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Identification of shared genetic susceptibility locus for coronary artery disease, type 2 diabetes and obesity: a meta-analysis of genome-wide studies
Chaoneng Wu, Yunguo Gong, Jie Yuan, Hui Gong, Yunzeng Zou, Junbo Ge
Cardiovascular Diabetology , 2012, DOI: 10.1186/1475-2840-11-68
Abstract: Type 2 diabetes (2DM), obesity, and coronary artery disease (CAD) are frequently coexisting disorders and major components of metabolic syndrome that cause a substantial public health and economic burden worldwide. Susceptibility to such complex diseases is strongly influenced by multiple genetic factors combined with environmental factors, and all these diseases are further characterized by a chronic inflammatory process. The strong genetic basis has been successfully revealed for each of these diseases. However, whether there are shared or interactive genetic background underlying all three diseases has remained largely unknown.Actually, evidence has showed that some loci confer risk for more than one of the studied diseases, and most common diseases arise from interaction between multiple genetic variations. This point suggested the concept of common genetic underpinnings for common diseases [1]. For example, a Wellcome Trust Case Control Consortium study evaluated 3,000 shared controls and 2,000 cases for each of seven complex human diseases—bipolar disorder, CAD, Crohn’s disease, hypertension, rheumatoid arthritis, type 1 diabetes, and 2DM—and demonstrated common susceptibility regions for rheumatoid arthritis and type 1 diabetes [2]. The common genetic basis for 2DM and obesity has also been indicated, with the common obesity genes being found through 2DM studies [3]. Further, CAD and 2DM have also been suggested to spring from shared genetic effects, rather than CAD being a complication of diabetes. These data indicates the potentially strong common genetic aspects among 2DM, obesity and CAD.Genome-wide association studies (GWAS) is one recent revolution, in which hundreds and thousands of single nucleotide polymorphisms (SNPs) are genotyped to capture indirectly most of the genome’s common variation [4]. Compared to the hypothesis-driven linkage and candidate-gene studies, GWAS is unbiased with regard to presumed functions or locations of causal variants. A
Supervised Feature Selection for Diagnosis of Coronary Artery Disease Based on Genetic Algorithm  [PDF]
Sidahmed Mokeddem,Baghdad Atmani,Mostefa Mokaddem
Computer Science , 2013, DOI: 10.5121/csit.2013.3305
Abstract: Feature Selection (FS) has become the focus of much research on decision support systems areas for which data sets with tremendous number of variables are analyzed. In this paper we present a new method for the diagnosis of Coronary Artery Diseases (CAD) founded on Genetic Algorithm (GA) wrapped Bayes Naive (BN) based FS. Basically, CAD dataset contains two classes defined with 13 features. In GA BN algorithm, GA generates in each iteration a subset of attributes that will be evaluated using the BN in the second step of the selection procedure. The final set of attribute contains the most relevant feature model that increases the accuracy. The algorithm in this case produces 85.50% classification accuracy in the diagnosis of CAD. Thus, the asset of the Algorithm is then compared with the use of Support Vector Machine (SVM), MultiLayer Perceptron (MLP) and C4.5 decision tree Algorithm. The result of classification accuracy for those algorithms are respectively 83.5%, 83.16% and 80.85%. Consequently, the GA wrapped BN Algorithm is correspondingly compared with other FS algorithms. The Obtained results have shown very promising outcomes for the diagnosis of CAD.
Genetic Links between Coronary Artery Disease and Type 2 Diabetes  [PDF]
Shivani Vats,Vasudha Sambyal,AJS Bhanwer
Human Biology Review , 2013,
Abstract: Type 2 diabetes (T2D) is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and lipid metabolism resulting from defects in insulin secretion, action or both. Cardiovascular morbidity and mortality is high among T2D subjects and of all the complications of T2D individuals, Coronary artery disease (CAD) is the most common and life threatening. It has been found that risk for CAD is high among diabetic subjects by the factor of 2 to 4 as compared to non diabetic subjects. T2D has been associated with endothelial dysfunction as it increases the inflammation and insulin resistance resulting in the increase of oxidized low density lipoprotein, endothelin 1, angiotensin II, oxidative stress and decreasing the action of nitric oxide and insulin or growth factors in endothelial cells. The candidate genes for T2D are potential candidate genes for CAD also because of the overlap of the various metabolic and hormonal derangements in both the conditions. Among these, genes like TCF7L2, ACE, PPAR gamma, IRS1, Adiponectin and TNF alpha have emerged as main candidate genes linking both the conditions. In the GWAS studies a common locus on 9p21.3 (ANRIL)has been found for both the diseases. In spite of a shared pathophysiology between both the conditions reports for their genetic association are scarce. Thus there is a strong need for further studies and development of a strategy for the prevention of CAD long before its onset in T2D patients. In this review we focused on the various pathophysiological links (insulin resistance, hyperglycaemia, inflammation, and defect in fibrinolytic and coagulation factors, dyslipidaemia) and genetic links between T2D and CAD
Risk factors, biochemical markers, and genetic polymorphisms in early coronary artery disease
Izar, Maria Cristina;Fonseca, Francisco Antonio Helfenstein;Ihara, Sílvia Saiuli Miki;Kasinski, Nelson;Sang, Won Han;Lopes, Ieda Edite Lanzarini;Pinto, Leonor do Espírito Santo de Almeida;Relvas, Waldir Gabriel Miranda;Louren?o, Daisy;Tufik, Sérgio;Paola, Angelo Amato Vincenzo de;Carvalho, Antonio Carlos Camargo;
Arquivos Brasileiros de Cardiologia , 2003, DOI: 10.1590/S0066-782X2003000400003
Abstract: objective: to assess the risk factors, lipid and apolipoprotein profile, hemostasis variables, and polymorphisms of the apolipoprotein ai-ciii gene in early coronary artery disease (cad). methods: case-control study with 112 patients in each group controlled by sex and age. after clinical evaluation and nutritional instruction, blood samples were collected for biochemical assays and genetic study. results: familial history of early cad (64 vs 39%), arterial hypertension (69 vs 36%), diabetes mellitus (25 vs 3%), and previous smoking (71 vs 46%) were more prevalent in the case group (p<0.001). hypertension and diabetes were independent risk factors. early cad was characterized by higher serum levels of total cholesterol (235 ± 6 vs 209 ± 4 mg/dl), of ldl-c (154 ± 5 vs 135 ± 4 mg/dl), triglycerides (205 ± 12 vs 143 ± 9 mg/dl), and apolipoprotein b (129 ± 3 vs 105 ± 3 mg/dl), and lower serum levels of hdl-c (40 ± 1 vs 46 ± 1 mg/dl) and apolipoprotein ai (134 ± 2 vs 146 ± 2mg/dl) [p<0.01], in addition to an elevation in fibrinogen and d-dimer (p<0.02). the simultaneous presence of the rare alleles of the apo ai-ciii genes in early cad are associated with hypertriglyceridemia (p=0.03). conclusion: of the classical risk factors, hypertension and diabetes mellitus were independently associated with early cad. in addition to an unfavorable lipid profile, an increase in the thrombotic risk was identified in this population. an additive effect of the apo ai-ciii genes was observed in triglyceride levels.
Genome-Wide Assessment for Genetic Variants Associated with Ventricular Dysfunction after Primary Coronary Artery Bypass Graft Surgery  [PDF]
Amanda A. Fox,Mias Pretorius,Kuang-Yu Liu,Charles D. Collard,Tjorvi E. Perry,Stanton K. Shernan,Philip L. De Jager,David A. Hafler,Daniel S. Herman,Steven R. DePalma,Dan M. Roden,Jochen D. Muehlschlegel,Brian S. Donahue,Dawood Darbar,J. G. Seidman,Simon C. Body,Christine E. Seidman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0024593
Abstract: Postoperative ventricular dysfunction (VnD) occurs in 9–20% of coronary artery bypass graft (CABG) surgical patients and is associated with increased postoperative morbidity and mortality. Understanding genetic causes of postoperative VnD should enhance patient risk stratification and improve treatment and prevention strategies. We aimed to determine if genetic variants associate with occurrence of in-hospital VnD after CABG surgery.
Genome-Wide Association Studies in Myocardial Infarction and Coronary Artery Disease
Pier Mannuccio Mannucci,Luca A Lotta,Flora Peyvandi
Journal of Tehran University Heart Center , 2010,
Abstract: Myocardial infarction (MI) and its major determinant, coronary artery disease (CAD), are complex diseases arising from the interaction between several genetic and environmental factors. Until recently, the genetic basis of these diseases was poorly understood. Genome-wide genetic association studies have afforded a comprehensive insight into the association between genetic variants and diseases. To date, seven genome-wide association studies have been conducted in CAD/MI,identifying thirteen genomic regions at which common genetic variants influence the predisposition to these diseases. This review article summarizes the progress achieved in the genetic basis of MI and CAD by means of genome-wide associationstudies and the potential clinical applications of these findings.
Genetic Polymorphisms of Estrogen Receptors in Iranian Women with Diabetes and Coronary Artery Disease
Shekufeh Golkhu,Mahboobe Ghaedi,Narges Mohammad Taghvaie,Mohammad Ali Boroumand
Iranian Journal of Medical Sciences , 2009,
Abstract: Estrogen might play an important role in the pathogenesis ofdiabetes mellitus type 2. Estrogens inhibit diabetes via distinctmechanisms particularly by reducing both hyperglycemia andplasma insulin levels. Estrogen exerts its physiological effectsmainly through estrogen receptors including α and β types. Estrogenreceptors are found in many tissues that participate in thepathogenesis of type 2 diabetes. Two common polymorphisms,PvuII and XbaI in estrogen receptor α gene, are reported to beassociated with decreased receptor activity and increased risk ofdiabetes. We aimed to investigate the association between estrogenreceptor α polymorphisms and diabetes, where a geneticcomponent may be the major risk factor for this disease. Onehundred women with diabetes type 2 were compared with onehundred women without diabetes for PvuII and XbaI polymorphisms.Of whom 61% of cases and 29% of controls had coronaryartery disease. The participants were genotyped for thesepolymorphisms using polymerase chain reaction and restrictionfragment length polymorphism (PCR-RFLP) analysis. Thegenotype distribution and frequency of mutated allele showedno significant differences between diabetic and non-diabeticgroups in PvuII (χ2=0.981; P=0.612) and XbaI (χ2=0.362;P=0.83) polymorphisms. When coronary artery disease as thepotential confounding factor was controlled by logistic regressionanalysis, it was found that the PvuII and XbaI variantswere not related to the type 2 diabetes mellitus (P=0.60 andP=0.99, respectively). Neither PvuII nor XbaI genotypes wasassociated with increased susceptibility to the type 2 diabetesmellitus in selected Iranian women with diabetes and coronaryartery disease.
GWAS for discovery and replication of genetic loci associated with sudden cardiac arrest in patients with coronary artery disease
Bradley E Aouizerat, Eric Vittinghoff, Stacy L Musone, Ludmila Pawlikowska, Pui-Yan Kwok, Jeffrey E Olgin, Zian H Tseng
BMC Cardiovascular Disorders , 2011, DOI: 10.1186/1471-2261-11-29
Abstract: Tagging SNPs (n = 338,328) spanning the genome were typed in a case-control study comparing 89 patients with coronary artery disease and sudden cardiac arrest due to ventricular tachycardia or ventricular fibrillation to 520 healthy controls.Fourteen SNPs including 7 SNPs among 7 genes (ACYP2, AP1G2, ESR1, DGES2, GRIA1, KCTD1, ZNF385B) were associated with sudden cardiac arrest (all p < 1.30 × 10-7), following Bonferroni correction and adjustment for population substructure, age, and sex; genetic variation in ESR1 (p = 2.62 × 10-8; Odds Ratio [OR] = 1.43, 95% confidence interval [CI]:1.277, 1.596) has previously been established as a risk factor for cardiovascular disease. In tandem, the role of 9 genes for monogenic long QT syndrome (LQT1-9) was assessed, yielding evidence of association with CACNA1C (LQT8; p = 3.09 × 10-4; OR = 1.18, 95% CI:1.079, 1.290). We also assessed 4 recently published gene associations for sudden cardiac arrest, validating NOS1AP (p = 4.50 × 10-2, OR = 1.15, 95% CI:1.003, 1.326), CSMD2 (p = 6.6 × 10-3, OR = 2.27, 95% CI:1.681, 2.859), and AGTR1 (p = 3.00 × 10-3, OR = 1.13, 95% CI:1.042, 1.215).We demonstrate 11 gene associations for sudden cardiac arrest due to ventricular tachycardia/ventricular fibrillation in patients with coronary artery disease. Validation studies in independent cohorts and functional studies are required to confirm these associations.Sudden cardiac arrest (SCA) remains a major public health problem, causing up to 450,000 deaths per year in the U.S [1]. Approximately 80% of sudden cardiac deaths (SCDs) occur in the setting of coronary artery disease (CAD)[2]. Ventricular tachycardia (VT) or ventricular fibrillation (VF) is the initiating event in the majority of SCAs[3]. Assessment of ejection fraction (EF) remains the only method to identify patients at risk for SCA and primary prevention implantable cardioverter-defibrillator (ICD) implantation, but is both insensitive and nonspecific[4]. Several epidemiologic studi
Association of Genetic Variants Influencing Lipid Levels with Coronary Artery Disease in Japanese Individuals  [PDF]
Fumihiko Takeuchi, Masato Isono, Tomohiro Katsuya, Mitsuhiro Yokota, Ken Yamamoto, Toru Nabika, Kazuro Shimokawa, Eitaro Nakashima, Takao Sugiyama, Hiromi Rakugi, Shuhei Yamaguchi, Toshio Ogihara, Yukio Yamori, Norihiro Kato
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046385
Abstract: Background/Objective In Japanese populations, we performed a replication study of genetic loci previously identified in European-descent populations as being associated with lipid levels and risk of coronary artery disease (CAD). Methods We genotyped 48 single nucleotide polymorphisms (SNPs) from 22 candidate loci that had previously been identified by genome-wide association (GWA) meta-analyses for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and/or triglycerides in Europeans. We selected 22 loci with 2 parallel tracks from 95 reported loci: 16 significant loci (p<1×10?30 in Europeans) and 6 other loci including those with suggestive evidence of lipid associations in 1292 GWA-scanned Japanese samples. Genotyping was done in 4990 general population samples, and 1347 CAD cases and 1337 controls. For 9 SNPs, we further examined CAD associations in an additional panel of 3052 CAD cases and 6335 controls. Principal Findings Significant lipid associations (one-tailed p<0.05) were replicated for 18 of 22 loci in Japanese samples, with significant inter-ethnic heterogeneity at 4 loci–APOB, APOE-C1, CETP, and APOA5–and allelic heterogeneity. The strongest association was detected at APOE rs7412 for LDL-C (p = 1.3×10?41), CETP rs3764261 for HDL-C (p = 5.2×10?24), and APOA5 rs662799 for triglycerides (p = 5.8×10?54). CAD association was replicated and/or verified for 4 loci: SORT1 rs611917 (p = 1.7×10?8), APOA5 rs662799 (p = 0.0014), LDLR rs1433099 (p = 2.1×10?7), and APOE rs7412 (p = 6.1×10?13). Conclusions Our results confirm that most of the tested lipid loci are associated with lipid traits in the Japanese, further indicating that in genetic susceptibility to lipid levels and CAD, the related metabolic pathways are largely common across the populations, while causal variants at individual loci can be population-specific.
Association of Four Genetic Polymorphisms of AGER and Its Circulating Forms with Coronary Artery Disease: A Meta-Analysis  [PDF]
Feng Peng, Dan Hu, Nan Jia, Xiaobo Li, Yuqiong Li, Shaoli Chu, Dingliang Zhu, Weifeng Shen, Jinxiu Lin, Wenquan Niu
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0070834
Abstract: Background Considerable efforts have been devoted to evaluating the association of the receptor for advanced glycation end-products (gene AGER and protein: RAGE) genetic variants to coronary artery disease (CAD); the results, however, are often irreproducible. To generate more information, we sought to explore four common polymorphisms of AGER and its circulating forms associated with the risk of CAD via a meta-analysis. Methodology/Principal Findings Articles were identified by searching PubMed, EMBASE, Wanfang and CNKI databases before March 2013. Qualified articles had case-control designs and investigated AGER four polymorphisms (T-429C, T-374A, Gly82Ser, G1704A) or circulating soluble RAGE (sRAGE) or endogenous secretory RAGE (esRAGE) levels associated with CAD. Twenty-seven articles involving 39 independent groups fulfilled the predefined criteria. Overall, no significance was observed for all examined polymorphisms under allelic and dominant models. When restricting groups to CAD patients with diabetes mellitus or renal disease, deviations of risk estimates from the unity were stronger than overall estimates for all polymorphisms except for G1704A due to limited available studies. For example, under dominant model, having -429C allele increased the odds of developing CAD in diabetic patients by 1.22-fold (95% confidence interval (95% CI) 0.99–1.51; P = 0.06; I2 = 6.7%) compared with that of overall estimate of 1.15-fold (95% CI: 0.97–1.36; P = 0.111; I2 = 18.0%). Circulating sRAGE levels were non-significantly lower in CAD patients than in controls, whereas this reduction was totally and significantly reversed in CAD patients with diabetes mellitus (weighted mean difference: 185.71 pg/ml; 95% CI: 106.82 to 264.61 pg/ml). Circulating esRAGE levels were remarkably lower in CAD patients, as well as in subgroups with or without diabetes mellitus and without renal disease. Conclusions Our findings demonstrated that association of AGER genetic polymorphisms with CAD was potentiated in patients with diabetes mellitus or renal disease. Practically, circulating esRAGE might be a powerful negative predictor for the development of CAD.
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