: There were significant phenotypic associations (HDL-C: hazard ratio (HR) = 0.76, 95%CI = 0.60-0.95; TG: HR = 1.08, 95%CI = 1.02-1.13) and global genetic correlations (HDL-C: [Formula: see text] = - 0.132, P = 1.00 × 10-4; TG: [Formula: see text] = 0.176; P = 2.66 × 10-5) between HDL-C, TG, and CKD risk. Partitioning the whole genome into 2353 LD-independent regions, twelve significant regions were observed for four lipids and CKD. The shared genetic basis was largely explained by 29 pleiotropic loci and 36 shared gene-tissue pairs. Mendelian randomization revealed an independent causal relationship of genetically predicted HDL-C (odds ratio = 0.91, 95%CI = 0.85-0.98), but not for LDL-C, TC, or TG, with the risk of CKD. Regarding eGFR, a similar pattern of correlation and pleiotropy was observed. CONCLUSIONS: Our work demonstrates a putative causal role of HDL-C in CKD and a significant biological pleiotropy underlying lipids and CKD in populations of European ancestry. Management of low HDL-C levels could potentially benefit in reducing the long-term risk of CKD.
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Estudio de Asociación del Genoma Completo , Insuficiencia Renal Crónica , Humanos , Estudios Prospectivos , HDL-Colesterol , LDL-Colesterol , Insuficiencia Renal Crónica/genéticaRESUMEN
BACKGROUND: Despite epidemiological evidence associating gallstone disease (GSD) with cardiovascular disease (CVD), a dilemma remains on the role of cholecystectomy in modifying the risk of CVD. We aimed to characterize the phenotypic and genetic relationships between GSD and two CVD events - stroke and coronary artery disease (CAD). METHODS: We first performed a meta-analysis of cohort studies to quantify an overall phenotypic association between GSD and CVD. We then investigated the genetic relationship leveraging the largest genome-wide genetic summary statistics. We finally examined the phenotypic association using the comprehensive data from UK Biobank (UKB). RESULTS: An overall significant effect of GSD on CVD was found in meta-analysis (relative risk [RR] = 1.26, 95% confidence interval [CI] = 1.19-1.34). Genetically, a positive shared genetic basis was observed for GSD with stroke ([Formula: see text]=0.16, P = 6.00 × 10-4) and CAD ([Formula: see text]=0.27, P = 2.27 × 10-15), corroborated by local signals. The shared genetic architecture was largely explained by the multiple pleiotropic loci identified in cross-phenotype association study and the shared gene-tissue pairs detected by transcriptome-wide association study, but not a causal relationship (GSD to CVD) examined through Mendelian randomization (MR) (GSD-stroke: odds ratio [OR] = 1.00, 95%CI = 0.97-1.03; GSD-CAD: OR = 1.01, 95%CI = 0.98-1.04). After a careful adjustment of confounders or considering lag time using UKB data, no significant phenotypic effect of GSD on CVD was detected (GSD-stroke: hazard ratio [HR] = 0.95, 95%CI = 0.83-1.09; GSD-CAD: HR = 0.98, 95%CI = 0.91-1.06), further supporting MR findings. CONCLUSIONS: Our work demonstrates a phenotypic and genetic relationship between GSD and CVD, highlighting a shared biological mechanism rather than a direct causal effect. These findings may provide insight into clinical and public health applications.
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Enfermedad de la Arteria Coronaria , Infarto del Miocardio , Accidente Cerebrovascular , Humanos , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/genética , Estudios Prospectivos , Oportunidad Relativa , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/genética , Estudios Observacionales como AsuntoRESUMEN
Although the impact of sex hormones on bone metabolism is well-documented, effect of their primary modulator, sex hormone-binding globulin (SHBG), remains inconclusive. This study aims to elucidate the genetic overlap between SHBG and heel estimated bone mineral density (eBMD), a widely-accepted tool for osteoporosis management and fracture risk assessment. Using summary statistics from large-scale genomewide association studies conducted for SHBG (N = 370,125), SHBG adjusted for body mass index (SHBGa, N = 368,929), and eBMD (N = 426,824), a comprehensive genomewide cross-trait approach was performed to quantify global and local genetic correlations, identify pleiotropic loci, and infer causal associations. A significant overall inverse genetic correlation was found for SHBG and eBMD (rg = -0.11, p = 3.34 × 10-10 ), which was further supported by the significant local genetic correlations observed in 11 genomic regions. Cross-trait meta-analysis revealed 219 shared loci, of which seven were novel. Notably, four novel loci (rs6542680, rs8178616, rs147110934, and rs815625) were further demonstrated to colocalize. Mendelian randomization identified a robust causal effect of SHBG on eBMD (beta = -0.22, p = 3.04 × 10-13 ), with comparable effect sizes observed in both men (beta = -0.16, p = 1.99 × 10-6 ) and women (beta = -0.19, p = 2.73 × 10-9 ). Replacing SHBG with SHBGa, the observed genetic correlations, pleiotropic loci and causal associations did not change substantially. Our work reveals a shared genetic basis between SHBG and eBMD, substantiated by multiple pleiotropic loci and a robust causal relationship. Although SHBG has been implicated in preventing and screening aging-related diseases, our findings support its etiological role in osteoporosis. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Densidad Ósea , Osteoporosis , Femenino , Humanos , Masculino , Densidad Ósea/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Minerales/metabolismo , Osteoporosis/genética , Osteoporosis/metabolismo , Fenotipo , Globulina de Unión a Hormona Sexual/genética , Globulina de Unión a Hormona Sexual/metabolismoRESUMEN
Biological membranes often play important functional roles in biomimetic drug delivery systems. We discover that the circulation time and targeting capability of biological membrane coated nanovehicles can be significantly improved by reducing cholesterol level in the coating membrane. A proof-of-concept system using cholesterol-reduced and PD-1-overexpressed T cell membrane to deliver a photothermal agent and a STING agonist is thus fabricated. Comparing with normal membrane, this engineered membrane increases tumor accumulation by ~2-fold. In a melanoma model in male mice, tumors are eliminated with no recurrence in >80% mice after intravenous injection and laser irradiation; while in a colon cancer model in male mice, ~40% mice are cured without laser irradiation. Data suggest that the engineered membranes escape immune surveillance to avoid blood clearance while keeping functional surface molecules exposed. In summary, we develop a simple, effective, safe and widely-applicable biological membrane modification strategy. This "subtractive" strategy displays some advantages and is worth further development.
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Biomimética , Neoplasias , Masculino , Animales , Ratones , Inmunoterapia , Membrana Celular , Sistemas de Liberación de Medicamentos , ColesterolRESUMEN
While a higher level of physical activity (PA) is inversely associated with a higher breast cancer (BC) risk, the health benefits of daily steps on obesity-related BC biomarkers remain unclear. We aimed to understand the associations of changes in step counts with levels of five obesity-related BC biomarkers during a two-year follow-up. In total, 144 non-cancer women (47.96 ± 5.72) were observed on both 2019 and 2021. A structured questionnaire, daily steps and fasting blood samples were collected before (t0, 2019) and after (t1, 2021). Levels of biomarkers (IGF-binding proteins 3, adiponectin, soluble leptin receptor, C-reactive protein, and resistin) were assayed by ELISA. Participants were divided into persistent low steps, decreasing steps, increasing steps, and persistent high steps. Associations of categories on proposed biomarkers were estimated using linear regression models, with persistent low steps as reference. Associations between time-varying step counts with biomarkers were quantified using mixed linear models. Compared with persistent low steps, increasing steps is associated with a reduction in C-reactive protein level (ß=-0.74, 95%CI=-1.23--0.26, P-value = 2.98 × 10-3). An inverse association between time-varying step counts with C-reactive protein level was identified, consistent across different obesity types and baseline step level categories. No association with daily step counts was observed for other proteins.
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Biomarcadores de Tumor , Neoplasias de la Mama , Humanos , Femenino , Actigrafía , Teléfono Inteligente , Proteína C-Reactiva , Obesidad , BiomarcadoresRESUMEN
While type 2 diabetes mellitus (T2DM) is commonly considered a putative causal risk factor for stroke, the effect of stroke on T2DM remains unclear. The intrinsic link underlying T2DM and stroke has not been thoroughly examined. We aimed to evaluate the phenotypic and genetic relationships underlying T2DM and stroke. We evaluated phenotypic associations using data from the UK Biobank (N = 472,050). We then investigated genetic relationships by leveraging genomic data in European ancestry for T2DM, with and without adjusting (adj) for BMI (T2DM: n = 74,124 case subjects/824,006 control subjects; T2DMadjBMI: n = 50,409 case subjects/523,897 control subjects), and for stroke (n = 73,652 case subjects/1,234,808 control subjects). We performed additional analyses using genomic data in East Asian ancestry for T2DM (n = 77,418 case subjects/356,122 control subjects) and for stroke (n = 27,413 case subjects/237,242 control subjects). Observational analyses suggested a significantly increased hazard of stroke among individuals with T2DM (hazard ratio 2.28 [95% CI 1.97-2.64]), but a slightly increased hazard of T2DM among individuals with stroke (1.22 [1.03-1.45]) which attenuated to 1.14 (0.96-1.36) in sensitivity analysis. A positive global T2DM-stroke genetic correlation was observed (rg = 0.35; P = 1.46 × 10-27), largely independent of BMI (T2DMadjBMI-stroke: rg = 0.27; P = 3.59 × 10-13). This was further corroborated by 38 shared independent loci and 161 shared expression-trait associations. Mendelian randomization analyses suggested a putative causal effect of T2DM on stroke in Europeans (odds ratio 1.07 [95% CI 1.06-1.09]), which remained significant in East Asians (1.03 [1.01-1.06]). Conversely, despite a putative causal effect of stroke on T2DM also observed in Europeans (1.21 [1.07-1.37]), it attenuated to 1.04 (0.91-1.19) in East Asians. Our study provides additional evidence to underscore the significant relationship between T2DM and stroke.
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BACKGROUND: Inflammatory adipokines and cytokines play a pivotal role in linking obesity and breast cancer (BC) risk in women. We investigated the longitudinal associations between BMI change and trajectories of inflammatory biomarkers related to BC risk. METHODS: A longitudinal study was conducted among 442 Chinese women with 3-year repeated measures from 2019 to 2021. Plasma circulating inflammatory biomarkers related to BC risk, including adiponectin (ADP), resistin (RETN), soluble leptin receptor (sOB-R), insulin-like growth factor-binding protein-3 (IGFBP-3), and C-reactive protein (CRP), were examined annually. Linear mixed-effect models (LMM) were applied to investigate associations of time-varying BMI with trajectories of biomarkers. We additionally examined the modification effect of baseline BMI groups, menopausal status, and metabolic syndrome. RESULTS: BMI was associated with increased levels of RETN, CRP, sOB-R, and decreased levels of ADP at baseline. An increasing BMI rate was significantly associated with an average 3-year increase in RETN (ß = 0.019, 95% CI 0.004 to 0.034) and sOB-R (ß = 0.022, 95% CI 0.009 to 0.035), as well as a decrease in ADP (ß = - 0.006, 95% CI - 0.012 to 0.001). These associations persisted across different baseline BMI groups. An increasing BMI rate was significantly associated with an average 3-year increase in CRP levels among normal weight (ß = 0.045, 95% CI 0.001 to 0.088) and overweight (ß = 0.060, 95% CI 0.014 to 0.107) women. As BMI increased over time, a more remarkable decrease in ADP was observed among women with metabolic syndrome (ß = - 0.016, 95% CI - 0.029 to - 0.004) than those without metabolic syndrome at baseline. CONCLUSIONS: A higher increase rate of BMI was associated with poorer trajectories of inflammatory biomarkers related to BC risk. Recommendations for BMI reduction may benefit BC prevention in women, particularly for those with metabolic syndrome.
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Neoplasias de la Mama , Síndrome Metabólico , Femenino , Humanos , Leptina/metabolismo , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/etiología , Estudios Longitudinales , Índice de Masa Corporal , Biomarcadores , Proteína C-Reactiva/metabolismo , AdiponectinaRESUMEN
The cuproptosis cell death pathway brings fresh opportunities for tumor therapy. However, efficient and targeted cuproptosis induction in tumors is still a challenge. Unfortunately, the well-known cuproptosis initiator, disulfiram and copper complex (DSF/Cu2+), also increases PD-L1 level in tumors, which may diminish the final therapeutic outcome. In this study, DSF/Cu2+-loading MXene nanosheets are coated with PD-1 overexpressing T cell membrane to generate CuX-P system. CuX-P could recognize and stick to PD-L1 on tumor cells like a patch, which promotes the endocytosis of both CuX-P and PD-L1 by tumor cells. Following internalization and release of DSF/Cu2+ in the cytoplasm, PD-L1 expression is upregulated. However, due to the presence of CuX-P in the tumor microenvironment, the then supplemented PD-L1 on tumor surface again binds CuX-P for internalization. This feedback loop keeps blocking and consuming the PD-L1 on tumor surface and promotes the enrichment of CuX-P in tumors to induce cuproptosis. After CuX-P treatment with laser irradiation, strong anti-tumor immune responses are stimulated in a mouse model with triple-negative breast cancer. Thus, this study develops a tumor-targeted biomimetic system that offers simultaneous cuproptosis killing, photothermal therapy (PTT) and immunotherapy in mice.
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Epidemiological studies demonstrate an association between migraine and chronic kidney disease (CKD), while the genetic basis underlying the phenotypic association has not been investigated. We aimed to help avoid unnecessary interventions in individuals with migraine through the investigation of phenotypic and genetic relationships underlying migraine, CKD, and kidney function. We first evaluated phenotypic associations using observational data from UK Biobank (N = 255,896). We then investigated genetic relationships leveraging genomic data in European ancestry for migraine (Ncase/Ncontrol = 48,975/540,381), CKD (Ncase/Ncontrol = 41,395/439,303), and two traits of kidney function (estimated glomerular filtration rate [eGFR, N = 567,460] and urinary albumin-to-creatinine ratio [UACR, N = 547,361]). Observational analyses suggested no significant association of migraine with the risk of CKD (HR = 1.13, 95% CI = 0.85-1.50). While we did not find any global genetic correlation in general, we identified four specific genomic regions showing significant for migraine with eGFR. Cross-trait meta-analysis identified one candidate causal variant (rs1047891) underlying migraine, CKD, and kidney function. Transcriptome-wide association study detected 28 shared expression-trait associations between migraine and kidney function. Mendelian randomization analysis suggested no causal effect of migraine on CKD (OR = 1.03, 95% CI = 0.98-1.09; P = 0.28). Despite a putative causal effect of migraine on an increased level of UACR (log-scale-beta = 0.02, 95% CI = 0.01-0.04; P = 1.92 × 10-3), it attenuated to null when accounting for both correlated and uncorrelated pleiotropy. Our work does not find evidence supporting a causal association between migraine and CKD. However, our study highlights significant biological pleiotropy between migraine and kidney function. The value of a migraine prophylactic treatment for reducing future CKD in people with migraine is likely limited.