Coronary Artery Disease Susceptibility Research Articles

Associations of genetic variation and mRNA expression of PDGF/PDGFRB pathway genes with coronary artery disease in the Chinese population.

Platelet-derived growth factors (PDGFs) and receptors (PDGFR) play a key role in the process of coronary atherosclerosis. We aimed to investigate the association of genetic variations and mRNA expressions of PDGF/PDGFRB pathway genes with coronary artery disease (CAD). In this case-control study (3139 CAD vs. 3270 controls), 13 single nucleotide polymorphisms (SNPs) at five pathway genes were genotyped and combined to construct a weighted genetic risk score (wGRS). Three hundred and six pairs of cases and controls were selected for mRNA quantification. Restricted cubic spline (RCS) analyses were conducted for the dose-response relationship between wGRS, mRNAs and CAD. Area under the curve (AUC) was estimated to evaluate the discrimination of wGRS, mRNAs, and traditional risk factors (TRF) for CAD. The wGRS exhibited a positive linear relationship with CAD (p for linearity <0.001), and the medium and high wGRS had 37% and 50% increased risk of CAD compared to the low wGRS group (p = 1.5 × 10-4; p = 5.7 × 10-5). mRNA expression levels of five genes in peripheral blood leukocytes were all lower among patients at admission than controls (p < 0.001). The PDGF/PDGFRB mRNA expressions had significant non-linear correlations with AMI, with "U"-shaped trend for PDGFA, PDGFB and "L"-shaped trend for PDGFC, PDGFD and PDGFRB. Adding wGRS and mRNAs to the TRF model significantly improved the discrimination for CAD with an AUC of 0.921 (95% CI, 0.898-0.943). Genetic variations in the PDGF/PDGFRB pathway contribute to CAD susceptibility with a significantly joint effect. The down-regulated PDGF/PDGFRB mRNAs in peripheral leukocytes have the potential as blood-based biomarkers for CAD with high discriminative value.

Micro-capture-C in vessel wall cell types identifies mechanisms underlying coronary artery disease susceptibility loci

Abstract Genetics is estimated to account for 50% of Coronary Artery Disease (CAD) risk. Genome-Wide Association Studies (GWAS) have revealed 100s of genomic loci which are associated with CAD (1). However, moving from GWAS signals to causal genes has proved challenging, slowing progress in developing interventions for CAD and other diseases. The greatest challenge in interpreting GWAS data is that only 10% of variants are in protein-coding regions and 90% are in "non-coding" genomic regions. Many of these non-coding variants are found in regulatory elements such as enhancers. Enhancers are distal regulatory elements that bind transcription factors and regulate genes up to 1 million base pairs away. This is achieved by DNA looping bringing enhancers into physical proximity with target genes. However, it is not possible to predict which gene(s) a given enhancer will regulate based on genomic location alone. We aimed to develop a generalisable workflow to solve CAD GWAS signals accurately and sensitively, by identifying causal enhancer SNPs and linking them mechanistically to output genes in a cell-type specific manner. We combined cell-specific epigenomic mapping with machine learning to prioritise 21,959 SNPs from 861 candidate CAD loci, in endothelial cells (HUVECs) and smooth muscle cells (HCASMCs). Micro-Capture-C (MCC) was used to resolve enhancer-promoter interactions at base-pair resolution (2). MNase footprinting determined differential transcription factor binding at specific enhancer SNPs. In HCASMCs, 20 putative enhancers containing CAD SNPs were found to interact with 32 genes, and in HUVECs 25 enhancers interacted with 48 genes. These genes were enriched for pathways including TGFb signalling, RUNX3 activity, and MAPK6/MAPK4 signalling. To prove causality at specific loci, heterozygous SNPs were identified in the individual primary cell lines. The interaction frequency at these elements was statistically compared between risk and non-risk alleles. For example, at the 9p21.3 locus, an enhancer containing a non-risk T allele was found to interact more strongly with the CDKN2B gene, compared to the risk G allele. Interestingly, this imbalance between allele interaction was potentiated by stimulation with TGFb, a key mediator in atherosclerosis. Furthermore, the transcription factor footprint at the SNP location was altered by the risk allele, indicating the mechanistic cause of the CAD-associated change in CDKN2B expression. We demonstrate a combined computational and experimental approach to identify causal non-coding variants in CAD risk loci, at scale. Among the key outputs of this study is the identification of the risk variant (rs1537373), output gene (CDKN2B), and specific cell type (HCASMC) underlying the 9p21.3 locus association with CAD risk. Using this approach to translate GWAS signals into cell-type specific outputs genes, will lead to a better understanding of the pathogenesis of CAD, and new therapeutic opportunities.

Genetic Associations of Plasminogen Activator Inhibitor-1-Related miRNA Variants with Coronary Artery Disease.

Coronary artery disease (CAD) is one of the most common types of cardiovascular disease and can lead to a heart attack as plaque gradually builds up inside the coronary arteries, blocking blood flow. Previous studies have shown that polymorphisms in the PAI-1 gene are associated with CAD; however, studies of the PAI-1 3'-untranslated region, containing a miRNA binding site, and the miRNAs that interact with it, are insufficient. To investigate the association between miRNA polymorphisms and CAD in the Korean population based on post-transcriptional regulation, we genotyped five polymorphisms in four miRNAs targeting the 3'-untranslated region of PAI-1 using real-time PCR and TaqMan assays. We found that the mutant genotype of miR-30c rs928508 A > G was strongly associated with increased CAD susceptibility. In a genotype combination analysis, the combination of the homozygous mutant genotype (GG) of miR-30c rs928508 with the wild-type genotype (GG) of miR-143 rs41291957 resulted in increased risk for CAD. Also, in an allele combination analysis, the combination of the mutant allele (G) of miR-30c rs928508 and the wild-type allele (G) of miR-143 rs41291957 resulted in increased risk for CAD. Furthermore, metabolic syndrome and diabetes mellitus showed synergistic effects on CAD risk when combined with miR-30c rs928508. These results can be applied to identify CAD prognostic biomarkers among miRNA polymorphisms and various clinical factors.

Carina: A major determinant in the pathophysiology and treatment of coronary bifurcation lesions.

Over the last decade, several in vivo and computational investigations have significantly advanced our understanding of the pathophysiology of coronary bifurcations, contributing to the enhancement of their percutaneous revascularization. The carina of the coronary bifurcations plays a substantial role in generating their main hemodynamic features, including distinctive flow patterns with secondary flows and specific shear stress patterns. These factors play a pivotal role in determining the susceptibility, development, and progression of atherosclerosis. The underlying pathophysiological mechanisms of atherosclerosis in coronary bifurcations are complex and multifactorial. Understanding these mechanisms is fundamental to comprehending lesions at the bifurcation level and informing future treatment strategies. This review aims to present the currently available data regarding the pathophysiological and prognostic role of the carina in coronary bifurcations, offering an interpretation of these findings from the perspective of interventional cardiologists, providing valuable insights for their clinical practice.

Lack of association between the -2549 insertion/deletion variant of vascular endothelial growth factor and coronary artery disease in the Turkish population.

Coronary artery disease is the leading cause of death worldwide. Vascular endothelial growth factor is known to induce endothelial cell migration and proliferation, increase vascular permeability, and modulate thrombogenicity. The aim of this study is to investigate the relationship between the VEGF insertion/deletion (I/D) variant (rs35569394) and coronary artery disease susceptibility in the Turkish population. A total of 206 subjects, including 106 coronary artery disease patients and 100 controls, were included in this study. The VEGF I/D variant was genotyped using the polymerase chain reaction method. The frequency of the I/I, I/D, and D/D genotypes was 35.84 versus 37%, 33.97 versus 36%, and 30.19 versus 27% in patients and the control group, respectively. VEGF I/D genotype and allele distribution were not statistically significant between coronary artery disease patients and controls (p>0.05). There was no significant difference between VEGF I/D genotype distribution and patient characteristics including age, gender, disease duration, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, history of hypertension, history of diabetes mellitus, and smoking (p>0.05). This study suggests that the VEGF I/D variant is not a predisposing factor to coronary artery disease disease in a Turkish sample.

Abstract Mo084: Stem Cell-Based Functional Genomics Unravel A Novel Vascular Smooth Muscle Cell State Induced By The 9p21 Coronary Artery Disease Risk Locus

Background: Genome-wide association studies have identified common genetic variants (Single Nucleotide Polymorphisms – SNPs) at ~300 human genomic loci linked to coronary artery disease (CAD) susceptibility. Among these genomic regions, the most impactful is the 9p21.3 CAD risk locus, which spans a 60 kb gene desert and encompasses ~80 SNPs in high linkage disequilibrium. We have previously generated isogenic induced Pluripotent Stem Cells (iPSCs) lines from risk and non-risk donors at 9p21.3 and performed a complete deletion of the locus. By using iPSC-derived vascular smooth muscle cells (iPSC-VSMCs) we demonstrated that the risk haplotype at 9p21.3 causes altered expression of numerous genes essential for muscle function, including contraction and adhesion. Notably, deletion of the risk haplotype restores the non-risk phenotype, suggesting a gain of function effect. Here, we aimed to identify the transcriptomic signature and state trajectories of VSMCs induced by the 9p21.3 risk haplotype and validate them through functional assays and ex-vivo analysis of human coronary arteries. Methods: We have used iPSCs from individuals carrying the risk and non-risk haplotype at 9p21.3 and isogenic knockout lines. After VSMCs differentiation induction, mature VSMCs were used for single cell RNA sequencing using 10X Chromium platform and functional assays. Results: Our analysis revealed that the 9p21.3 risk haplotype prompts VSMCs to acquire a novel cellular state showing reduced plasticity and divergent from other VSMC states previously linked to CAD. We found markers of alternative lineages, including osteogenic and neuronal, coupled with altered expression of genes within other CAD loci, and functional defects. We identified a set of new molecular markers crucial to define risk-associated VSMCs and uncovered their upstream regulators. Conclusions: Our study provides insights into CAD pathogenesis driven by the 9p21.3 risk locus and identified new gene regulatory networks essential for maintaining the normal functionality of the muscle layer of the arteries. Leveraging the power of iPSCs we present novel concepts about the biology of VSMCs and shed light on the impact of the strongest CAD genetic risk factor in preserving a healthy cellular state within the vasculature.

The 9p21.3 coronary artery disease risk locus drives vascular smooth muscle cells to an osteochondrogenic state.

Genome-wide association studies have identified common genetic variants at ~400 human genomic loci linked to coronary artery disease (CAD) susceptibility. Among these genomic regions, the most impactful is the 9p21.3 CAD risk locus, which spans a 60 kb gene desert and encompasses ~80 SNPs in high linkage disequilibrium. Despite nearly two decades since its discovery, the functional mechanism of this genomic region remains incompletely resolved. To investigate the transcriptional gene programs mediated by 9p21.3 risk locus, we applied a model of induced pluripotent stem cells (iPSCs) from risk and non-risk donors at 9p21.3, as well as isogenic lines with a full haplotype deletion. Upon differentiation to vascular smooth muscle cells (VSMC), single-cell transcriptomic profiling demonstrated iPSC-VSMC phenotypes resembling those from native human coronary arteries, confirming the robustness of this model. Remarkably, our analyses revealed that VSMCs harboring the 9p21.3 risk haplotype preferentially adopt an osteochondrogenic state. Importantly, we identified LIMCH1 and CRABP1 as signature genes critical for defining this transcriptional program. Our study provides new insights into the mechanism at the 9p21.3 risk locus and defines its role in driving a disease-prone transcriptional state in VSMCs.

Modifiable risk factors, oxidative stress markers, and SOD2 rs4880 SNP in coronary artery disease: an association study.

Coronary artery disease (CAD) has been linked to single nucleotide polymorphism (SNP) in superoxide dismutase 2 (SOD 2) gene. Additionally, several modifiable risk factors are also known to influence the CAD risk. To investigate the association between selected modifiable risk factors and oxidative stress markers with the SOD2 rs4880 SNP in CAD patients. A cohort of 150 angiographically confirmed CAD patients, and 100 control subjects in the same geographic area were enrolled. SOD levels and lipid peroxidation were assessed in the blood samples using standard protocols. The genotyping of the SOD2 gene was conducted through the PCR-sequencing method. This study indicated that CAD patients with the rs4880 SNP having heterozygous AG and mutated homozygous GG genotypes have increased oxidative stress, decreased SOD activity, and a positive association with CAD risk (OR 2.85) in comparison with control individuals. The investigation among CAD patients was then carried out based on modifiable risk factors. The risk factors selected were clinical characteristics, physical habits, nutritional status, and body mass index. In all the cases, MDA levels showed a positive association, and SOD activity showed a negative association with the selected polymorphism. The study suggests that the selected modifiable risk factors have an important role in the higher oxidative stress found in patients, which may lead to SOD2 polymorphism. It also suggests that the SOD2 locus can be identified as a marker gene for CAD susceptibility.

Mendelian randomization analyses clarify the effects of height on cardiovascular diseases.

An inverse correlation between stature and risk of coronary artery disease (CAD) has been observed in several epidemiologic studies, and recent Mendelian randomization (MR) experiments have suggested causal association. However, the extent to which the effect estimated by MR can be explained by cardiovascular, anthropometric, lung function, and lifestyle-related risk factors is unclear, with a recent report suggesting that lung function traits could fully explain the height-CAD effect. To clarify this relationship, we utilized a well-powered set of genetic instruments for human stature, comprising >1,800 genetic variants for height and CAD. In univariable analysis, we confirmed that a one standard deviation decrease in height (~6.5 cm) was associated with a 12.0% increase in the risk of CAD, consistent with previous reports. In multivariable analysis accounting for effects from up to 12 established risk factors, we observed a >3-fold attenuation in the causal effect of height on CAD susceptibility (3.7%, p = 0.02). However, multivariable analyses demonstrated independent effects of height on other cardiovascular traits beyond CAD, consistent with epidemiologic associations and univariable MR experiments. In contrast with published reports, we observed minimal effects of lung function traits on CAD risk in our analyses, indicating that these traits are unlikely to explain the residual association between height and CAD risk. In sum, these results suggest the impact of height on CAD risk beyond previously established cardiovascular risk factors is minimal and not explained by lung function measures.

Abstract 2072: The 9p21.3 Coronary Artery Disease Risk Locus Induces Cell State Transitions In Vascular Smooth Muscle Cells

Background: Genome-wide association studies have identified common genetic variants (Single Nucleotide Polymorphisms - SNPs) at ~300 human genomic loci linked to coronary artery disease (CAD) susceptibility. Among these genomic regions, the most impactful is the 9p21.3 CAD risk locus, which spans a 60 kb gene desert and encompasses ~80 SNPs in high linkage disequilibrium. We have previously generated isogenic induced Pluripotent Stem Cells (iPSCs) lines from risk and non-risk donors at 9p21.3 and performed a complete deletion of the locus. By using iPSC-derived vascular smooth muscle cells (iPSC-VSMCs) we demonstrated that the risk haplotype at 9p21.3 causes altered expression of numerous genes essential for muscle function, including contraction and adhesion. Notably, deletion of the risk haplotype restores the non-risk phenotype, suggesting a gain of function effect. Hypothesis: The 9p21.3 risk haplotype alters VSMCs plasticity and induces dedifferentiation and alternative lineage acquisition. Aims: Identify transcriptomic signatures and trajectories of VSMCs induced by the 9p21.3 risk haplotype Methods: We have used iPSCs from individuals carrying the risk and non-risk haplotype at 9p21.3 and isogenic knockout lines. After VSMCs differentiation induction, mature VSMCs were used for single cell RNA sequencing using 10X Chromium platform. Results: Our analysis revealed that the 9p21.3 risk haplotype prompts VSMCs to acquire a novel cellular state showing reduced plasticity and divergent from other VSMC states previously linked to CAD. We found markers of alternative lineages, including osteogenic and neuronal, coupled with altered expression of genes within other CAD loci. We identified a set of new molecular markers crucial to define risk-associated VSMCs and uncovered their upstream regulators. Conclusions: Our study provides insights into CAD pathogenesis driven by the 9p21.3 risk locus and identified new gene regulatory networks essential for maintaining the normal functionality of the muscle layer of the arteries. Leveraging the power of iPSCs we present novel concepts about the biology of VSMCs and shed light on the impact of CAD genetic risk factors in preserving a healthy cellular state within the vasculature.

The potential influence of GSTT1 null genetic polymorphism on coronary artery disease: A pilot study in a South Indian cohort

BackgroundIndians are known to have the highest rates of coronary artery disease (CAD), with the conventional risk factors failing to explain the increased risk. Possible candidate genes to study both the environmental and genetic risk associated with CAD is the glutathione S-transferase (GST) family, as it is involved in detoxification. MethodsThis case–control assessed the association between GSTM1 and GSTT1 polymorphisms in Indian patients with CAD. Fifty patients with CAD and 50 healthy volunteers were genotyped for the two polymorphisms by polymerase chain reaction. The genotype frequencies between the groups were compared, where a p-value of less than 0.05 was considered as statistically significant. ResultsThere was a significant inverse association between GSTT1 null polymorphism and CAD susceptibility.

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.

Contribution of genetic variants in the development of familial premature coronary artery disease in a cohort of cardiac patients.

Coronary artery disease (CAD), the most prevalent cardiovascular disease, is the leading cause of death worldwide. Heritable factors play a significant role in the pathogenesis of CAD. It has been proposed that approximately one-third of patients with CAD have a positive family history, and individuals with such history are at ~1.5-fold increased risk of CAD in their lifespans. Accordingly, the long-recognized familial clustering of CAD is a strong risk factor for this disease. Our study aimed to identify candidate genetic variants contributing to CAD by studying a cohort of 60 large Iranian families with at least two members in different generations afflicted with premature CAD (PCAD), defined as established disease at ≤45 years in men and ≤55 years in women. Exome sequencing was performed for a subset of the affected individuals, followed by prioritization and Sanger sequencing of candidate variants in all available family members. Subsequently, apparently healthy carriers of potential risk variants underwent coronary computed tomography angiography (CCTA), followed by co-segregation analysis of the combined data. Putative causal variants were identified in seven genes, ABCG8, CD36, CYP27A1, PIK3C2G, RASSF9, RYR2, and ZFYVE21, co-segregating with familial PCAD in seven unrelated families. Among these, PIK3C2G, RASSF9, and ZFYVE21 are novel candidate CAD susceptibility genes. Our findings indicate that rare variants in genes identified in this study are involved in CAD development.

MRAS in coronary artery disease-Unchartered territory.

Genome-wide association studies (GWAS) have identified coronary artery disease (CAD) susceptibility locus on chromosome 3q22.3. This locus contains a cluster of several genes that includes muscle rat sarcoma virus (MRAS). Common MRAS variants are also associated with CAD causing risk factors such as hypertension, dyslipidemia, obesity, and type II diabetes. The MRAS gene is an oncogene that encodes a membrane-bound small GTPase. It is involved in a variety of signaling pathways, regulating cell differentiation and cell survival (mitogen-activated protein kinase [MAPK]/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase) as well as acute phase response signaling (tumor necrosis factor [TNF] and interleukin 6 [IL6] signaling). In this review, we will summarize the role of genetic MRAS variants in the etiology of CAD and its comorbidities with the focus on tissue distribution of MRAS isoforms, cell type/tissue specificity, and mode of action of single nucleotide variants in MRAS associated complex traits. Finally, we postulate that CAD risk variants in the MRAS locus are specific to smooth muscle cells and lead to higher levels of MRAS, particularly in arterial and cardiac tissue, resulting in MAPK-dependent tissue hypertrophy or hyperplasia.

Association between haptoglobin polymorphism and coronary artery disease: a meta-analysis.

Previous studies have investigated the association between the haptoglobin rs72294371 polymorphism and coronary artery disease (CAD) risk, but the results are controversial and uncertain. Therefore, this study aimed to systematically review the literature on haptoglobin polymorphism and susceptibility to CAD. PubMed, Embase, Web of Science, Cochrane Library, and Wanfang databases were used to identify relevant studies from their inception to April 2024. The pooled odds ratio (OR) with corresponding 95% confidence interval (CI) were used to assess the strength of the association. An OR value greater than one suggested an increased risk; otherwise, it suggested a protective risk. A total of 15 studies comprising 8,632 individuals (2,988 cases and 5,644 controls) were included. In the current meta-analysis, a significant association between haptoglobin polymorphism and CAD was found under recessive model (OR:0.74, 95% CI:0.60-0.92), dominant model (OR: 0.82, 95% CI: 0.71-0.95), homozygote model (OR: 0.70, 95% CI: 0.53-0.92), and allelic genetic model (OR: 0.80, 95% CI: 0.69-0.94). In the analysis stratified by ethnicity, a statistically significant association was observed in Asians rather than Caucasian population. This meta-analysis indicates that haptoglobin polymorphism is associated with CAD susceptibility, especially in Asians.

Sleep quality associate with the increased prevalence of cognitive impairment in coronary artery disease patients: A retrospective case-control study.

The pathogenesis of cognitive impairment (CI) in coronary artery disease (CAD) patients is still unclear and numerous influence factors could affect the CI status. The current studies suggest that sleep quality and behavior pattern are significant influence factors associated with CAD susceptibility. A total of 223 participants including 90 CAD patients with CI and 133 controls were enrolled into this retrospective study. Demographic information, laboratory test results, clinical diagnostic data, and questionnaire survey were collected to recognize the influencing factors of CI in CAD patients. Appropriate statistical methods are used to analyze these collected data. Univariate analysis results of demographic information, laboratory test results, and questionnaire survey data revealed that the differences in fatigue symptom, age, HDL, TG, and sleep quality were statistically significant (p = 0.006, p = 0.000, p = 0.019, p = 0.028, and p = 0.037, respectively). Logistic regression analysis showed that age, fatigue, and sleep quality were the influence factors for CI in CAD population (p = 0.000, p = 0.035, and p = 0.017). Sleep quality, fatigue, and age were associated with the increased susceptibility of CI in CAD patients. Both CI state and its related factors were involved in the pathological process of CAD, these findings could offer additional information for the prevention and control of CAD.

Genetically predicted HLA-DR+ natural killer cells as potential mediators in the lipid-coronary artery disease/ calcification (CAD/CAC) causal pathway.

Coronary artery disease (CAD) imposes a significant global health burden, necessitating a deeper comprehension of its genetic foundations to uncover innovative therapeutic targets. Employing a comprehensive Mendelian randomization (MR) approach, we aimed to explore the genetic associations between lipid profiles, immune cell phenotypes, and CAD risk. Utilizing data from recent large-scale genome-wide association studies (GWAS), we scrutinized 179 lipid and 731 immune cell phenotypes to delineate their genetic contributions to CAD pathogenesis, including coronary artery calcification (CAC). Moreover, specific immune cell phenotypes were examined as potential mediators of the lipid-CAD/CAC causal pathway. Among the 162 lipid species with qualified instrumental variables (IVs) included in the analysis, we identified 36 lipids that exhibit a genetic causal relationship with CAD, with 29 being risk factors and 7 serving as protective factors. Phosphatidylethanolamine (18:0_20:4) with 8 IVs (OR, 95% CI, P-value: 1.04, 1.02-1.06, 1.50E-04) met the Bonferroni-corrected significance threshold (0.05/162=3.09E-04). Notably, all 18 shared lipids were determined to be risk factors for both CAD and CAC, including 16 triacylglycerol traits (15 of which had ≥ 3 IVs), with (50:1) exhibiting the highest risk [OR (95% CI) in CAC: 1.428 (1.129-1.807); OR (95% CI) in CAD: 1.119 (1.046-1.198)], and 2 diacylglycerol traits. Furthermore, we identified HLA DR+ natural killer cells (IVs = 3) as nominally significant with lipids and as potential mediators in the causal pathway between diacylglycerol (16:1_18:1) or various triacylglycerols and CAD (mediated effect: 0.007 to 0.013). This study provides preliminary insights into the genetic correlations between lipid metabolism, immune cell dynamics, and CAD susceptibility, highlighting the potential involvement of natural killer cells in the lipid-CAD/CAC causal pathway and suggesting new targets for therapy. Further evidence is necessary to substantiate our findings.

Coronary artery disease patients with rs7904519 (TCF7L2) are at a persistent risk of type 2 diabetes

AimsType 2 diabetes (T2D) and coronary artery disease (CAD) often coexist and share genetic factors.This study aimed to investigate the common genetic factors underlying T2D and CAD in patients with CAD. MethodsA three-step association approach was conducted: a) a discovery step involving 943 CAD patients with T2D and 1,149 CAD patients without T2D; b) an eliminating step to exclude CAD or T2D specific variants; and c) a replication step using the UK Biobank data. ResultsTen genetic loci were associated with T2D in CAD patients. Three variants were specific to either CAD or T2D. Five variants lost significance after adjusting for covariates, while two SNPs remained associated with T2D in CAD patients (rs7904519*G: TCF7L2 and rs17608766*C: GOSR2). The T2D susceptibility rs7904519*G was associated with increased T2D risk, while the CAD susceptibility rs17608766*C was negatively associated with T2D in CAD patients. These associations were replicated in a UK Biobank data, confirming the results. ConclusionsNo significant common T2D and CAD susceptibility genetic association was demonstrated indicating distinct disease pathways. However, CAD patients carrying the T2D susceptibility gene TCF7L2 remain at higher risk for developing T2D emphasizing the need for frequent monitoring in this subgroup.

Association of epistatic effects of MTHFR, ACE, APOB, and APOE gene polymorphisms with the risk of myocardial infarction and unstable angina in Egyptian patients

Despite remarkable discoveries in the genetic susceptibility of coronary artery disease (CAD), a large part of heritability awaits identification. Epistasis or gene‐gene interaction has a profound influence on CAD and might contribute to its missed genetic variability; however, this impact was largely unexplored. Here, we appraised the associations of gene-gene interactions and haplotypes of five polymorphisms, namely methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, angiotensin converting enzyme (ACE) insertion/deletion (I/D), apolipoprotein B (APOB) R3500Q, and apolipoprotein E (APOE) ε4 with the risk of myocardial infarction (MI) and unstable angina (UA). Gene-environment interactions with traditional risk factors and clinical data were also scrutinized. This study recruited 100 MI, 50 UA patients, and 100 apparently healthy controls. Logistic regression models were employed in association analyses. We remarked that the single locus effect of individual polymorphisms was relatively weak; however, a magnified effect of their combination via gene-gene interaction may predict MI risk after adjustment for multiple comparisons. Only MTHFR C677T, ACE I/D, and APOB R5300Q were associated with the risk of UA, and the ACE I/D-R3500Q interaction posed a decreased UA risk. APOB R3500Q was in strong linkage disequilibrium with MTHFR C677T, ACE I/D, and APE ε4 polymorphisms. The TCDGε3, CADGε4, and TADGε4-C677T-A1298C-ACE I/D-R3500Q-APOE haplotypes were associated with escalating MI risk, while the CDG or CIG-C677T-ACE I/D-R3500Q haplotype was highly protective against UA risk compared to controls. Interestingly, the CADGε4 and CAIGε3 haplotypes were strongly associated with the presence of diabetes and hypertension, respectively in MI patients; both haplotypes stratified patients according to the ECHO results. In UA, the CDG haplotype was negatively associated with the presence of diabetes or dilated heart. Conclusively, our results advocate that a stronger combined effect of polymorphisms in MTHFR, ACE, APOB, and APOE genes via gene-gene and gene-environment interactions might help in risk stratification of MI and UA patients.

PSRC1 rs599839 G allele may promote protection from coronary artery disease in a Madeira Island population

Abstract Previous research associates the PSRC1 gene on the chromosomal locus 1p13.3 with coronary artery disease (CAD). Specifically, the A wild allele of the PSRC1 rs599539 A&amp;gt;G was identified as a risk allele for CAD, and the mutated G minor allele with a reduced risk of CAD. However, the underlying genetic mechanism is not yet fully understood and is controversial in other populations. Aim To investigate the association of rs599839 A&amp;gt;G variant with CAD risk and lipid profile in a Portuguese population from Madeira Island. Materials and Methods We performed a case-control study including 3161 participants, 1724 patients with CAD (78.7% male) and 1437 controls (76.3% male). Coronary patients were recruited from the Madeira Central Hospital, and controls were from the normal population. PSRC1 was genotyped by TaqMan allelic discrimination assay (Applied Biosystems, 7300 Real-Time PCR). Pearson´s Chi-squared test evaluated the association between CAD-genotypes and the t Student test for genotypes-lipid levels. Results PSRC1 rs599839 A&amp;gt;G variant was within Hardy -Weinberg equilibrium. The wild dominant model (AA+AG) conferred a trend for CAD risk (OR=1.16; p=0.414), and the mutated dominant model (GG+GA) presented slight protection for CAD susceptibility. However, the minor G (protector) allele was associated with low levels of total cholesterol (p=0.003) and LDL-cholesterol (p=0.004). Conclusions This finding is consistent with previous reports indicating a decrease in LDL-C and total cholesterol levels in carriers of the minor allele G of rs599839. Recent research refers that this allele could affect PSRC1 expression, resulting in lower levels of LDL cholesterol and reduced risk of CAD. In contrast, the A wild allele is associated with high LDL levels. PSRC1, lipid, and CAD risk is a complex topic involving genetic, epigenetic and environmental factors.