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Cardiovascular Research Jul 2024Vascular smooth muscle cells (SMCs) and their derivatives are key contributors to the development of atherosclerosis. However, studying changes in SMC gene expression in...
AIMS
Vascular smooth muscle cells (SMCs) and their derivatives are key contributors to the development of atherosclerosis. However, studying changes in SMC gene expression in heterogeneous vascular tissues is challenging due to the technical limitations and high cost associated with current approaches. In this paper, we apply translating ribosome affinity purification sequencing to profile SMC-specific gene expression directly from tissue.
METHODS AND RESULTS
To facilitate SMC-specific translatome analysis, we generated SMCTRAP mice, a transgenic mouse line expressing enhanced green fluorescent protein (EGFP)-tagged ribosomal protein L10a (EGFP-L10a) under the control of the SMC-specific αSMA promoter. These mice were further crossed with the atherosclerosis model Ldlr-/-, ApoB100/100 to generate SMCTRAP-AS mice and used to profile atherosclerosis-associated SMCs in thoracic aorta samples of 15-month-old SMCTRAP and SMCTRAP-AS mice. Our analysis of SMCTRAP-AS mice showed that EGFP-L10a expression was localized to SMCs in various tissues, including the aortic wall and plaque. The TRAP fraction demonstrated high enrichment of known SMC-specific genes, confirming the specificity of our approach. We identified several genes, including Cemip, Lum, Mfge8, Spp1, and Serpina3, which are known to be involved in atherosclerosis-induced gene expression. Moreover, we identified several novel genes not previously linked to SMCs in atherosclerosis, such as Anxa4, Cd276, inter-alpha-trypsin inhibitor-4 (Itih4), Myof, Pcdh11x, Rab31, Serpinb6b, Slc35e4, Slc8a3, and Spink5. Among them, we confirmed the SMC-specific expression of Itih4 in atherosclerotic lesions using immunofluorescence staining of mouse aortic roots and spatial transcriptomics of human carotid arteries. Furthermore, our more detailed analysis of Itih4 showed its link to coronary artery disease through the colocalization of genome-wide association studies, splice quantitative trait loci (QTL), and protein QTL signals.
CONCLUSION
We generated a SMC-specific TRAP mouse line to study atherosclerosis and identified Itih4 as a novel SMC-expressed gene in atherosclerotic plaques, warranting further investigation of its putative function in extracellular matrix stability and genetic evidence of causality.
Topics: Animals; Myocytes, Smooth Muscle; Atherosclerosis; Muscle, Smooth, Vascular; Disease Models, Animal; Aortic Diseases; Ribosomal Proteins; Plaque, Atherosclerotic; Mice, Inbred C57BL; Male; Gene Expression Regulation; Gene Expression Profiling; Phenotype; Transcriptome; Receptors, LDL; Apolipoprotein B-100; Mice, Knockout; Humans; Green Fluorescent Proteins; Mice; Mice, Transgenic; Aorta; Female
PubMed: 38289873
DOI: 10.1093/cvr/cvae028 -
Arthritis Research & Therapy Jan 2024The etiology of giant cell arteritis (GCA) and its predictors are incompletely understood. Previous studies have indicated reduced risk of future development of GCA in...
BACKGROUND
The etiology of giant cell arteritis (GCA) and its predictors are incompletely understood. Previous studies have indicated reduced risk of future development of GCA in individuals with obesity and/or diabetes mellitus. There is limited information on blood lipids before the onset of GCA. The objective of the study was to investigate the relation between apolipoprotein levels and future diagnosis of GCA in a nested case-control analysis.
METHODS
Individuals who developed GCA after inclusion in a population-based health survey (the Malmö Diet Cancer Study; N = 30,447) were identified by linking the health survey database to the local patient administrative register and the national patient register. A structured review of medical records was performed. Four controls for every validated case, matched for sex, year of birth, and year of screening, were selected from the database. Anthropometric measures, self-reported physical activity, based on a comprehensive, validated questionnaire, and non-fasting blood samples had been obtained at health survey screening. Concentrations of apolipoprotein A-I (ApoA-I) and apolipoprotein B (ApoB) in stored serum were measured using an immunonephelometric assay. Potential predictors of GCA were examined in conditional logistic regression models.
RESULTS
There were 100 cases with a confirmed clinical diagnosis of GCA (81% female; mean age at diagnosis 73.6 years). The median time from screening to diagnosis was 12 years (range 0.3-19.1). The cases had significantly higher ApoA-I at baseline screening compared to controls (mean 168.7 vs 160.9 mg/dL, odds ratio [OR] 1.57 per standard deviation (SD); 95% confidence interval [CI] 1.18-2.10) (SD 25.5 mg/dL). ApoB levels were similar between cases and controls (mean 109.3 vs 110.4 mg/dL, OR 0.99 per SD; 95% CI 0.74-1.32) (SD 27.1 mg/dL). The ApoB/ApoA1 ratio tended to be lower in cases than in controls, but the difference did not reach significance. The association between ApoA-I and GCA development remained significant in analysis adjusted for body mass index and physical activity (OR 1.48 per SD; 95% CI 1.09-1.99).
CONCLUSION
Subsequent development of GCA was associated with significantly higher levels of ApoA-I. These findings suggest that a metabolic profile associated with lower risk of cardiovascular disease may predispose to GCA.
Topics: Humans; Female; Aged; Male; Giant Cell Arteritis; Risk Factors; Apolipoprotein A-I; Case-Control Studies; Apolipoproteins; Apolipoproteins B
PubMed: 38281009
DOI: 10.1186/s13075-024-03273-1 -
European Stroke Journal Jun 2024Low density lipoprotein (LDL-C) and other atherogenic lipoproteins are coated by apolipoprotein B100 (apoB). The correlation between LDL-C and apoB is usually thight,...
BACKGROUND AND AIMS
Low density lipoprotein (LDL-C) and other atherogenic lipoproteins are coated by apolipoprotein B100 (apoB). The correlation between LDL-C and apoB is usually thight, but in some cases LDL-C underestimates apoB levels and residual cardiovascular risk. We aimed to assess if a discordance of LDL-C-levels with apoB levels is associated with LAA stroke.
METHODS
We included patients with an acute ischemic stroke from two prospective studies enrolled at the University Hospital Bern, Basel and Zurich, Switzerland. LDL-C and apoB were measured within 24 h of symptom onset. By linear regression, for each LDL-C, we computed the expected apoB level assuming a perfect correlation. Higher-than-expected apoB was defined as apoB level being in the upper residual tertile.
RESULTS
Overall, we included 1783 patients, of which 260 had a LAA stroke (15%). In the overall cohort, higher-than-expected apoB values were not associated with LAA. However, a significant interaction with age was present. Among the 738 patients ⩽70 years of age, a higher-than-expected apoB was more frequent in patients with LAA- versus non LAA-stroke (48% vs 36%, = 0.02). In multivariate analysis, a higher-than-expected apoB was associated with LAA stroke (aOR = aOR 2.48, 95%CI 1.14-5.38). Among those aged ⩽70 years and with LAA, 11.7% had higher than guideline-recommended apoB despite LDL-C ⩽ 1.8 mmol/L (<70 mg/dl), compared to 5.9% among patients with other stroke etiologies ( = 0.04). A triglyceride cut-off of ⩾0.95 mmol/L had, in external validation, a sensitivity of 71% and specificity of 52% for apoB ⩾ 0.65 g/L among patients with LDL-C <1.8 mmol/L.
CONCLUSIONS
Among patients aged ⩽70 years, a higher-than-expected apoB was independently associated with LAA stroke. Measuring apoB may help identify younger stroke patients potentially benefiting from intensified lipid-lowering therapy.
Topics: Humans; Female; Male; Ischemic Stroke; Aged; Middle Aged; Cholesterol, LDL; Apolipoproteins B; Atherosclerosis; Prospective Studies; Apolipoprotein B-100; Age Factors; Risk Factors; Stroke
PubMed: 38279527
DOI: 10.1177/23969873231221619 -
Frontiers in Endocrinology 2023Previous observational studies have investigated the association between endocrine and metabolic factors and idiopathic pulmonary fibrosis (IPF), yet have produced...
BACKGROUND
Previous observational studies have investigated the association between endocrine and metabolic factors and idiopathic pulmonary fibrosis (IPF), yet have produced inconsistent results. Therefore, it is imperative to employ the Mendelian randomization (MR) analysis method to conduct a more comprehensive investigation into the impact of endocrine and metabolic factors on IPF.
METHODS
The instrumental variables (IVs) for 53 endocrine and metabolic factors were sourced from publicly accessible genome-wide association study (GWAS) databases, with GWAS summary statistics pertaining to IPF employed as the dependent variables. Causal inference analysis encompassed the utilization of three methods: inverse-variance weighted (IVW), weighted median (WM), and MR-Egger. Sensitivity analysis incorporated the implementation of MR-PRESSO and leave-one-out techniques to identify potential pleiotropy and outliers. The presence of horizontal pleiotropy and heterogeneity was evaluated through the MR-Egger intercept and Cochran's Q statistic, respectively.
RESULTS
The IVW method results reveal correlations between 11 traits and IPF. After correcting for multiple comparisons, seven traits remain statistically significant. These factors include: "Weight" (OR= 1.44; 95% CI: 1.16, 1.78; =8.71×10), "Body mass index (BMI)" (OR= 1.35; 95% CI: 1.13, 1.62; =1×10), "Whole body fat mass" (OR= 1.40; 95% CI: 1.14, 1.74; =1.72×10), "Waist circumference (WC)" (OR= 1.54; 95% CI: 1.16, 2.05; =3.08×10), "Trunk fat mass (TFM)" (OR=1.35; 95% CI: 1.10,1.65; =3.45×10), "Body fat percentage (BFP)" (OR= 1.55; 95% CI: 1.15,2.08; =3.86×10), "Apoliprotein B (ApoB)" (OR= 0.78; 95% CI: 0.65,0.93; =5.47×10). Additionally, the sensitivity analysis results confirmed the reliability of the MR results.
CONCLUSION
The present study identified causal relationships between seven traits and IPF. Specifically, ApoB exhibited a negative impact on IPF, while the remaining six factors demonstrated a positive impact. These findings offer novel insights into the underlying etiopathological mechanisms associated with IPF.
Topics: Humans; Genome-Wide Association Study; Mendelian Randomization Analysis; Reproducibility of Results; Idiopathic Pulmonary Fibrosis; Apolipoproteins B
PubMed: 38260151
DOI: 10.3389/fendo.2023.1321576 -
European Heart Journal Mar 2024RNA-based, antibody-based, and genome editing-based therapies are currently under investigation to determine if the inhibition of angiopoietin-like protein-3 (ANGPTL3)...
BACKGROUND AND AIMS
RNA-based, antibody-based, and genome editing-based therapies are currently under investigation to determine if the inhibition of angiopoietin-like protein-3 (ANGPTL3) could reduce lipoprotein-lipid levels and atherosclerotic cardiovascular disease (ASCVD) risk. Mendelian randomisation (MR) was used to determine whether genetic variations influencing ANGPTL3 liver gene expression, blood levels, and protein structure could causally influence triglyceride and apolipoprotein B (apoB) levels as well as coronary artery disease (CAD), ischaemic stroke (IS), and other cardiometabolic diseases.
METHODS
RNA sequencing of 246 explanted liver samples and genome-wide genotyping was performed to identify single-nucleotide polymorphisms (SNPs) associated with liver expression of ANGPTL3. Genome-wide summary statistics of plasma protein levels of ANGPTL3 from the deCODE study (n = 35 359) were used. A total of 647 carriers of ANGPTL3 protein-truncating variants (PTVs) associated with lower plasma triglyceride levels were identified in the UK Biobank. Two-sample MR using SNPs that influence ANGPTL3 liver expression or ANGPTL3 plasma protein levels as exposure and cardiometabolic diseases as outcomes was performed (CAD, IS, heart failure, non-alcoholic fatty liver disease, acute pancreatitis, and type 2 diabetes). The impact of rare PTVs influencing plasma triglyceride levels on apoB levels and CAD was also investigated in the UK Biobank.
RESULTS
In two-sample MR studies, common genetic variants influencing ANGPTL3 hepatic or blood expression levels of ANGPTL3 had a very strong effect on plasma triglyceride levels, a more modest effect on low-density lipoprotein cholesterol, a weaker effect on apoB levels, and no effect on CAD or other cardiometabolic diseases. In the UK Biobank, the carriers of rare ANGPTL3 PTVs providing lifelong reductions in median plasma triglyceride levels [-0.37 (interquartile range 0.41) mmol/L] had slightly lower apoB levels (-0.06 ± 0.32 g/L) and similar CAD event rates compared with non-carriers (10.2% vs. 10.9% in carriers vs. non-carriers, P = .60).
CONCLUSIONS
PTVs influencing ANGPTL3 protein structure as well as common genetic variants influencing ANGPTL3 hepatic expression and/or blood protein levels exhibit a strong effect on circulating plasma triglyceride levels, a weak effect on circulating apoB levels, and no effect on ASCVD. Near-complete inhibition of ANGPTL3 function in patients with very elevated apoB levels may be required to reduce ASCVD risk.
Topics: Humans; Acute Disease; Brain Ischemia; Diabetes Mellitus, Type 2; Pancreatitis; Stroke; Atherosclerosis; Coronary Artery Disease; Angiopoietin-Like Protein 3; Antibodies; Apolipoproteins B; Triglycerides
PubMed: 38243829
DOI: 10.1093/eurheartj/ehad845 -
BMC Medical Genomics Jan 2024Breast cancer is the second leading cause of cancer-related death in women, and drug resistance during treatment is a major challenge. However, the mechanisms underlying...
BACKGROUND
Breast cancer is the second leading cause of cancer-related death in women, and drug resistance during treatment is a major challenge. However, the mechanisms underlying drug resistance are not fully understood. Here we applied whole-exome sequencing (WES) to clarify resistant rules to Herceptin and tyrosine kinase inhibitors (TKIs).
METHODS
There are 12 HER2+ breast cancer patients who were done WES. Samples from tumor and surrounding tissues underwent DNA sequencing and analysis. Various experimental and bioinformatics techniques were employed, including genomic capture, mutation analysis (Genome Analysis Toolkit (GATK), etc.), bioinformatics assessments, and drug-gene interaction investigations. Ultimately, the study explored the association of APOB gene expression with breast cancer recurrence rates, immune cell infiltration, and drug response.
RESULTS
The C > T mutation frequency was highest in the Herceptin-insensitive (HI) and verification groups, codenamed YI, contrasting with the Herceptin-sensitive (HE) group. No microsatellite instability (MSI)-H patients were in the HE group, but both HI and YI groups had 1 each. Significant differences in transition-transversion (TiTv) were observed in the HI and YI groups rather than the HE group. In the TKI- insensitive (TI) group, C > T mutations were highest, differing from the TKI-sensitive (TE) group. TE group included 2 MSI-H patients. Significant differences in TiTv were found in the TI group rather than the TE group. Mutated APOB may resist Herceptin and TKI, increasing immune infiltration. We identified potential drugs targeting it.
CONCLUSIONS
Our study suggested that a higher percentage of C > T mutations, significant differences in TiTv, and MSI-H status may indicate Herceptin resistance, while a higher percentage of C > T mutations, significant differences in TiTv, and the absence of MSI-H may indicate TKI resistance in breast cancer patients. For patients resistant to both Herceptin and TKI, mutated APOB may play a crucial role in resistance.
Topics: Humans; Female; Trastuzumab; Breast Neoplasms; Exome Sequencing; Drug Resistance, Neoplasm; Neoplasm Recurrence, Local; Mutation; Apolipoproteins B
PubMed: 38243282
DOI: 10.1186/s12920-023-01762-x -
JAMA Network Open Jan 2024Apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) are associated with coronary artery disease (CAD). However, trial evidence...
IMPORTANCE
Apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) are associated with coronary artery disease (CAD). However, trial evidence for the association of intensive LDL-C lowering and TG lowering with mortality is less definitive.
OBJECTIVES
To investigate the associations of apoB, LDL-C, and TG with CAD and mortality, both overall and by sex and age, and to characterize the shapes of these associations.
DESIGN, SETTING, AND PARTICIPANTS
This genetic association study used linear and nonlinear mendelian randomization (MR) to analyze a population-based cohort of individuals of European ancestry from the UK Biobank, which recruited participants from 2006 to 2010 with follow-up information updated until September 2021. Data analysis occurred from December 2022 to November 2023.
EXPOSURES
Genetically predicted apoB, LDL-C, and TG.
MAIN OUTCOMES AND MEASURES
The primary outcomes were CAD, all-cause mortality, and cause-specific mortality. Genetic associations with CAD were calculated using logistic regression, associations with all-cause mortality using Cox proportional hazards regression, and associations with cause-specific mortality using cause-specific Cox proportional hazards regression with censoring for other causes of mortality.
RESULTS
This study included 347 797 participants (mean [SD] age, 57.2 [8.0] years; 188 330 female [54.1%]). There were 23 818 people who developed CAD and 23 848 people who died. Genetically predicted apoB was positively associated with risk of CAD (odds ratio [OR], 1.65 per SD increase; 95% CI 1.57-1.73), all-cause mortality (hazard ratio [HR], 1.11; 95% CI, 1.06-1.16), and cardiovascular mortality (HR, 1.36; 95% CI, 1.24-1.50), with some evidence for larger associations in male participants than female participants. Findings were similar for LDL-C. Genetically predicted TG was positively associated with CAD (OR, 1.60; 95% CI 1.52-1.69), all-cause mortality (HR, 1.08; 95% CI, 1.03-1.13), and cardiovascular mortality (HR, 1.21; 95% CI, 1.09-1.34); however, sensitivity analyses suggested evidence of pleiotropy. The association of genetically predicted TG with CAD persisted but it was no longer associated with mortality outcomes after controlling for apoB. Nonlinear MR suggested that all these associations were monotonically increasing across the whole observed distribution of each lipid trait, with no diminution at low lipid levels. Such patterns were observed irrespective of sex or age.
CONCLUSIONS AND RELEVANCE
In this genetic association study, apoB (or, equivalently, LDL-C) was associated with increased CAD risk, all-cause mortality, and cardiovascular mortality, all in a dose-dependent way. TG may increase CAD risk independent of apoB, although the possible presence of pleiotropy is a limitation. These insights highlight the importance of apoB (or, equivalently, LDL-C) lowering for reducing cardiovascular morbidity and mortality across its whole distribution.
Topics: Humans; Male; Female; Middle Aged; Coronary Artery Disease; Cholesterol, LDL; Risk Factors; Apolipoproteins B; Triglycerides
PubMed: 38241044
DOI: 10.1001/jamanetworkopen.2023.52572 -
Journal of the American College of... Jan 2024
Topics: Humans; Lipoprotein(a); Cardiovascular Diseases; Risk Factors; Apolipoproteins B
PubMed: 38233021
DOI: 10.1016/j.jacc.2023.09.836 -
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 -
Journal of the American College of... Jan 2024Lipoprotein(a) (Lp(a)) is recognized as a causal factor for coronary heart disease (CHD) but its atherogenicity relative to that of low-density lipoprotein (LDL) on a...
BACKGROUND
Lipoprotein(a) (Lp(a)) is recognized as a causal factor for coronary heart disease (CHD) but its atherogenicity relative to that of low-density lipoprotein (LDL) on a per-particle basis is indeterminate.
OBJECTIVES
The authors addressed this issue in a genetic analysis based on the fact that Lp(a) and LDL both contain 1 apolipoprotein B (apoB) per particle.
METHODS
Genome-wide association studies using the UK Biobank population identified 2 clusters of single nucleotide polymorphisms: one comprising 107 variants linked to Lp(a) mass concentration, the other with 143 variants linked to LDL concentration. In these Lp(a) and LDL clusters, the relationship of genetically predicted variation in apoB with CHD risk was assessed.
RESULTS
The Mendelian randomization-derived OR for CHD for a 50 nmol/L higher Lp(a)-apoB was 1.28 (95% CI: 1.24-1.33) compared with 1.04 (95% CI: 1.03-1.05) for the same increment in LDL-apoB. Likewise, use of polygenic scores to rank subjects according to difference in Lp(a)-apoB vs difference in LDL-apoB revealed a greater HR for CHD per 50 nmol/L apoB for the Lp(a) cluster (1.47; 95% CI: 1.36-1.58) compared with the LDL cluster (1.04; 95% CI: 1.02-1.05). From these data, we estimate that the atherogenicity of Lp(a) is approximately 6-fold (point estimate of 6.6; 95% CI: 5.1-8.8) greater than that of LDL on a per-particle basis.
CONCLUSIONS
We conclude that the atherogenicity of Lp(a) (CHD risk quotient per unit increase in particle number) is substantially greater than that of LDL. Therefore, Lp(a) represents a key target for drug-based intervention in a significant proportion of the at-risk population.
Topics: Humans; Lipoprotein(a); Genome-Wide Association Study; Cholesterol, LDL; Apolipoproteins B; Coronary Disease; Risk Factors
PubMed: 38233012
DOI: 10.1016/j.jacc.2023.10.039