Genetics and genomics in cardiovascular disease

The presentation aims at providing information on current applications of genetics and genomics into dissecting pathogenesis of cardiovascular disease and namely into their diagnosis and treatment.

At first, the applications of genetics to cardiology were limited to characterization of genetic variants underlying inherited defined cardiovascular disease, not only congenital heart disease but also other pathologies with clear monogenic component, namely channelopathies (e.g. long QT syndrome, Brugada syndrome) and other pathological states (cardiomyopathies)². The programmes of genetic testing in cardiology have been gradually established in many tertiary referral centres.

Later, with the expansion of genomewide analyses, geneticists jointly with cardiologists have embarked on GWAS projects aiming at identification of polymorphic markers contributing to development/manifestation of complex cardiovascular pathologies such as coronary heart disease and their specific phenotypes, including myocardial infarction^6,8. The major loci so far associated with coronary heart disease are 9p21 (CDKN2A,2B,2B-AS [ANRIL]), 1p13 (SORT1) and 10q23 (LIPA)⁸. Besides the area of genome-wide markers and their possible functional significance for cardiovascular pathologies, current research efforts have been directed at epigenetics and transcriptomics, e.g. to investigating the role of regulatory microRNAs in atherosclerosis and cardiovascular disease in general^4,7. The ultimate aim of these studies, preferably supplemented with bioinformatics and metaanalytical approaches, is to provide new therapeutic targets and possibly also novel biomarkers.

Lastly, regarding the growing area of personalised treatment of cardiovascular disease and their complications, clinical researchers focus on evaluation of providing evidence for practical utilization of pharmacogenetic analyses of drug metabolising enzymes such as cytochrome P450, particularly for constructing algorhitms guiding the dosing of antiplatelet and anticoagulation therapy including eventual drug replacement in specific conditions such as atrial fibrillation or coronary stenting^1,3,5. Thus, molecular pathologists with expert knowledge of molecular genetics are becoming important partners for clinical cardiologists in providing valuable information for their diagnostic workup and decisions of adequate treatment options.

Grant support: CZ.1.05/2.1.00/01.0030; IGA_PU_LF_2012_07

References and further reading

1. Hulot J-S, Hajjar R, Montalescot G. Clopidogrel and CYP2C19 testing: ready for clinical prime time? Clin. Chem. 2012; 58: 154–157.
2. Sabeh MK, MacRae CA: The genetics of atrial fibrillation. Curr. Opin. Cardiol. 2010; 25: 186–191.
3. Mega JL, Close SL, Wiviott SD, Shen I, Walker JR et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet 2010; 376: 1312–1319.
4. Ono K, Kuwabara Y, Han J. MicroRNAs and cardiovascular diseases. FEBS J 2011; 278: 1619–1633.
5. Petrek M, Kriegova E, Schneiderova P, Petrkova J. Characterisation of risk genotypes for Clopidogrel response in Czech patients with coronary stenting: genotyping CYP2C19/PON1 polymorphisms using Sequenom technology. Atherosclerosis, Suppl. 2012 (in press)
6. Reilly MP, Li M, He J, Ferguson JF, Stylianou IM, Mehta NN et al. Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies. Lancet 2011; 377: 383–392.
7. Tomankova J, Petrek M, Gallo J, Kriegova J. microRNAs: emerging regulators of immune-mediated disease. Scand. J. Immunol. 2011 doi: 10.1111/j.1365–3083.2011.02650.x. (epub ahead of print)
8. Zeller T, Blankenberg S, Diemert P. Genomewide association studies in cardiovascular disease. Clin. Chem. 2012; 58: 92–103