Impacts of pro-inflammatory cytokines variant on cardiometabolic profile and premature coronary artery disease: A systematic review and meta-analysis.

Interleukin-6 (IL-6), a pivotal pro-inflammatory cytokine, is closely linked to vascular wall thickening and atherosclerotic lesion. Since serum IL-6 levels are largely determined by the genetic variant in IL-6, this study was conducted to investigate whether the IL-6 variant impacts cardiometabolic profile and the risk of premature coronary artery disease (PCAD). PubMed, Cochrane Library, Central, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and ClinicalTrials.gov were searched from May 13, 2022 to June 28, 2023. In total, 40 studies (26,543 individuals) were included for the analysis. The rs1800795 (a function variant in the IL-6 gene) C allele was linked to higher levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), fasting plasma glucose (FPG), body mass index (BMI), and waist circumference (WC), and a lower levels of high-density lipoprotein cholesterol (HDL-C). However, no significant association was observed of rs1800795 with triglycerides (TG), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Interestingly, a significant association was detected between rs1800795 and PCAD. Subgroup analyses indicted that the impacts of rs1800795 on cardiometabolic risk factors were significant in Caucasians but stronger in obese patients. In contrast, the impact of rs1800795 on PCAD was significant in brown race population. In summary, rs1800795 had a slight but significant impact on cardiometabolic risk factors and PCAD. IL-6 inhibition with ziltivekimab or canakinumab may benefit high-risk populations (e.g. brown race population, Caucasians, obese patients, etc.) with rs1800795 to prevent PCAD.

Enhancing prediction accuracy of coronary artery disease through machine learning-driven genomic variant selection.

Machine learning (ML) methods are increasingly becoming crucial in genome-wide association studies for identifying key genetic variants or SNPs that statistical methods might overlook. Statistical methods predominantly identify SNPs with notable effect sizes by conducting association tests on individual genetic variants, one at a time, to determine their relationship with the target phenotype. These genetic variants are then used to create polygenic risk scores (PRSs), estimating an individual's genetic risk for complex diseases like cancer or cardiovascular disorders. Unlike traditional methods, ML algorithms can identify groups of low-risk genetic variants that improve prediction accuracy when combined in a mathematical model. However, the application of ML strategies requires addressing the feature selection challenge to prevent overfitting. Moreover, ensuring the ML model depends on a concise set of genomic variants enhances its clinical applicability, where testing is feasible for only a limited number of SNPs. In this study, we introduce a robust pipeline that applies ML algorithms in combination with feature selection (ML-FS algorithms), aimed at identifying the most significant genomic variants associated with the coronary artery disease (CAD) phenotype. The proposed computational approach was tested on individuals from the UK Biobank, differentiating between CAD and non-CAD individuals within this extensive cohort, and benchmarked against standard PRS-based methodologies like LDpred2 and Lassosum. Our strategy incorporates cross-validation to ensure a more robust evaluation of genomic variant-based prediction models. This method is commonly applied in machine learning strategies but has often been neglected in previous studies assessing the predictive performance of polygenic risk scores. Our results demonstrate that the ML-FS algorithm can identify panels with as few as 50 genetic markers that can achieve approximately 80% accuracy when used in combination with known risk factors. The modest increase in accuracy over PRS performances is noteworthy, especially considering that PRS models incorporate a substantially larger number of genetic variants. This extensive variant selection can pose practical challenges in clinical settings. Additionally, the proposed approach revealed novel CAD-genetic variant associations.

Association of a single-nucleotide polymorphism in C12orf43 region with the risk of coronary artery disease.

The genetics of organisms play a vital role in the development of coronary artery disease (CAD), with its heritability estimated at approximately 50-60%. For this purpose, we examined the relationship between CAD risk and C12orf43/rs2258287 polymorphisms in the Pakistani population. In this study based on the genetic approach to dyslipidemia, a total of 200 subjects were included from the southern Punjab. The biochemical analysis of parameters (total cholesterol, triglycerides, blood glucose, high-density lipoprotein, and low-density lipoprotein) was carried out along with molecular analysis using an ARMS-PCR-based assay for single-nucleotide polymorphism (SNP) C12orf43/rs2258287 to identify the genotype. Genotypes showed a substantial correlation with both family history and metabolic markers. The cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides and blood glucose levels were higher while the high-density lipoprotein cholesterol (HDL-C) level was lower significantly (p<0.05) in cases than in controls. Age, pulse rate, diabetes, physical activity, smoking, family history, and dietary habits were also significantly associated (p<0.05) with CAD individuals. The SNP C12orf43/rs2258287 also showed an association with CAD in the population of southern Punjab. Based upon this study, it could be concluded that CAD is characterized by an unfavorable lipid profile in association with SNP C12orf43/rs2258287.

Integration of polygenic and gut metagenomic risk prediction for common diseases.

Multiomics has shown promise in noninvasive risk profiling and early detection of various common diseases. In the present study, in a prospective population-based cohort with ~18 years of e-health record follow-up, we investigated the incremental and combined value of genomic and gut metagenomic risk assessment compared with conventional risk factors for predicting incident coronary artery disease (CAD), type 2 diabetes (T2D), Alzheimer disease and prostate cancer. We found that polygenic risk scores (PRSs) improved prediction over conventional risk factors for all diseases. Gut microbiome scores improved predictive capacity over baseline age for CAD, T2D and prostate cancer. Integrated risk models of PRSs, gut microbiome scores and conventional risk factors achieved the highest predictive performance for all diseases studied compared with models based on conventional risk factors alone. The present study demonstrates that integrated PRSs and gut metagenomic risk models improve the predictive value over conventional risk factors for common chronic diseases.

Genetic Counseling and Genetic Testing for Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is one of the most common autosomal codominant Mendelian diseases. The major complications of FH include tendon and cutaneous xanthomas and coronary artery disease (CAD) associated with a substantial elevation of serum low-density lipoprotein levels (LDL). Genetic counseling and genetic testing for FH is useful for its diagnosis, risk stratification, and motivation for further LDL-lowering treatments. In this study, we summarize the epidemiology of FH based on numerous genetic studies, including its pathogenic variants, genotype-phenotype correlation, prognostic factors, screening, and usefulness of genetic counseling and genetic testing. Due to the variety of treatments available for this common Mendelian disease, genetic counseling and genetic testing for FH should be implemented in daily clinical practice.

An update on the cell-free DNA-derived methylome as a non-invasive biomarker for coronary artery disease.

Cardiovascular diseases are the foremost contributor to global mortality, presenting a complex etiology and an expanding array of risk factors. Coronary artery disease characterized by atherosclerotic plaque build-up in the coronary arteries, imposes significant mortality and financial burdens, especially in low- and middle-income nations. The pathogenesis of coronary artery disease involves a multifaceted interplay of genetic, environmental, and epigenetic factors. Epigenetic regulation contributes to the dynamic control of gene expression without altering the underlying DNA sequence. The mounting evidence that highlights the pivotal role of epigenetic regulation in coronary artery disease development and progression, offering potential avenues for the development of novel diagnostic biomarkers and therapeutic targets. Abnormal DNA methylation patterns are linked to the modulation of gene expression involved in crucial processes like lipid metabolism, inflammation, and vascular function in the context of coronary artery disease. Cell-free DNA has become invaluable in tumor biology as a liquid biopsy, while its applications in coronary artery disease are limited, but intriguing. Atherosclerotic plaque rupture causes myocardial infarction, by depriving heart muscles of oxygen, releasing cell-free DNA from dead cardiac cells, and providing a minimally invasive source to explore tissue-specific epigenetic alterations. We discussed the methodologies for studying the global methylome and hydroxy-methylome landscape, their advantages, and limitations. It explores methylome alterations in coronary artery disease, considering risk factors and their relevance in coronary artery disease genesis. The review also details the implications of MI-derived cell-free DNA for developing minimally invasive biomarkers and associated challenges.

Apolipoprotein E E3/E4 genotype is associated with an increased risk of type 2 diabetes mellitus complicated with coronary artery disease.

OBJECTIVE: Dyslipidemia is a co-existing problem in patients with diabetes mellitus (DM) and coronary artery disease (CAD), and apolipoprotein E (APOE) plays an important role in lipid metabolism. However, the relationship between the APOE gene polymorphisms and the risk of developing CAD in type 2 DM (T2DM) patients remains controversial. The aim of this study was to assess this relationship and provide a reference for further risk assessment of CAD in T2DM patients. METHODS: The study included 378 patients with T2DM complicated with CAD (T2DM + CAD) and 431 patients with T2DM alone in the case group, and 351 individuals without DM and CAD were set as controls. The APOE rs429358 and rs7412 polymorphisms were genotyped by polymerase chain reaction (PCR) - microarray. Differences in APOE genotypes and alleles between patients and controls were compared. Multiple logistic regression analysis was performed after adjusting for age, gender, body mass index (BMI), history of smoking, and history of drinking to access the relationship between APOE genotypes and T2DM + CAD risk. RESULTS: The frequencies of the APOE ɛ3/ɛ4 genotype and ε4 allele were higher in the T2DM + CAD patients, and the frequencies of the APOE ɛ3/ɛ3 genotype and ε3 allele were lower than those in the controls (all p < 0.05). The T2DM + CAD patients with ɛ4 allele had higher level in low-density lipoprotein cholesterol (LDL-C) than those in patients with ɛ2 and ɛ3 allele (p < 0.05). The results of logistic regression analysis showed that age ≥ 60 years old, and BMI ≥ 24.0 kg/m2 were independent risk factors for T2DM and T2DM + CAD, and APOE ɛ3/ɛ4 genotype (adjusted odds ratio (OR) = 1.93, 95% confidence interval (CI) = 1.18-3.14, p = 0.008) and ɛ4 allele (adjusted OR = 1.97, 95% CI = 1.23-3.17) were independent risk factors for T2DM + CAD. However, the APOE genotypes and alleles were not found to have relationship with the risk of T2DM. CONCLUSIONS: APOE ε3/ε4 genotype and ε4 allele were independent risk factors for T2DM complicated with CAD, but not for T2DM.

Association between CBS gene T833C, G919A and 844ins68 polymorphisms in the 8th exon region and coronary artery disease: a meta-analysis.

BACKGROUND: Several studies indicate that the cystathionine ß-synthase (CBS) gene T833C, G919A and 844ins68 polymorphisms in the 8th exon region may be correlated with coronary artery disease (CAD) susceptibility, but the results have been inconsistent and inconclusive. Thus, a meta-analysis was conducted to provide a comprehensive estimate of these associations. METHODS: On the basis of searches in the PubMed, EMBASE, Cochrane Library, Wanfang, VIP, and CNKI databases, we selected 14 case - control studies including 2123 cases and 2368 controls for this meta-analysis. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated accordingly using a fixed-effect or random-effect model. RESULTS: The results indicated an increased risk between the CBS T833C gene polymorphisms and susceptibility to CAD under the dominant model (CC+CT vs. TT: OR = 1.92, 95% CI: 1.11 ~ 3.32), recessive model (CC vs. CT+TT: OR = 1.88, 95% CI: 1.17 ~ 3.03), and homozygous model (CC vs. TT: OR = 2.46, 95% CI: 1.04 ~ 5.83). In these three genetic models, no significant association was identified for CBS G919A (AA+AG vs. GG: OR = 1.48, 95% CI: 0.45 ~ 4.82),(AA vs. AG+GG: OR = 1.58, 95% CI: 0.93 ~ 2.70),(AA vs. GG: OR = 1.66, 95% CI: 0.40 ~ 6.92) or CBS 844ins68 (II+ID vs. DD: OR = 1.04, 95% CI: 0.80 ~ 1.35),(II vs. ID+DD: OR = 1.09, 95% CI: 0.51 ~ 2.36),(II vs. DD: OR = 1.10, 95% CI: 0.51 ~ 2.39). CONCLUSIONS: This meta-analysis suggests that the CBS T833C gene polymorphism is significantly associated with the risk of CAD and it shows a stronger association in Asian populations. Individuals with the C allele of the CBS gene T833C polymorphism might be particularly susceptible to CAD.

Iron Status and Risk of Heart Disease, Stroke, and Diabetes: A Mendelian Randomization Study in European Adults.

BACKGROUND: The relevance of iron status biomarkers for coronary artery disease (CAD), heart failure (HF), ischemic stroke (IS), and type 2 diabetes (T2D) is uncertain. We compared the observational and Mendelian randomization (MR) analyses of iron status biomarkers and hemoglobin with these diseases. METHODS AND RESULTS: Observational analyses of hemoglobin were compared with genetically predicted hemoglobin with cardiovascular diseases and diabetes in the UK Biobank. Iron biomarkers included transferrin saturation, serum iron, ferritin, and total iron binding capacity. MR analyses assessed associations with CAD (CARDIOGRAMplusC4D [Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus The Coronary Artery Disease Genetics], n=181 522 cases), HF (HERMES [Heart Failure Molecular Epidemiology for Therapeutic Targets), n=115 150 cases), IS (GIGASTROKE, n=62 100 cases), and T2D (DIAMANTE [Diabetes Meta-Analysis of Trans-Ethnic Association Studies], n=80 154 cases) genome-wide consortia. Observational analyses demonstrated J-shaped associations of hemoglobin with CAD, HF, IS, and T2D. In contrast, MR analyses demonstrated linear positive associations of higher genetically predicted hemoglobin levels with 8% higher risk per 1 SD higher hemoglobin for CAD, 10% to 13% for diabetes, but not with IS or HF in UK Biobank. Bidirectional MR analyses confirmed the causal relevance of iron biomarkers for hemoglobin. Further MR analyses in global consortia demonstrated modest protective effects of iron biomarkers for CAD (7%-14% lower risk for 1 SD higher levels of iron biomarkers), adverse effects for T2D, but no associations with IS or HF. CONCLUSIONS: Higher levels of iron biomarkers were protective for CAD, had adverse effects on T2D, but had no effects on IS or HF. Randomized trials are now required to assess effects of iron supplements on risk of CAD in high-risk older people.

Genome-Wide Search Links Senescence-Associated Secretory Proteins With Susceptibility for Coronary Artery Disease in Mouse and Human.

Advanced age is an independent risk factor for coronary artery disease (CAD), the leading global cause of mortality. Senescent vascular cells in the atherosclerotic plaques exhibit senescence-associated secretory phenotype (SASP). How SASP contributes to atherosclerosis and CAD, however, remains unclear. Here, we integrated RNA-array datasets of senescent human coronary arterial endothelial cells (HCAECs) and aortic smooth muscle cells (HASMCs) as well as genome-wide association data for CAD. We identified 26 genes from HCAECs and 6 genes from HASMCs related to SASP and CAD in both in-house and published datasets. Of which, Cystatin C (CST3), a CAD susceptibility gene, was found to be expressed in both HCAECs and HASMCs, thus, it was prioritized for further investigation. We demonstrated it was significantly elevated in senescent vascular cells, aged arteries, and early atherosclerosis. In vitro experiments showed that CST3 enhances the monocyte-endothelial cell adhesion. Additionally, ligand-receptor pairing analyses revealed two important pathways, COL4A1-ITGA1 and LPL-LRP1 pathways, linked to the critical processes in the development of atherosclerosis, including cell adhesion, inflammation response, extracellular matrix organization, and lipid metabolism. We further demonstrated a reduced monocyte-endothelial cell adhesion following the knockdown of COL4A1 or ITGA1 and a significantly increased expression of COL4A1, ITGA1, and LPL in arterial intima of aged mice and ApoE-/- mice. Our findings demonstrate that vascular cell-derived SASP proteins increase the CAD susceptibility and identify CST3 functionally contributing to atherosclerosis.

Convergence of coronary artery disease genes onto endothelial cell programs.

Linking variants from genome-wide association studies (GWAS) to underlying mechanisms of disease remains a challenge1-3. For some diseases, a successful strategy has been to look for cases in which multiple GWAS loci contain genes that act in the same biological pathway1-6. However, our knowledge of which genes act in which pathways is incomplete, particularly for cell-type-specific pathways or understudied genes. Here we introduce a method to connect GWAS variants to functions. This method links variants to genes using epigenomics data, links genes to pathways de novo using Perturb-seq and integrates these data to identify convergence of GWAS loci onto pathways. We apply this approach to study the role of endothelial cells in genetic risk for coronary artery disease (CAD), and discover 43 CAD GWAS signals that converge on the cerebral cavernous malformation (CCM) signalling pathway. Two regulators of this pathway, CCM2 and TLNRD1, are each linked to a CAD risk variant, regulate other CAD risk genes and affect atheroprotective processes in endothelial cells. These results suggest a model whereby CAD risk is driven in part by the convergence of causal genes onto a particular transcriptional pathway in endothelial cells. They highlight shared genes between common and rare vascular diseases (CAD and CCM), and identify TLNRD1 as a new, previously uncharacterized member of the CCM signalling pathway. This approach will be widely useful for linking variants to functions for other common polygenic diseases.

Single-Cell Transcriptome Reveals Potential Mechanisms for Coronary Artery Lesions in Kawasaki Disease.

BACKGROUND: Coronary artery lesions (CALs) are the most common and major complication of Kawasaki disease (KD) in developed countries. However, the underlying immunologic mechanisms of CAL development in KD remain unclear. METHODS: Here, we conducted single-cell transcriptome analyses of 212 210 peripheral blood mononuclear cells collected from a cross-sectional cohort of 16 children, including 4 patients with KD with CALs, 5 patients with KD without CALs, 4 healthy controls, and 3 febrile controls. RESULTS: KD altered the proportion of peripheral blood mononuclear cells, including an increasing trend in inflammatory cells (megakaryocytes and monocytes) and a decreasing trend in lymphocytes (eg, CD4+ T, CD8+ T, mucosal-associated invariant T, natural killer, and γδ T cells), highlighting the potential presence of lymphopenia phenomenon in KD. Our data indicated the presence of inflammatory cytokine storm in patients with KD with CALs, caused by systemic upregulation of TNFSF13B (tumor necrosis factor superfamily member 13b), CXCL16 (C-X-C motif chemokine ligand 16), TNFSF10 (tumor necrosis factor superfamily member 10), and IL1RN (interleukin 1 receptor antagonist), mainly produced by monocytes (especially for the Mono_CD14-CD16 cluster) and megakaryocytes. We also found that myeloid cells of patients with KD, particularly in those with CALs, might play a role in vascular injury (eg, increased MMP [matrix metalloproteinase] 9, MMP17, and MMP25) and immune cell recruitment. The immune landscape of patients with KD with CALs was featured by lower exhaustion levels in natural killer cells, a high cytotoxic state in the CD8_Pro cluster, and activation of the complement system in monocytes. Additionally, the activation of B cells was more pronounced in the early stage of KD. CONCLUSIONS: Collectively, this study provides a comprehensive understanding of the roles of various immune cells and inflammatory cytokine storms in the development of CALs in KD and offers a valuable resource for identifying novel therapeutic targets for patients with KD with CALs.

Interleukin 6 polymorphisms are associated with cardiovascular risk factors in premature coronary artery disease patients and healthy controls of the GEA Mexican study.

BACKGROUND AND AIMS: Interleukin-6 (IL-6) is an acute-phase protein that plays an important role in the inflammatory response, vascular inflammation, and atherosclerosis process. The study aimed to establish whether IL-6 gene polymorphisms and IL-6 concentrations are associated with premature coronary artery disease (pCAD) and cardiovascular risk factors. METHODS: The IL-6 concentrations and the rs2069827, rs1800796, and rs1800795 IL-6 polymorphisms were determined in 1150 pCAD patients and 1083 healthy controls (coronary artery calcium equal to zero determined by tomography). RESULTS: The IL-6 polymorphisms studied were not associated with pCAD, but they were associated with cardiovascular risk factors in patients and controls. In controls, under the dominant model, the rs1800795 C allele and the rs2069827 T allele were associated with a low risk of central obesity (OR = 0.401, p = 0.017 and OR = 0.577, p = 0.031, respectively), hypoalphalipoproteinemia (OR = 0.581, p = 0.027 and OR = 0.700, p = 0.014, respectively) and hypertriglyceridemia (OR = 0.575, p = 0.030 and OR = 0.728, p = 0.033, respectively). In pCAD, the rs1800795 C allele was associated with an increased risk of hypoalphalipoproteinemia (OR = 1.370, padditive = 0.025) and increased C-reactive protein (CRP) concentrations (OR = 1.491, padditive = 0.007). pCAD patients had significantly higher serum IL-6 concentrations compared to controls (p = 0.002). In the total population, individuals carrying the rs1800795 GC + CC genotypes had higher levels of IL-6 than carriers of the GG genotype (p = 0.025). In control individuals carrying the C allele (CG + CC), an inverse correlation was observed between IL-6 and HDL-cholesterol levels (p = 0.003). CONCLUSIONS: In summary, the IL-6 polymorphisms were not associated with pCAD, however, they were associated with cardiovascular risk factors in pCAD patients and healthy controls. Individuals carrying the rs1800795 GC + CC genotypes had higher levels of IL-6 than carriers of the GG genotype.

Haplotype of the Lipoprotein(a) Gene Variants rs10455872 and rs3798220 Is Associated with Parameters of Coagulation, Fibrinolysis, and Inflammation in Patients after Myocardial Infarction and Highly Elevated Lipoprotein(a) Values.

Lipoprotein(a) (Lp(a)) is an independent risk factor for future coronary events. Variants rs10455872 and rs3798220 in the gene encoding Lp(a) are associated with an increased Lp(a) concentration and risk of coronary artery disease. We aimed to determine whether in high-risk coronary artery disease patients these two genetic variants and the kringle IV type 2 (KIV-2) repeats are associated with impairment of inflammatory and hemostatic parameters. Patients after myocardial infarction with elevated Lp(a) levels were included. Blood samples underwent biochemical and genetic analyses. In carriers of the AC haplotype, the concentrations of tumor necrosis factor (TNF)-α (4.46 vs. 3.91 ng/L, p = 0.046) and plasminogen activator inhibitor-1 (PAI-1) (p = 0.026) were significantly higher compared to non-carriers. The number of KIV-2 repeats was significantly associated with the concentration of high-sensitivity C-reactive protein (ρ = 0.251, p = 0.038) and overall fibrinolytic potential (r = -0.253, p = 0.038). In our patients, a direct association between the AC haplotype and both TNF-α and PAI-1 levels was observed. Our study shows that the number of KIV-2 repeats not only affects proatherosclerotic and proinflammatory effects of Lp(a) but is also associated with its antifibrinolytic properties.

Prediction of Coronary Artery Disease Risk Using Genetic and Phenotypic Variables.

Coronary artery disease (CAD) has the highest disease burden worldwide. To manage this burden, predictive models are required to screen patients for preventative treatment. A range of variables have been explored for their capacity to predict disease, including phenotypic (age, sex, BMI and smoking status), medical imaging (carotid artery thickness) and genotypic. We use a machine learning models and the UK Biobank cohort to measure the prediction capacity of these 3 variable categories, both in combination and isolation. We demonstrate that phenotypic variables from the Framingham risk score have the best prediction capacity, although a combination of phenotypic, medical imaging and genotypic variables deliver the most specific models. Furthermore, we demonstrate that Variant Spark, a random forest based GWAS platform, performs effective feature selection for SNP-based genotype variables, identifying 115 significantly associated SNPs to the CAD phenotype.

Impact of missense TSBP1 variants on the susceptibility to coronary heart disease.

BACKGROUND: A genome-wide association study has recognized C6orf10-BTNL2 polymorphism in coronary artery disease. The goal of this study was to explore the potential correlation of nine missense TSBP1 variants with coronary heart disease (CHD) risk in the Chinese Han population. METHODS: Nine TSBP1 missense single nucleotide polymorphisms (SNPs) were selected for genotyping by the Agena MassARRAY platform. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to analyze the contribution of TSBP1 SNPs to CHD predisposition by logistic regression models adjusted by age, sex, drinking, and smoking. The correlation of TSBP1 variants with clinical data in CHD patients was examined by Kruskal-Wallis test. RESULTS: rs9268368-C (p = 0.039, OR = 1.18, 95 % CI: 1.01-1.38) was related to an increased risk of CHD, while rs3749966-C (p = 0.032, OR = 0.49, 95 % CI: 0.25-0.96) and rs3129941-A (p = 0.011, OR = 0.74, 95 % CI: 0.59-0.93) might be protective factors against CHD occurrence in the Chinese Han population. We also observed the effects of demographic characteristics (age, sex, alcohol consumption, and smoking) and complications (hypertension and diabetes) on the interactive association of TSBP1 polymorphisms with CHD susceptibility. rs139993810 was related to the levels of high-density lipoprotein cholesterol (HDL-C, p = 0.030). CONCLUSIONS: Our findings determined the association of TSBP1 rs9268368, rs3749966, and rs3129941 with CHD occurrence in the Chinese Han population, and highlighted the influence of demographic characteristics and complications on the interactive association of TSBP1 polymorphisms with CHD risk.

Role of dysregulated macrophage subpopulation ratios and functional changes in the development of coronary atherosclerosis.

Coronary heart disease is one of the most significant risk factors affecting human health worldwide. Its pathogenesis is intricate, with atherosclerosis being widely regarded as the leading cause. Aberrant lipid metabolism in macrophages is recognized as one of the triggering factors in atherosclerosis development. To investigate the role of macrophages in the formation of coronary artery atherosclerosis, we utilized single-cell data from wild-type mice obtained from the aortic roots and ascending aortas after long-term high-fat diet feeding, as deposited in GSE131776. Seurat software was employed to refine the single-cell data in terms of scale and cell types, facilitating the identification of differentially expressed genes. Through the application of differential expression genes, we conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses at 0, 8 and 16 weeks, aiming to uncover pathways with the most pronounced functional alterations as the high-fat diet progressed. The AddModuleScore function was employed to score the expression of these pathways across different cell types. Subsequently, macrophages were isolated and further subdivided into subtypes, followed by an investigation into intercellular communication within these subtypes. Subsequent to this, we induced THP-1 cells to generate foam cells, validating critical genes identified in prior studies. The results revealed that macrophages underwent the most substantial functional changes as the high-fat diet progressed. Furthermore, two clusters were identified as potentially playing pivotal roles in macrophage functional regulation during high-fat diet progression. Additionally, macrophage subtypes displayed intricate functionalities, with mutual functional counterbalances observed among these subtypes. The proportions of macrophage subtypes and the modulation of anti-inflammatory and pro-inflammatory functions played significant roles in the development of coronary artery atherosclerosis.

Clonal hematopoiesis of indeterminate potential in persons with HIV.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with older age, inflammation and with risk of coronary artery disease (CAD). We aimed to characterize the burden of CHIP, and to explore the association between CHIP, inflammatory markers, and CAD in older persons with HIV (PWH). METHODS: From the Copenhagen Comorbidity in HIV Infection (COCOMO) study, we included 190 individuals older than 55 years of age. We defined CHIP as variant allele fraction at least 2%. CAD was categorized according to the most severe coronary artery lesion on coronary computed tomography (CT) angiography as no coronary atherosclerosis; any atherosclerosis defined as at least 1% stenosis and obstructive CAD defined as at least 50% stenosis. RESULTS: In the entire population (median age 66 years, 87% men), we identified a total of 62 mutations distributed among 49 (26%) participants. The three most mutated genes were DNMT3A , TET2 , and ASXL1 , accounting for 49, 25, and 16% of mutations, respectively. Age and sex were the only variables associated with CHIP. IL-1ß, IL-1Ra, IL-2, IL-6, IL-10, soluble CD14, soluble CD163 and TNF-α were not associated with CHIP, and CHIP was not associated with any atherosclerosis or with obstructive CAD in adjusted analyses. CONCLUSION: In older, well treated, Scandinavian PWH, more than one in four had at least one CHIP mutation. We did not find evidence of an association between CHIP and inflammatory markers or between CHIP and CAD. CHIP is an unlikely underlying mechanism to explain the association between inflammation and CAD in treated HIV disease.

Severity of coronary artery disease is associated with diminished circANRIL expression: A possible blood based transcriptional biomarker in East Africa.

Antisense Noncoding RNA in the INK4 Locus (ANRIL) is the prime candidate gene at Chr9p21, the well-defined genetic risk locus associated with coronary artery disease (CAD). ANRIL and its transcript variants were investigated for the susceptibility to CAD in adipose tissues (AT) and peripheral blood mononuclear cells (PBMCs) of the study group and the impact of 9p21.3 locus mutations was further analysed. Expressions of ANRIL, circANRIL (hsa_circ_0008574), NR003529, EU741058 and DQ485454 were detected in epicardial AT (EAT) mediastinal AT (MAT), subcutaneous AT (SAT) and PBMCs of CAD patients undergoing coronary artery bypass grafting and non-CAD patients undergoing heart valve surgery. ANRIL expression was significantly upregulated, while the expression of circANRIL was significantly downregulated in CAD patients. Decreased circANRIL levels were significantly associated with the severity of CAD and correlated with aggressive clinical characteristics. rs10757278 and rs10811656 were significantly associated with ANRIL and circANRIL expressions in AT and PBMCs. The ROC-curve analysis suggested that circANRIL has high diagnostic accuracy (AUC: 0.9808, cut-off: 0.33, sensitivity: 1.0, specificity: 0.88). circANRIL has high diagnostic accuracy (AUC: 0.9808, cut-off: 0.33, sensitivity: 1.0, specificity: 0.88). We report the first data demonstrating the presence of ANRIL and its transcript variants expressions in the AT and PBMCs of CAD patients. circANRIL having a synergetic effect with ANRIL plays a protective role in CAD pathogenesis. Therefore, altered circANRIL expression may become a potential diagnostic transcriptional biomarker for early CAD diagnosis.

The effect of miR-223-3p on endothelial cells in coronary artery disease.

Endothelial cell damage and dysfunction are crucial factors in the development and early stages of coronary artery disease (CAD) and apoptosis plays a significant role in this process. In this study, We aimed to simulate the CAD vascular microenvironment by treating endothelial cells with tumor necrosis factor alpha (TNF-α) to construct an endothelial cell apoptosis model. Our findings revealed that the TNF-α model resulted in increased micro-RNA 223-3p (miR-223-3p) mRNA and Bax protein expression, decreased kruppel-like factor 15 (KLF15) and Bcl-2 protein expression, and decreased cell viability. More importantly, in the TNF-α-induced endothelial cell apoptosis model, transfection with the miR-223-3p inhibitor reversed the effects of TNF-α on Bcl-2, Bax expression. We transfected miRNA-223-3p mimics or inhibitors into endothelial cells and assessed miR-223-3p levels using RT-PCR. Cell viability was detected using CCK8. Western blot technology was used to detect the expression of Bcl-2, Bax, and KLF15. In summary, this study demonstrates the role and possible mechanism of miR-223-3p in endothelial cells during CAD, suggesting that miR-223-3p may serve as a promising therapeutic target in CAD by regulating KLF15.