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Stroke Jun 2024Ischemic stroke (IS) is a major cause of disability and mortality worldwide. Increasing evidence suggests a strong association between blood pressure, blood glucose,...
BACKGROUND
Ischemic stroke (IS) is a major cause of disability and mortality worldwide. Increasing evidence suggests a strong association between blood pressure, blood glucose, circulating lipids, and IS. Nonetheless, the genetic association of these 3 risk factors with IS remains elusive.
METHODS
We screened genetic instruments related to blood pressure, blood glucose, and circulating lipids and paired them with IS genome-wide association study data to conduct Mendelian randomization analysis. Positive Mendelian randomization findings were then subjected to colocalization analysis. Subsequently, we utilized the Gene Expression Omnibus data set to perform differential expression analysis, aiming to identify differentially expressed associated genes. We determined the importance scores of these differentially expressed associated genes through 4 machine learning models and constructed a nomogram based on these findings.
RESULTS
The combined results of the Mendelian randomization analysis indicate that blood pressure (systolic blood pressure: odds ratio [OR], 1.02 [95% CI, 1.01-1.02]; diastolic blood pressure: OR, 1.03 [95% CI, 1.03-1.04]) and some circulating lipids (low-density lipoprotein cholesterol: OR, 1.06 [95% CI, 1.01-1.12]; apoA1: OR, 0.95 [95% CI, 0.92-0.98]; apoB: OR, 1.05 [95% CI, 1.01-1.09]; eicosapentaenoic acid: OR, 2.36 [95% CI, 1.41-3.96]) have causal relationships with the risk of IS onset. We identified 73 genes that are linked to blood pressure and circulating lipids in the context of IS, and 16 are differentially expressed associated genes. , , , , and were identified as feature genes for constructing the nomogram that provides a quantitative prediction of the risk of IS onset.
CONCLUSIONS
This study indicates that there are causal links between blood pressure, certain circulating lipids, and the development of IS. The potential mechanisms underlying these causal relationships involve the regulation of lipid metabolism, blood pressure, DNA repair and methylation, cell apoptosis and autophagy, immune inflammation, and neuronal protection, among others.
Topics: Humans; Risk Factors; Mendelian Randomization Analysis; Genome-Wide Association Study; Ischemic Stroke; Blood Pressure; Computational Biology; Blood Glucose; Cholesterol, LDL; Apolipoprotein A-I; Mitochondrial Precursor Protein Import Complex Proteins; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease; Apolipoprotein B-100; Machine Learning
PubMed: 38591222
DOI: 10.1161/STROKEAHA.123.044424 -
Environmental Research Aug 2023Dyslipidemia, an imbalance of lipids and a major risk factor for cardiovascular disease, has been associated with elevated blood and urine levels of several heavy...
Dyslipidemia, an imbalance of lipids and a major risk factor for cardiovascular disease, has been associated with elevated blood and urine levels of several heavy metals. Using data from a Canadian Health Measures Survey (CHMS), we tested associations between blood levels of cadmium, copper, mercury, lead, manganese, molybdenum, nickel, selenium, and zinc, and the lipids triglycerides (TG), total cholesterol (TC), low density lipoproteins (LDL), high density lipoproteins (HDL) and apolipoproteins A1 (APO A1), and B (APO B). All adjusted associations between single metals and lipids were positive and significant, except for APO A1 and HDL. The joint effect of an interquartile range increase in heavy metals was positively associated with percentage increases of TC, LDL and APO B of 8.82% (95%CI: 7.06, 10.57), 7.01% (95%CI: 2.51, 11.51) and 7.15% (95%CI: 0.51, 13.78), respectively. Future studies are warranted to determine if reducing environmental exposure to heavy metals favorably influences lipid profiles and the risk of cardiovascular disease.
Topics: Humans; Lipoproteins; Lipids; Apolipoprotein A-I; Cardiovascular Diseases; Cross-Sectional Studies; Canada; Apolipoproteins B; Triglycerides; Cholesterol, HDL
PubMed: 37187310
DOI: 10.1016/j.envres.2023.116107 -
Hepatology (Baltimore, Md.) Nov 2023The assembly and secretion of VLDL from the liver, a pathway that affects hepatic and plasma lipids, remains incompletely understood. We set out to identify players in...
BACKGROUND AND AIMS
The assembly and secretion of VLDL from the liver, a pathway that affects hepatic and plasma lipids, remains incompletely understood. We set out to identify players in the VLDL biogenesis pathway by identifying genes that are co-expressed with the MTTP gene that encodes for microsomal triglyceride transfer protein, key to the lipidation of apolipoprotein B, the core protein of VLDL. Using human and murine transcriptomic data sets, we identified small leucine-rich protein 1 ( SMLR1 ), encoding for small leucine-rich protein 1, a protein of unknown function that is exclusively expressed in liver and small intestine.
APPROACH AND RESULTS
To assess the role of SMLR1 in the liver, we used somatic CRISPR/CRISPR-associated protein 9 gene editing to silence murine Smlr1 in hepatocytes ( Smlr1 -LKO). When fed a chow diet, male and female mice show hepatic steatosis, reduced plasma apolipoprotein B and triglycerides, and reduced VLDL secretion without affecting microsomal triglyceride transfer protein activity. Immunofluorescence studies show that SMLR1 is in the endoplasmic reticulum and Cis-Golgi complex. The loss of hepatic SMLR1 in female mice protects against diet-induced hyperlipidemia and atherosclerosis but causes NASH. On a high-fat, high-cholesterol diet, insulin and glucose tolerance tests did not reveal differences in male Smlr1 -LKO mice versus controls.
CONCLUSIONS
We propose a role for SMLR1 in the trafficking of VLDL from the endoplasmic reticulum to the Cis-Golgi complex. While this study uncovers SMLR1 as a player in the VLDL assembly, trafficking, and secretion pathway, it also shows that NASH can occur with undisturbed glucose homeostasis and atheroprotection.
Topics: Animals; Female; Humans; Male; Mice; Apolipoproteins B; Atherosclerosis; Leucine; Lipoproteins, VLDL; Liver; Non-alcoholic Fatty Liver Disease; Small Leucine-Rich Proteoglycans; Triglycerides
PubMed: 36053190
DOI: 10.1002/hep.32709 -
Journal of the American College of... Jan 2024
Topics: Humans; Lipoprotein(a); Apolipoproteins B; Lipoproteins, LDL
PubMed: 38233013
DOI: 10.1016/j.jacc.2023.11.008 -
BMC Medical Genomics Dec 2023In response to the controversy surrounding observational studies of the association between lipid profiles and the risk of insomnia, the aim of this study was to analyze...
OBJECTIVES
In response to the controversy surrounding observational studies of the association between lipid profiles and the risk of insomnia, the aim of this study was to analyze lipid profiles, including triglycerides (TG), apolipoprotein A-1 (ApoA-1), apolipoprotein B (ApoB) and lipoprotein A (LPA), in a European population to further assess the causal relationship between these lipid types and insomnia.
MATERIALS AND METHODS
This study explores the causal effect of lipid profiles on insomnia based on a genome-wide association study (GWAS)-derived public dataset using two-sample and multivariate Mendelian randomization (MVMR) analysis. The main MR analyses used inverse variance weighting (IVW) odds ratio (OR), and the sensitivity analyses included weighted median (WM) and MR‒Egger.
RESULTS
Both MR and MVMR showed that lowering ApoA-1 and LPA levels had causal effects on the risk of insomnia [MR: per 10 units, ApoA-1: OR: 0.7546, 95% CI: 0.6075-0.9372, P = 0.011; LPA: OR: 0.8392, 95% CI: 0.7202-0.9778, P = 0.025; MVMR: per 10 units, ApoA-1: OR: 0.7600, 95% CI: 0.6362-0.9079, P = 0.002; LPA, OR: 0.903, 95% CI: 0.8283-0.9845, P = 0.021]. There were no causal effects of TG or ApoB on insomnia (all P > 0.05). The MR‒Egger intercept test, funnel plot, and IVW methods all suggested an absence of strong directional pleiotropy, and leave-one-out permutation analysis did not detect any single single-nucleotide polymorphism that had a strong influence on the results.
CONCLUSION
Elevated levels of ApoA-1 and LPA were independently and causally associated with the risk of insomnia, suggesting that elevated ApoA-1 and LPA levels may contribute to a reduced risk of insomnia.
Topics: Humans; Apolipoprotein A-I; Apolipoproteins B; Genome-Wide Association Study; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Sleep Initiation and Maintenance Disorders; Triglycerides
PubMed: 38087303
DOI: 10.1186/s12920-023-01761-y -
Environment International Jan 2024Per- and polyfluoroalkyl substances (PFAS) can disrupt liver homeostasis. Studies have shown that a single exposure to PFAS may provoke abnormal liver function; however,...
Per- and polyfluoroalkyl substances (PFAS) can disrupt liver homeostasis. Studies have shown that a single exposure to PFAS may provoke abnormal liver function; however, few studies have investigated the overall effect of PFAS mixtures. We aimed to investigate associations between exposure to PFAS mixtures and liver function indices and explore the relevant mechanisms. This study included 278 adult males from Guangzhou, China. Serum metabolite profiles were analyzed using untargeted metabolomics. We applied weighted quantile sum (WQS) regression as well as Bayesian kernel machine regression (BKMR) to analyze the association of nine PFAS mixtures with 14 liver function indices. PFAS mixtures were positively associated with apolipoprotein B (APOB) and gamma-glutamyltransferase (GGT) and negatively associated with direct bilirubin (DBIL) and total bilirubin (TBIL) in both the WQS and BKMR analyses. In addition, Spearman's correlation test showed individual PFAS correlated with APOB, GGT, TBIL, and DBIL, while there's little correlation between individual PFAS and other liver function indices. In linear regression analysis, PFHxS, PFOS, PFHpS, PFNA, PFDA, and PFUdA were associated with APOB; PFOA, PFDA, PFOS, PFNA, and PFUdA were associated with GGT. Subsequently, a metabolome-wide association study and mediation analysis were combined to explore metabolites that mediate these associations. The mechanisms linking PFAS to APOB and GGT are mainly related with amino acid and glycerophospholipid metabolism. High-dimensional mediation analysis showed that glycerophospholipids are the main markers of the association between PFAS and APOB, and that (R)-dihydromaleimide, Ile Leu, (R)-(+)-2-pyrrolidone-5-carboxylic acid, and L-glutamate are the main markers of the association between PFAS and GGT. In summary, overall associations between PFAS and specific indices of liver function were found using two statistical methods; the metabolic pathways and markers identified here may serve to prompt more detailed study in animal-based systems, as well as a similar detailed analysis in other populations.
Topics: Animals; Male; Bayes Theorem; Apolipoproteins B; Bilirubin; Liver; Fluorocarbons; Environmental Pollutants; Alkanesulfonic Acids
PubMed: 38163401
DOI: 10.1016/j.envint.2023.108405 -
European Journal of Clinical... Jun 2024Substantial focus has been placed on atrial fibrillation (AF) treatment and associated stroke prevention rather than preventing AF itself. We employed Mendelian...
BACKGROUND
Substantial focus has been placed on atrial fibrillation (AF) treatment and associated stroke prevention rather than preventing AF itself. We employed Mendelian randomization (MR) approach to examine the causal relationships between 50 modifiable risk factors (RFs) and AF.
METHODS
Instrumental variables for genetically predicted exposures were derived from corresponding genome-wide association studies (GWASs). Summary-level statistical data for AF were obtained from a GWAS meta-analysis (discovery dataset, N = 1,030,836) and FinnGen (validation dataset, N = 208,594). Univariable and multivariable MR analyses were performed, primarily using inverse variance weighted method with a series of robust sensitivity analyses.
RESULTS
Genetic predisposition to insomnia, daytime naps, apnea, smoking initiation, moderate to vigorous physical activity and obesity traits, including body mass index, waist-hip ratio, central and peripheral fat/fat-free mass, exhibited significant associations with an increased risk of AF. Coffee consumption and ApoB had suggestive increased risks. Hypertension (odds ratio (OR) 95% confidence interval (CI): 5.26 (4.42, 6.24)), heart failure (HF) (OR 95% CI, 4.77 (2.43, 9.37)) and coronary artery disease (CAD) (OR 95% CI: 1.20 (1.16, 1.24)) were strongly associated with AF, while college degree, higher education attachment and HDL levels were associated with a decreased AF risk. Reverse MR found a bidirectional relationship between genetically predicted AF and CAD, HF and ischemic stroke. Multivariable analysis further indicated that obesity-related traits, systolic blood pressure and lower HDL levels independently contributed to the development of AF.
CONCLUSIONS
This study identified several lifestyles and cardiometabolic factors that might be causally related to AF, underscoring the importance of a holistic approach to AF management and prevention.
Topics: Atrial Fibrillation; Humans; Mendelian Randomization Analysis; Genome-Wide Association Study; Obesity; Risk Factors; Hypertension; Body Mass Index; Coronary Artery Disease; Heart Failure; Smoking; Waist-Hip Ratio; Genetic Predisposition to Disease; Exercise; Apolipoproteins B; Apolipoprotein B-100
PubMed: 38438337
DOI: 10.1111/eci.14194 -
Frontiers in Endocrinology 2023Research has shown that the disordered serum lipid profile may be associated with the risk of differentiated thyroid cancer (DTC). Whether this association reflect...
BACKGROUND
Research has shown that the disordered serum lipid profile may be associated with the risk of differentiated thyroid cancer (DTC). Whether this association reflect causal effect is still unclear. The aim of this study was to evaluate the causality of circulating lipoprotein lipids on DTC.
METHODS
Mendelian randomization (MR) analysis was conducted to evaluate the relationship between the circulating lipoprotein lipids and DTC risk using single-nucleotide polymorphisms (SNPs) from a genome-wide association (GWA) study containing a high-incidence Italian population of 690 cases samples with DTC and 497 controls.
RESULTS
Univariate and multivariate mendelian randomization analysis demonstrated that 'total cholesterol', 'HDL cholesterol', 'apolipoprotein B' and 'ratio of apolipoprotein B to apolipoprotein A1' were correlated with DTC. According to sensitivity analysis, our results were reliable. Furthermore, multivariate analysis revealed that there is no causative association between DTC and any of the many cause factors when they interact with one another, suggesting that there was a deep interaction between the four factors, which could affect each other. Finally, the mechanism of the related effects each other as well as the target genes with significant SNP regulatory effects in DTC was explored by conducting functional enrichment analysis and constructing the regulatory networks.
CONCLUSIONS
We obtained four exposure factors (total cholesterol, HDL cholesterol, apolipoprotein B and ratio of apolipoprotein B to apolipoprotein A1) closely related to DTC, which laid a theoretical foundation for the treatment of DTC.
Topics: Humans; Apolipoprotein A-I; Genome-Wide Association Study; Mendelian Randomization Analysis; Adenocarcinoma; Apolipoproteins B; Cholesterol, HDL; Lipid Metabolism Disorders; Thyroid Neoplasms
PubMed: 38189054
DOI: 10.3389/fendo.2023.1291445 -
The American Journal of Cardiology Aug 2023The present study aimed to examine the association between discordant apolipoprotein B (Apo B) with low-density lipoprotein cholesterol (LDL-C) or non-high-density...
The present study aimed to examine the association between discordant apolipoprotein B (Apo B) with low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) and cardiovascular disease (CVD) risk in the Chinese population and to determine whether adding information on Apo B to LDL-C and HDL-C improves CVD risk prediction. This study collected data from the China Health and Nutrition Survey from 2009 to 2015. Discordant Apo B with LDL-C and non-HDL-C were defined based on residual differences and medians. Logistic regression was used to examine the association between discordant Apo B with LDL-C or non-HDL-C and CVD risk. Areas under the receiver operating characteristic curve and categorical net reclassification improvement were utilized to assess the incremental predictive value of Apo B levels for CVD risk. A total of 7,117 participants were included, the mean age was 50.8 ± 14.3 years, 53.6% were female. During the 6-year follow-up, 207 CVD cases were identified. Participants with discordant high Apo B relative to LDL-C or non-HDL-C were at higher risk of CVD than those with the concordant group (odds ratio 1.38, 95% confidence interval 1.01 to 1.87; odds ratio 1.40, 95% confidence interval 1.01 to 1.94, respectively). However, Apo B had no significant contribution to the predictive value of the China atherosclerotic CVD (ASCVD) risk score (areas under the receiver operating characteristic curve 0.788 for China ASCVD score alone vs 0.790 for China ASCVD score plus Apo B). In conclusion, Apo B has the strongest association with CVD risk in healthy Chinese participants than LDL-C and non-HDL-C. However, it has minimal value in CVD risk assessment and discrimination.
Topics: Humans; Female; Adult; Middle Aged; Aged; Male; Cardiovascular Diseases; Cholesterol, LDL; Prospective Studies; Risk Factors; Cholesterol, HDL; Apolipoproteins; Apolipoproteins B; Cholesterol; Lipoproteins; Heart Disease Risk Factors
PubMed: 37352662
DOI: 10.1016/j.amjcard.2023.05.052 -
Journal of Alzheimer's Disease : JAD 2024Apolipoproteins and contactin 5 are proteins associated with Alzheimer's disease (AD) pathophysiology. Apolipoproteins act on transport and clearance of cholesterol and...
BACKGROUND
Apolipoproteins and contactin 5 are proteins associated with Alzheimer's disease (AD) pathophysiology. Apolipoproteins act on transport and clearance of cholesterol and phospholipids during synaptic turnover and terminal proliferation. Contactin 5 is a neuronal membrane protein involved in key processes of neurodevelopment.
OBJECTIVE
To investigate the interactions between contactin 5 and apolipoproteins in AD, and the role of these proteins in response to neuronal damage.
METHODS
Apolipoproteins (measured by Luminex), contactin 5 (measured by Olink's proximity extension assay), and cholesterol (measured by liquid chromatography mass spectrometry) were assessed in the cerebrospinal fluid (CSF) and plasma of cognitively unimpaired participants (n = 93). Gene expression was measured using polymerase chain reaction in the frontal cortex of autopsied-confirmed AD (n = 57) and control subjects (n = 31) and in the hippocampi of mice following entorhinal cortex lesions.
RESULTS
Contactin 5 positively correlated with apolipoproteins B (p = 5.4×10-8), D (p = 1.86×10-4), E (p = 2.92×10-9), J (p = 2.65×10-9), and with cholesterol (p = 0.0096) in the CSF, and with cholesterol (p = 0.02), HDL (p = 0.0143), and LDL (p = 0.0121) in the plasma. Negative correlations were seen between CNTN5, APOB (p = 0.034) and APOE (p = 0.015) mRNA levels in the brains of control subjects. In the mouse model, apoe and apoj gene expression increased during the reinnervation phase (p < 0.05), while apob (p = 0.023) and apod (p = 0.006) increased in the deafferentation stage.
CONCLUSIONS
Extensive interactions were observed between contactin 5 and apolipoproteins and cholesterol, possibly due to neuronal damage. The alterations in gene expression of apolipoproteins suggest a role in axonal, terminal, and synaptic remodeling in response to entorhinal cortex damage.
Topics: Humans; Mice; Animals; Alzheimer Disease; Apolipoproteins; Apolipoproteins E; Apolipoproteins B; Cholesterol; Contactins
PubMed: 38578887
DOI: 10.3233/JAD-231003