Genetic factors in coronary heart disease (Developments in Cardiovascular Medicine)

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This in turn may be translated into preventive approaches to help reduce the risk of CAD using genetic and epigenetic approaches. Although CAD mortality in the Indians is highest than other populations[ 14 , 15 ], the reason for increased risk, which has been recorded in both the Asian immigrants and among Indians in urban India; are not yet clear hence more systematic and comprehensive studies are required to understand the spectrum of genetic and epigenetic influences on CAD. Atherosclerosis involves multiple factors, hence understanding the genetic and environmental basis of this complex disease requires holistic approaches[ 16 - 18 ].

A range of candidate genes e. There are very few examples where single genes have played a role in causing atherosclerosis[ 19 , 20 ]. Mostly, CAD is caused by the environmental factors however the risk increases when some risk associated genes are also present. A detailed analysis of the many known CAD susceptibility genes and studies is beyond the scope of this overview. Risk factors for coronary heart disease can be subdivided into those that are determined significantly by genetic differences and those that are largely environmental Based on Lusis et al[ 58 ] Very low density lipoprotein; LDL: Low density lipoprotein; HDL: Familial hyper cholesterolemia FH is a classic genetic disease in which increased cholesterol, tendon xanthomas, and early heart disease segregates together.

This variable penetrance is modified by genes and other risk factors such as diet, smoking, and physical activity level[ 23 ]. Heterozygote frequency for this disease relatively high, approximately 1 in [ 24 ] in most populations, however DNA screening and effective treatments are available now[ 25 , 26 ].

This comparatively common hypercholesterolemia approximately 1 in , results from mutations in the major protein of LDL called Apolipoprotein B ApoB. The majority of patients of this disorder carry a dominant mutation codon and have lower cholesterol levels compared to FH patients. During last 30 years, there have been many advancements in molecular genetic technology, development of sophisticated statistical tools and analyses which have contributed to improvements in human genetic research. One of the early developments was positional cloning technique, which allowed genetic mapping of many Mendelian diseases and traits.

However for complex diseases, which involve many genes and environmental influences, this technique did not provide any major insights into genetic basis. Some examples of these are given below. Apolipoprotein E ApoE is one of the extensively studied genetic locus as it plays a pivotal role in lipid metabolism and mediates the uptake of chylomicron and very low-density lipoprotein VLDL remnants. Utermann and colleagues[ 27 ] identified genetic polymorphism at ApoE locus and its association with cholesterol levels and type III hyperlipidemia.

The polymorphism and its CAD associations have been replicated in many global populations. E4 allele carriers have increased plasma cholesterol levels compared to E3 allele carriers while E2 carriers have decreased plasma cholesterols. Type III hyperlipidemia, a relatively rare phenotype, are homozygous for the E2 allele, but not all E2 homozygous individuals have this disorder[ 29 ].

Therefore, genotype-phenotype relationships may require contribution of other genetic or environmental factors. Dyslipidemia, a metabolic disorder, caused due to the defects in the synthesis, processing and catabolism of lipoprotein particles. It has been suggested that understanding variation at these loci along with other newer genetic loci will provide a better understanding of the disease processes and contribution to personalized medicine.

ApoC3 prevents lipoprotein lipase and plays a key role in the catabolism of TG-rich lipoproteins. ApoA5 is detectable in very low-density lipoprotein, HDL, and chylomicrons and its concentrations are low compared to other apolipoproteins. Intercellular adhesion molecule; IL: Platelet endothelial cell adhesion molecule; TGF: Transforming growth factor; TNF: Tumor necrosis factor; VNTR: Variable number of tandem repeats.

One of the limitations of case control studies is that many false positive or false negative associations may emerge between different genetic markers and complex diseases like CAD. The reason for such results are: In general, results of small sample size studies patients and control subjects should be interpreted with caution and should be replicated with larger sample sizes. It is important to confirm that genotype distributions are not skewed, especially in the control group.

Large deviations from the Hardy-Weinberg equilibrium, may suggest that the control group is not necessarily the representative of healthy and randomly sampled individuals. This departure may also highlight issues with genotype scoring. Recent genome-wide sequencing research has revealed extensive level of variation and heterogeneity between individuals and populations, which should be considered when choosing SNPs and interpreting SNP data.

Some of the early SNP association studies failed to include the effect of the polymorphism on gene expression or protein function and genotype-phenotype correlations. This information could reveal if an SNP is the actual cause or solely a marker which may be in linkage disequilibrium another causal variant.

These analyses could provide significant clues for understanding the pathophysiologic mechanisms behind clinical outcomes. There should be a holistic approach to understand the role of genes, environment and life style factors in CAD susceptibilities and progression. Recently, genetic analyses have expanded to whole genome sequence analysis and genome-wide association studies GWAS as these analyses eliminates biases in the selection of the candidate genes. A number of GWAS studies have identified new loci in previously unsuspected genomic regions.

These analyses have shown, novel biological pathways involved in the disease states and development of novel therapies. Many recent studies have shown only limited evidences may exist where the genetic variants may be associated with MI or only with CAD.

A care has to be taken in interpreting the GWAS data as large number of variant alleles may be found but one should consider only elegant systems genetics approach to Plaisier et al[ 47 ] used similar approach and found that FADS3 is a causal gene for familial combined hyperlipidemia FCHL and elevated triglycerides in Mexicans. The authors used network gene co-expression analysis and SNP data to assign a function to the genetic variants rs 1qq23 in USF1 gene, which was previously identified to be associated with FCHL.

It is envisaged that new methods like Network medicine[ 48 ] will play an important role in these analyses and the advancement of our understanding of pathophysiological mechanisms of diseases like CAD and MI. This overview has highlighted some of the important challenges regarding the use of genetic approaches to investigate complex diseases.

The recent research using genomic, epigenomics and exposomic approaches is providing a range of patient centric tools which will help better classification of phenotypes and personalised medicine for CAD patients. Hence the future challenges are 1 discovering new genetic variants through large-scale meta-analyses, using pathway-based approaches, and high throughput sequencing; 2 illustrating the mechanisms for the identified loci to CAD; and 3 translating the findings from CAD- GWASs and epigenetic analyses to novel and optimized therapeutic strategies.

Wen LL L- Editor: National Center for Biotechnology Information , U. Journal List World J Cardiol v. Published online Aug Suraksha Agrawal and Sarabjit Mastana. Author information Article notes Copyright and License information Disclaimer. Agrawal S and Mastana S wrote the initial draft and were involved in editing and collation of tables and figures. This article has been cited by other articles in PMC. Abstract Cardiovascular diseases are affected by multiple factors like genetic as well as environmental hence they reveal factorial nature.

It is likely that many of the challenges encountered in GWAS will be experienced, perhaps to a greater degree, in NGS studies, particularly those surrounding statistical power. The availability in the next few years of large data sets from high-resolution sequencing projects, for example from the Genomes Project www. Genomic advances in the past 10 years have catalysed growth in our understanding of the genetic basis of CHD.

We are, however in the very early phases of the clinical translation. Techniques such as MR provide unprecedented potential to understand disease causality and identify drug targets, and are already bearing fruit. However, other areas such as the useful incorporation of genetic information into predicting an individual's risk of CHD or the routine clinical use of pharmacogenetics in stratifying medical therapy will take longer to translate, although the use of gene scores appears promising. While we equip ourselves with the statistical and technological advances to make this possible, we should not lose focus of the dramatic leaps the scientific community has made in uncovering new information which will be of undoubted benefit for preventing disease in future generations.

The genetics of heart disease: An update

SEH is the Medical Director of the UCL genetic testing company Storegene and has received honoraria for speaking at educational meetings with a pharmaceutical sponsor, but has donated these in whole or part to various medical charities. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Close mobile search navigation Article navigation. Lessons from monogenic coronary disease. GWA studies and coronary heart disease. Exploitation of GWAS findings for prevention, therapeutics and pathophysiology.

Predicting drug response in individuals: The genetics of coronary heart disease Daniel I. View large Download slide. MR studies where causality for a biomarker in CHD has been confirmed or refuted.

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A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. A mutation that impairs the ability of lipoprotein receptors to localise in coated pits on the cell surface of human fibroblasts. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B Association of mutations in the apolipoprotein B gene with hypercholesterolemia and the risk of ischemic heart disease. Mortality in treated heterozygous familial hypercholesterolaemia: Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: Lipid abnormalities in male and female survivors of myocardial infarction and their first-degree relatives.

Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Cost-effectiveness analysis of a genetic screening program in the close relatives of Spanish patients with familial hypercholesterolemia. Familial hypercholesterolemia in Spain: Investigating the genetic determinants of cardiovascular disease using candidate genes and meta-analysis of association studies. International human genome sequencing consortium initial sequencing and analysis of the human genome. Drinking from the fire hose—statistical issues in genomewide association studies.

Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Common and rare variants in multifactorial susceptibility to common diseases. Four genetic loci influencing electrocardiographic indices of left ventricular hypertrophy. Utility of genetic and non-genetic risk factors in prediction of type 2 diabetes: Whitehall II prospective cohort study.

A multilocus genetic risk score for coronary heart disease: A common variant on chromosome 9p21 affects the risk of myocardial infarction. Genome-wide association study of 14, cases of seven common diseases and 3, shared controls. Coronary heart disease risk prediction in the era of genome-wide association studies: Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Comparing strategies to fine-map the association of common SNPs at chromosome 9p21 with type 2 diabetes and myocardial infarction. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm.

Coronary artery disease-associated locus on chromosome 9p21 and early markers of atherosclerosis. Comparative analysis of genome-wide-association studies signals for lipids, diabetes, and coronary heart disease: Cardiovascular Biomarker Genetics Collaboration. Functional analysis of the chromosome 9p Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Association between a literature-based genetic risk score and cardiovascular events in women.

INTRODUCTION

C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. Association between C reactive protein and coronary heart disease: Mendelian randomisation analysis based on individual participant data.

Does high C-reactive protein concentration increase atherosclerosis? The Whitehall II study. Insight into the nature of the CRP-coronary event association using Mendelian randomization. Triglyceride-mediated pathways and coronary disease: Clinical and genetic determinants of warfarin pharmacokinetics and pharmacodynamics during treatment initiation.

Role of genomics in cardiovascular medicine

For now, the genetic risk score test isn't available outside of a research setting. The score was derived almost exclusively from people of European ancestry, so researchers need to clarify how to interpret the test in people with different ethnic backgrounds, Dr. And even after they're validated, all genetic tests must meet professional ethical guidelines that deal with various issues, such as how to explain the results to patients — something Dr.

Natarajan spends a lot of time doing. But risk is a population-based concept.

Imagine people exactly like you, with the same genes and other lifestyle variables," he says. And remember, you can change those odds, regardless of your level of risk. For some, that might involve statins and other medications. Recent discoveries hold the promise of better detection and treatment of coronary artery disease. Heart Health Heart Disease.

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