Abstract 12291: Contribution of Rare Mutations in Mendelian Hypercholesterolemia Genes to Risk for Premature Coronary Artery Disease in the Population

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Hong-Hee Won ◽  
Ron Do ◽  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Null Allele ◽  
Coronary Revascularization ◽  
Null Alleles ◽  
Premature Coronary Artery Disease ◽  
Rare Mutations ◽  
Increased Risk ◽  
Artery Disease ◽  
Cad Risk

Introduction: Low-density lipoprotein cholesterol (LDL-C) is a causal risk factor for coronary artery disease (CAD). Rare mutations in at least 6 genes lead to Mendelian forms of high or reduced LDL-C; three ( APOB, LDLR, PCSK9 ) act in a dominant pattern whereas three ( ABCG5, ABCG8, LDLRAP1 ) in a recessive pattern. We address to what extent rare mutations in Mendelian LDL-C genes contribute to early CAD risk in the population. Methods: We sequenced the exons of the 6 genes in 9,329 early CAD cases (myocardial infarction, angiographic CAD, or coronary revascularization in men≤50 and women≤60) and 10,245 controls from 9 studies using targeted and whole exome next-generation sequencing. We tested 3 sets: ‘Null alleles’ (nonsense, splice-site, or frameshift); ‘Deleterious (7/7)’ (null and missense annotated as damaging by 7 algorithms); and ‘Deleterious (6/7)’ (null and missense annotated as damaging by at least 6 algorithms). Given the rarity of deleterious mutations, we aggregated these mutations in each gene and tested for an excess or deficit in cases vs . controls. Results: Counts of mutations are provided in Table. Null mutations in LDLR , carried by 1:500 participants, confered a 8-fold increase in CAD risk (P=8х10 -7 ) whereas heterozygosity for a null mutation in ABCG5 (1:650 frequency) was associated with a 3-fold increased risk (P=5х10 -3 ). ‘Deleterious (7/7)’ mutations in LDLR , carried by 1:100 participants, confered a 4-fold increased risk (P=8х10 -17 ) whereas heterozygosity for a ‘Deleterious (7/7)’ mutation in ABCG5 (1:250 frequency) was associated with a 2-fold increased risk (P=2х10 -3 ). Heterozygous null allele carriers at LDLR and ABCG5 had increased LDL-C (P<0.001). Conclusions: Of early CAD cases, 2-3% carry a rare, deleterious mutation at LDLR or ABCG5 associated with increased risk. Although previously reported to cause recessive sitosterolemia, we find that heterozygosity for a null allele at ABCG5 is associated with markedly higher early CAD risk.

Abstract 13601: Risk of Coronary Artery Disease Associated With Familial Hypercholesterolemia Genetic Variants is Independent of Historical Low-density Lipoprotein Cholesterol Exposure

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Shoa L Clarke ◽  
Catherine Tcheandjieu ◽  
Austin Hilliard ◽  
Kyung Min Lee ◽  
julie lynch ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Familial Hypercholesterolemia ◽  
Index Date ◽  
Coronary Revascularization ◽  
African Ancestry ◽  
Increased Risk ◽  
Artery Disease ◽  
Incident Cases ◽  
Cad Risk

Introduction: Familial Hypercholesterolemia (FH) variants confer risk for coronary artery disease (CAD) even after adjusting for a single baseline LDL measure. Hypothesis: We hypothesized that a model incorporating serial LDL measures over many years may account for the risk associated with FH variants. Methods: We analyzed 418,790 participants in the Million Veteran Program with electronic health records (EHR) spanning up to 15 years prior to and 7 years after enrollment. FH variants were defined using ClinVar and standard bioinformatic approaches. Carriers were identified by custom genotype array. CAD cases were identified by chart codes for acute MI and coronary revascularization. We used a nested case-control design conditional on survival to enrollment. Controls were matched on year of first LDL, time between first LDL and the case index date, age, sex, and ancestry. Logistic regression was used to estimate CAD risk among FH carriers while adjusting for CAD risk factors and the first, maximum (max), or mean LDL prior to the index date. Results: We found 53 LDLR , 2 APOB , and 2 PCSK9 variants, and FH prevalence was 1:303. We identified 23,091 cases with ≥1 LDL measure prior to the diagnosis of CAD and matched 10 controls per case. Cases had a median of 6 LDL measures over a median of 49 months prior to the index date. Carriers had an increased risk for CAD compared to non-carriers. Adjusting for the first, max, and mean LDL progressively attenuated risk of CAD associated with FH, but residual FH risk remained substantial ( Figure ). This pattern did not change in the subset of subjects with the most extensive LDL data nor in the subset of incident cases. We additionally found evidence of modifying effects of sex and ancestry, with higher within-group risk for females and subjects of African ancestry ( Figure ). Conclusion: The risk associated with FH variants cannot be fully captured by the LDL data available in the EHR, even when considering multiple LDL measurements spanning several years.

scholarly journals Impact of established cardiovascular disease on 10-year death after coronary revascularization for complex coronary artery disease

2021 ◽  
Author(s):  
Rutao Wang ◽  
Scot Garg ◽  
Chao Gao ◽  
Hideyuki Kawashima ◽  
Masafumi Ono ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Coronary Revascularization ◽  
Long Term Outcomes ◽  
Vital Status ◽  
Increased Risk ◽  
Artery Disease ◽  
The Impact

Abstract Aims To investigate the impact of established cardiovascular disease (CVD) on 10-year all-cause death following coronary revascularization in patients with complex coronary artery disease (CAD). Methods The SYNTAXES study assessed vital status out to 10 years of patients with complex CAD enrolled in the SYNTAX trial. The relative efficacy of PCI versus CABG in terms of 10-year all-cause death was assessed according to co-existing CVD. Results Established CVD status was recorded in 1771 (98.3%) patients, of whom 827 (46.7%) had established CVD. Compared to those without CVD, patients with CVD had a significantly higher risk of 10-year all-cause death (31.4% vs. 21.7%; adjusted HR: 1.40; 95% CI 1.08–1.80, p = 0.010). In patients with CVD, PCI had a non-significant numerically higher risk of 10-year all-cause death compared with CABG (35.9% vs. 27.2%; adjusted HR: 1.14; 95% CI 0.83–1.58, p = 0.412). The relative treatment effects of PCI versus CABG on 10-year all-cause death in patients with complex CAD were similar irrespective of the presence of CVD (p-interaction = 0.986). Only those patients with CVD in ≥ 2 territories had a higher risk of 10-year all-cause death (adjusted HR: 2.99, 95% CI 2.11–4.23, p < 0.001) compared to those without CVD. Conclusions The presence of CVD involving more than one territory was associated with a significantly increased risk of 10-year all-cause death, which was non-significantly higher in complex CAD patients treated with PCI compared with CABG. Acceptable long-term outcomes were observed, suggesting that patients with established CVD should not be precluded from undergoing invasive angiography or revascularization. Trial registration SYNTAX: ClinicalTrials.gov reference: NCT00114972. SYNTAX Extended Survival: ClinicalTrials.gov reference: NCT03417050. Graphic abstract

scholarly journals Prevalence, Epidemiological Characteristics, and Pharmacotherapy of Coronary Artery Disease among Patients with Atrial Fibrillation: Data from Jo-Fib Study

Medicina ◽  
2021 ◽  
Vol 57 (6) ◽  
pp. 605
Author(s):  
Hanna K. Al-Makhamreh ◽  
Mohammed Q. Al-Sabbagh ◽  
Ala’ E. Shaban ◽  
Abdelrahman F. Obiedat ◽  
Ayman J. Hammoudeh
Keyword(s):  
Risk Factors ◽  
Atrial Fibrillation ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Antiplatelet Agents ◽  
Retrospective Case ◽  
Increased Risk ◽  
Artery Disease ◽  
Epidemiological Characteristics ◽  
Cad Risk

Background and Objectives: Patients with AF are at increased risk for Coronary Artery Disease (CAD) owing to their shared etiologies and risk factors. This study aimed to assess the prevalence, cardiovascular risk factors, and used medications of CAD in AF patients. Materials and Methods: This retrospective, case-control study utilized data from the Jordanian Atrial Fibrillation (Jo-Fib) registry. Investigators collected clinical features, history of co-existing comorbidities, CHA2DS2-VASc, and HAS BLED scores for all AF patients aged >18 visiting 19 hospitals and 30 outpatient cardiology clinics. A multivariable binary logistic regression was used to asses for factors associated with higher odds of having CAD. Results: Out of 2000 patients with AF, 227 (11.35%) had CAD. Compared to the rest of the sample, those with CAD had significantly higher prevalence of hypertension (82.38%; p < 0.01), hypercholesterolemia (66.52%, p < 0.01), diabetes (56.83%, p < 0.01), and smoking (18.06%, p = 0.04). Patients with AF and CAD had higher use of anticoagulants/antiplatelet agents combination (p < 0.01) compared to the rest of the sample. Females had lower CAD risk than males (OR = 0.35, 95% CI: 0.24–0.50). AF Patients with dyslipidemia (OR = 2.5, 95% CI: 1.8–3.4), smoking (OR = 1.7, 95% CI: 1.1–2.6), higher CHA2DS2-VASc score (OR = 1.5, 95% CI: 1.4–1.7), and asymptomatic AF (OR = 1.9, 95% CI: 1.3–2.6) had higher risk for CAD. Conclusions: Owing to the increased prevalence of CAD in patients with AF, better control of cardiac risk factors is recommended for this special group. Future studies should investigate such interesting relationships to stratify CAD risk in AF patients. We believe that this study adds valuable information regarding the prevalence, epidemiological characteristics, and pharmacotherapy of CAD in patients with AF.

scholarly journals Association between Polymorphisms of Antioxidant Gene (MnSOD, CAT, and GPx1) and Risk of Coronary Artery Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Hseng-Long Yeh ◽  
Li-Tang Kuo ◽  
Fung-Chang Sung ◽  
Chih-Ching Yeh
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Manganese Superoxide Dismutase ◽  
Medical Center ◽  
Stress Test ◽  
Genetic Effect ◽  
Multivariate Logistic Regression Model ◽  
Increased Risk ◽  
Artery Disease ◽  
Cad Risk

Objective. Reactive oxygen species (ROS) been cited as one of the major causes of atherosclerosis and coronary artery disease which are possible agents inducing DNA damage. Manganese superoxide dismutase (MnSOD), catalase (CAT), and glutathione peroxidase-1 (GPx1) have evolved to address primary defense against free radical mediated damage in mitochondria. The aim of this study was to delineate the association ofMnSOD,CAT, andGPx1polymorphisms and risk of CAD in Taiwan.Methods. We conducted a case-control study with 657 participants recruited at a medical center. All subjects were evaluated by noninvasive stress test and then quantitative coronary angiography to confirm the diagnosis of CAD. 447 CAD cases were defined as >50% stenosis of coronary artery and 210 controls were stenosed below 50%. Polymorphisms ofMnSOD(Val16Ala),CAT(C-262T), andGPx1(Pro198Leu) genes were determined by polymerase chain reaction methods. Multivariate logistic regression model was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs).Results. TheMnSODVal/Ala+Ala/Ala genotype was significantly associated with an increased risk of CAD compared to the Val/Val genotype (OR = 1.86, 95% CI = 1.15-3.01). This polymorphism was also associated with the severity of CAD of single and two vessel diseases. The corresponding ORs were 2.31 (95% CI = 1.32-4.03) and 1.92 (95% CI = 1.02-3.61), respectively. Among cigarette smokers, the harmful genetic effect ofMnSODAla allele on CAD risk was much higher (OR = 2.23, 95% CI = 1.02-4.88). However, the interaction betweenMnSODgenotype and cigarette smoking on CAD risk was not significant. No significant association betweenCATandGPx1polymorphisms and CAD risk was observed.Conclusion. Our results suggest thatMnSODpolymorphism is an independent risk factor for susceptibility to CAD in the Chinese population.

scholarly journals Genetic susceptibility of five tagSNPs in the endothelin-1 (EDN1) gene to coronary artery disease in a Chinese Han population

2018 ◽  
Vol 38 (5) ◽  
Author(s):  
Li-li Liang ◽  
Lin Chen ◽  
Meng-yuan Zhou ◽  
Meng-yun Cai ◽  
Jie Cheng ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Chinese Han Population ◽  
Chinese Han ◽  
Han Population ◽  
Endothelin 1 ◽  
Increased Risk ◽  
Artery Disease ◽  
Cad Risk

Endothelin-1 (ET-1) plays important roles in endothelial dysfunction, vascular physiology, inflammation, and atherosclerosis. Nonetheless, the role of ET-1 (EDN1) gene variants on coronary artery disease (CAD) risk remains poorly understood. The aim of the present study was to evaluate the role of EDN1 gene polymorphisms on individual susceptibility to CAD. We genotyped five tagSNPs (single-nucleotide polymorphisms) (rs6458155, rs4145451, rs9369217, rs3087459, and rs2070699) within EDN1 gene in 525 CAD patients and 675 control subjects. In a multivariate logistic regression analysis, we detected an association of rs6458155 in EDN1 gene with the CAD risk; compared with the TT homozygotes, the CT heterozygotes (odds ratio (OR) = 1.53, 95% confidence interval (CI) = 1.02–2.29, P=0.040) and the CC homozygotes (OR = 1.55, 95% CI = 1.01–2.36, P=0.043) were statistically significantly associated with the increased risk for CAD. A similar trend of the association was found in dominant model (OR = 1.53, 95% CI = 1.05–2.25, P=0.029). Consistently, the haplotype rs6458155C-rs4145451C containing rs6458155 C allele exhibited the increased CAD risk (OR = 1.22, 95% CI = 1.03–1.43, and P=0.018). In addition, CT genotype of rs6458155 conferred the increased plasma ET-1 levels compared with TT genotype (P<0.05). No association of the other four tagSNPs in EDN1 gene with CAD risk was observed. In conclusion, our study provides the first evidence that EDN1 tagSNP rs6458155 is associated with CAD risk in the Chinese Han population, which is probably due to the influence of the circulating ET-1 levels.

scholarly journals Raet1e Polymorphisms Are Associated with Increased Risk of Developing Premature Coronary Artery Disease and with Some Cardiometabolic Parameters: The GEA Mexican Study

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Rosalinda Posadas-Sánchez ◽  
Bladimir Roque-Ramírez ◽  
José Manuel Rodríguez-Pérez ◽  
Nonanzit Pérez-Hernández ◽  
José Manuel Fragoso ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Premature Coronary Artery Disease ◽  
Functional Effect ◽  
Increased Risk ◽  
Family Medical History ◽  
History Of ◽  
Premature Cad ◽  
Artery Disease ◽  
First Time

In an animal model, new evidence has been reported supporting the role of raet1e as an atherosclerosis-associated gene. Our objective was to establish if raet1e polymorphisms are associated with the risk of developing premature coronary artery disease (CAD) or with the presence of cardiometabolic parameters. After an informatic analysis, five polymorphisms were chosen and determined in 1158 patients with premature CAD and 1104 controls using 5′ exonuclease TaqMan genotyping assays. Standardized questionnaires were applied to all participants to obtain family medical history, demographic information, history of nutritional habits, physical activity, alcohol consumption, and pharmacological treatment. The functional effect of the rs7756850 polymorphism was analyzed by luciferase assays. Under different models, adjusted by age, gender, body mass index, current smoking, and type 2 diabetes mellitus, the rs6925151 (OR=1.250, pheterozygote=0.026; OR=1.268, pcodominant1=0.034), rs9371533 (OR=1.255, pheterozygote=0.024), rs7756850 (OR=1.274, pheterozygote=0.016; OR=1.294, pcodominant1=0.031), and rs9383921 (OR=1.232, pheterozygote=0.037) polymorphisms were associated with increased risk of premature CAD. When compared to the rs7756850 G allele, the C allele showed a decreased luciferase activity. In premature CAD patients, associations with low levels of adiponectin, with a high presence of hypertension, and with high levels of gamma-glutamyltransferase and total cholesterol were observed. In healthy controls, associations with a decrease in LDL pattern B, aspartate aminotransaminase, and hypo-α-lipoproteinemia were detected. An association of the raet1e polymorphisms with an increased risk of developing premature CAD and with cardiometabolic parameters has been shown for the first time. In addition, the functional effect of the rs7756850 polymorphism was defined.

scholarly journals The (G>A) rs11573191 Polymorphism ofPLA2G5Gene Is Associated with Premature Coronary Artery Disease in the Mexican Mestizo Population: The Genetics of Atherosclerotic Disease Mexican Study

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Gilberto Vargas-Alarcón ◽  
Carlos Posadas-Romero ◽  
Teresa Villarreal-Molina ◽  
Edith Alvarez-León ◽  
Javier Angeles-Martinez ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Linkage Disequilibrium ◽  
Coronary Artery ◽  
Additive Models ◽  
Premature Coronary Artery Disease ◽  
Increased Risk ◽  
Premature Cad ◽  
Artery Disease ◽  
Mexican Mestizo Population ◽  
Excessive Inflammatory Response

Coronary artery disease (CAD) is a multifactorial disorder that results from an excessive inflammatory response. Secretory phospholipase A2-V (sPLA2-V) encoded byPLA2G5gene promotes diverse proinflammatory processes. The aim of the present study was to analyze ifPLA2G5gene polymorphisms are associated with premature CAD. ThreePLA2G5polymorphisms (rs11573187, rs2148911, and rs11573191) were analyzed in 707 patients with premature CAD and 749 healthy controls. Haplotypes were constructed after linkage disequilibrium analysis. Under dominant, recessive, and additive models, the rs11573191 polymorphism was associated with increased risk of premature CAD (OR = 1.51,Pdom= 3.5 × 10−3; OR = 2.95,Prec= 0.023; OR = 1.51,Padd= 1.2 × 10−3). According to the informatics software, this polymorphism had a functional effect modifying the affinity of the sequence by the MZF1 transcription factor.PLA2G5polymorphisms were in linkage disequilibrium and theCGAhaplotype was associated with increased risk of premature CAD (OR = 1.49,P= 0.0023) and with hypertension in these patients (OR = 1.75,P= 0.0072). Our results demonstrate the association of thePLA2G5rs11573191 polymorphism with premature CAD. In our study, it was possible to distinguish one haplotype associated with increased risk of premature CAD and hypertension.

scholarly journals Cis-epistasis at the LPA locus and risk of coronary artery disease

2019 ◽  
Author(s):  
Lingyao Zeng ◽  
Nazanin Mirza-Schreiber ◽  
Claudia Lamina ◽  
Stefan Coassin ◽  
Christopher P. Nelson ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Association Studies ◽  
Arterial Disease ◽  
Genome Wide Association Studies ◽  
Interaction Patterns ◽  
Cardiovascular Risks ◽  
Increased Risk ◽  
Artery Disease ◽  
Cad Risk

AbstractIdentification of epistasis affecting complex human traits has been challenging. Focusing on known coronary artery disease (CAD) risk loci, we explore pairwise statistical interactions between 8,068 SNPs from ten CAD genome-wide association studies (n=30,180). We discovered rs1800769 and rs9458001 in the vicinity of the LPA locus to interact in modulating CAD risk (P=1.75×10−13). Specific genotypes (e.g., rs1800769 CT) displayed either significantly decreased or increased risk for CAD in the context of genotypes of the respective other SNP (e.g., rs9458001 GG vs. AA). In the UK Biobank (n=450,112) significant interaction of this SNP pair was replicated for CAD (P=3.09×10−22), and was also found for aortic valve stenosis (P=6.95×10−7) and peripheral arterial disease (P=2.32×10−4). Identical interaction patterns affected circulating lipoprotein(a) (n=5,953; P=8.7×10−32) and hepatic apolipoprotein(a) (apo(a)) expression (n=522, P=2.6×10−11). We further interrogated potential biological implications of the variants and propose a mechanism explaining epistasis that ultimately may translate to substantial cardiovascular risks.

Abstract 534: A Common Null Allele of LPA is Associated With Lp(a) Levels and Coronary Artery Disease Risk

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Theodosios Kyriakou ◽  
Udo Seedorf ◽  
Anuj Goel ◽  
Jemma C Hopewell ◽  
Robert Clarke ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Null Allele ◽  
Disease Risk ◽  
Case Control ◽  
Control Cohort ◽  
Apolipoprotein A ◽  
Artery Disease ◽  
The Relationship ◽  
Cad Risk

Objective: Increased levels of Lp(a) lipoprotein are a highly heritable risk factor for coronary artery disease (CAD). The genetic determinants of Lp(a) levels are mainly due to genetic variation in the apolipoprotein(a) gene (LPA). We have tested the association of a null allele of LPA with Lp(a) levels and CAD risk in a large case-control cohort. We have also examined how null allele genotyping complements apolipoprotein(a) isoform typing to refine the relationship between LPA isoform size and circulating Lp(a) levels. Approach and Results: The LPA null allele (rs41272114) was genotyped in the PROCARDIS case-control cohort (4,073 CAD cases, 4,225 controls). Lp(a) lipoprotein levels were measured in 909 CAD cases and 922 controls; apolipoprotein(a) isoform size was estimated using SDS-agarose gel electrophoresis and a high-throughput qPCR based method. Null carriers are common (null allele frequency 3%) and have significantly lower circulating Lp(a) levels (p=2.1x10-10) and reduced CAD risk (p=0.023) compared to non-carriers. An additive allelic model of apolipoprotein(a) isoform size, refined by null allele genotype and qPCR values, showed a sigmoid relationship with Lp(a) levels with baseline levels for longer isoform alleles and progressively higher levels of Lp(a) for shorter isoform alleles. Conclusions: The LPA null allele (rs41272444) is associated with decreased circulating Lp(a) levels and decreased CAD risk. A joint genomic and isoform analysis revealed details of the relationship between apolipoprotein(a) isoform size and circulating Lp(a) level consistent with a threshold effect on lipoprotein secretion.

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