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An Important Region in Coronary Artery Disease: a Panel Approach to Investigation of the Coronary Artery Disease Etiology

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An Important Region in Coronary Artery Disease: a Panel Approach to Investigation of the Coronary Artery Disease Etiology Int J Cardiovasc Pract Review Article April 2019, Volume 4, Issue 2 (21-35) 9P21.3 locus; An Important Region in Coronary Artery Disease: A Panel Approach to Investigation of the Coronary Artery Disease Etiology Soodeh Omidi 1, Fatemeh Ebrahimzadeh 2, Samira Kalayinia 3,* 1 Department of Genetic, Faculty of Advanced Medical Technologies, Golestan University of Medical Science (GUMS), Gorgan, Iran 2 Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences (ZUMS), Zanjan, Iran 3 Cardiogenetics Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran * Corresponding author: Samira Kalayinia, Ph.D. Cardiogenetics Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical DOI: 10.29252/ijcp-25001 Sciences, Tehran, Iran. Tel: +98-2123923033, Fax: +98-2122663213, E-mail: [email protected] Submitted: 07-04-2019 Abstract Accepted: 06-05-2019 Coronary artery disease (CAD) is a disease of major concern worldwide. It is the main Keywords: cause of mortality in many societies and improving the understanding about the CAD Etiology mechanism, progression and treatment, is necessary. Recent discovery of genetic factors Heart Disease underlying CAD has improved our knowledge of the disease in support of well-known Genome Wide Association traditional risk factors. Genotype-environment interaction is known as the main risk Study factor. Loci on many different chromosomes have been identified as a risk factors that © 2019. International Journal increase CAD susceptibility. Here we performed a comprehensive literature review of Cardiovascular Practice. pinpointing hotspot loci involved in CAD pathogenicity. The 9p21.3 locus is the most common region associated with CAD and its specific structure and function have been remarkable in many studies. Moreover, the variations in the 9p21.3 locus have been implicated in CAD patients in different populations around the world. According to conclusions from this the 9p21.3 locus can be the first point of focus in etiology investigations of CAD patients. INTRODUCTION Cardiovascular diseases (CVD) involve the heart and decisions are critical for CAD prevention in all blood vessels. Coronary heart disease (CHD) is one of populations [3]. Family history as a traditional factor a subset of CVD and a consequence of coronary artery that is independent from other risk factors can be useful disease (CAD) [1]. CAD is due to plaque aggregation in in prediction of common diseases, e.g., CAD coronary arteries that leads to decreased blood supply to susceptibility in family members [4]. New technologies the heart muscle. This can lead to a wide spectrum of in recent years have improved the diagnosis of genetic clinical manifestations ranging from asymptomatic to differences between individuals in interacting with disease symptoms such as angina, silent myocardial environment factors, such as the increased level of infarction (MI), acute MI, and/or sudden death. It is a fibrinogen, homocysteine, C-reactive protein, low complex multifactorial disease to which genetic and density lipoproteins (LDL), very low density environmental factors contribute. According to World lipoproteins (VLDL), cholesterol, triglyceride, systolic Health Organization (WHO) reports, ischemic heart blood pressure, diastolic blood pressure, body mass disease and stroke have been the most common causes index (BMI), lipoprotein A, decreased levels of high of mortality in the last 15 years [2], and CHD as an density lipoprotein (HDL), type 2 diabetes (T2D), ischemic heart disease is a global problem for all some vitamin deficiencies, cofactor Q10, and other communities. It seems that national health control factors that increase over time [5, 6]. Copyright © 2019 The Author(s); Published by International Journal of Cardiovascular Practice. This is an open access article, distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses /by-nc/4.0/) which permits others to copy and redistribute material just in noncommercial usages, provided the original work is properly cited. Omidi, et al. International Journal of Cardiovascular Practice factor is associated with CAD and MI [16]. In another study three missense mutations including N263S, Genetic Factors in Cad Causality P279L and G283D identified in MEF2A caused According to twin and pedigree studies, genetic factors reductions in transcription factor activity and hence account for about 45% of the variation in CAD [7]. were associated with CAD [17]. Swedish and Danish twin registry studies showed that Mutations p.Val99Met and p.*337Qext*20 in the gene genetic factors are important contributory causes of ST6GALNAC5 were associated with CAD in the Iranian death of CHD patients, with the same frequency in population. The mutant alleles of ST6GALNAC5, males and females [8, 9]. Therefore, genetic- which encodes the sialyltransferase 7e, causes increased environment interactions have been known as the main activity of the enzyme [18, 19]. risk factor. Linkage studies also helped to identify Iranloorahatloo et al. demonstrated that the mutation inherited genes in large families with affected and p.Arg225His in gene CYP27A1 is associated with CAD unaffected individuals in different generations [10]. A in the Iranian population. CYP27A1 encodes the monogenic forms of CAD were observed in a few cases enzyme sterol 27-hydroxylase that is involved in vitamin of this disease and familial linkage studies established D metabolism and reverse transportation of cholesterol. they were due to mutations in genes involved in known The mutant enzyme likely affects the reverse pathways of CAD such as lipid metabolism. Some of transportation of cholesterol [20]. Gene LRP6 encodes these cases are associated with increased LDL level, such LDL receptor-related protein 6 and a missense mutation as mutation in genes LDL receptor, ApoB-100, ARH and named p.R611C in an Iranian ancestry is associated with PCSK9 [11]. Low-density lipoprotein (LDL) consists of CAD. The mutation is associated with high levels of cholesteryl ester as the molecular which coated by LDL and TG but has no direct effect on HDL level [21]. phospholipid and Apolipoprotein B-100. About 600 Mutations in genes ABCG5 and ABCG8, which encode mutations in the LDL receptor gene leading to increased transporters that influence cholesterol absorption, are level of plasma LDL have been related to familial the most causes of sitosterolemia and involve hyper hypercholesterolemia. Mutations in the ApoB-100 and absorption of sterols and cholesterol, again leading to ARH genes are responsible for reduced LDL uptake increased risk of CAD [12]. from plasma and elevated LDL levels, leading to familial Recent Approaches in Assessing Diseases ligand-defective Apo lipoprotein B-100 and autosomal Etiology recessive hypercholesterolemia, respectively [12]. The PCSK9 gene encodes a protease enzyme that is involved The recent sequencing of the entire human genome by in degradation of LDL receptor, and affects LDL the Human Genome Project and linkage disequilibrium metabolism leading to CHD. Overexpression of the (LD) patterns revealed in the Hap Map project led to PCSK9 gene, or gain of function mutations, is related to discovery of single nucleotide polymorphisms (SNP) hypercholesterolemia versus loss-of-function using microarray technology approaches and to the mutations, or inactivation of the enzyme, is related to ability to perform genome-wide association studies hypocholesterolemia which has a protective effect on (GWAS) [10]. GWAS detects statistical associations CHD. Therefore, we can target the PCSK9 gene as a way between SNP as genome markers with the phenotype of treatment of CHD in the future [13]. (disease) with no previous hypothesis [22, 23]. Plasma HDL reduction as a risk factor for CAD is due to Candidate gene studies are another type of association mutations in genes such as ApoA1, ABCA1, and LCAT analysis. This type of study has been used for complex that cause familial hypoalphalipoproteinemia, Tangier diseases and is based on comparisons of selected loci or disease, and Norum disease, respectively. Reduction of alleles identified in earlier studies [22]. Since candidate HDL and increased risk of CAD are observed in these gene studies are based on previous hypotheses loci in disorders [11]. CAD has also been associated with unknown pathways of disease pathogenesis cannot be polymorphisms in genes such as ApoA1-75A, R219K in studied. Conflicting and difficult confirmation results ApoA1 and ABCA1 [14, 15]. High level of plasma are disadvantages of Candidate gene study [24], Whole- triglyceride as a risk factor for CAD is associated with genome sequencing (WGS) is a technology based on mutations in genes such as LPL and ApoCII that lead to sequencing entire genomes and the method has focused hyperlipoproteinemia type I and hyperlipoproteinemia mainly on simply inherited disorders and identification type Ib, respectively [11]. Mutations in another group of of rare variants with large effects [22]. Due to lack of genes without a direct effect on alteration of plasma lipid distinction between causal and non-causal variants in levels including MEF2A, LRP6, CYP27A1, the pathogenesis of the disease, this approach is useful ST6GALNAC5, ABCG5, and ABCG8 also increase the for identification of mutations or genes that were risk of CAD. confirmed in previous
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