European Heart Journal Advance Access originally published online on July 27, 2006
European Heart Journal 2006 27(18):2150-2151; doi:10.1093/eurheartj/ehl172
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Genotypes or phenotypes in cardiovascular diagnosis?
1 Department of Medicine and Cardiology and Department of Neurology, Aarhus Sygehus, Aarhus, Denmark
2 Cardiovascular Medicine, National Heart and Lung Institute, Charing Cross Campus, Imperial College, London, UK
* Corresponding author. Tel: +45 86 97 90 67; Telefax: +45 89 49 76 49. E-mail address: dorte.damgaard{at}dadlnet.dk
This editorial refers to ‘Diagnosing familial hypercholesterolemia: the relevance of genetic testing’
by E.S. van Aalst-Cohen et al., on page 2240
What should be the role of genetic testing in cardiovascular medicine? If we adopt genetic testing on a broad scale, moreover, should we also base diagnosis of disease on molecular genetic rather than clinical criteria whenever molecular genetic analysis is possible? These two questions arise from reading the report in this issue of the EHJ by van Aalst-Cohen et al. on familial hypercholesterolaemia (FH).1
The Dutch group of researchers is experienced in studying FH, which in many countries was the first cardiovascular disease for which genetic testing was implemented as part of a screening program. By screening relatives of an index patient for the particular mutation in the index patient known or thought to be responsible for the clinical picture of FH, the Dutch group has identified a large number of FH patients (2818 index cases and 7079 relatives with a mutation in either the LDL receptor gene or the apoB gene).2 They have also shown that participation in such a screening program (cascade genetic testing) importantly raises the number of patients on cholesterol-lowering treatment,3 and researchers in the UK have shown that cascade genetic testing is more cost-effective than screening of the general population.4 There is little doubt, therefore, that genetic testing is valuable when a mutation can be demonstrated in the index patient. The tricky issue is nosological, i.e. the use of molecular genetic analysis for the purpose of defining disease.
For the report published in the current issue of the EHJ, the Dutch group studied 2400 patients considered, by their physicians, to have FH. The cardinal finding was that there was a demonstrable mutation in the gene for the LDL-receptor in only 52% of the patients, and patients with and without such mutations differed somewhat with respect to concentrations of plasma lipids, blood pressure, etc. The authors believe that many of the patients without a detectable mutation in the LDL-receptor gene had some form of dyslipidaemia other than FH, a belief logically connected to their statement that demonstration of a mutation in the LDL-receptor gene is necessary to make an unequivocal diagnosis of FH.
Patients could be included in the study if they had either a mutation in the LDL-receptor gene or a high plasma LDL in combination with one or more clinical or family criteria. As acknowledged by the authors, patients with and without mutations in the LDL-receptor gene, therefore, necessarily differed from each other phenotypically, a feature of the study design that might have weakened the relationship of genotype to clinical phenotype.
Underlying this methodological issue is the larger nosological issue of whether to define diseases phenotypically or genotypically. The authors subscribe to the latter view, which has been prevalent in lipidology, but not in all areas of cardiovascular medicine. Hypertrophic cardiomyopathy, for example, is usually defined phenotypically in terms of unexplained ventricular hypertrophy, and demonstration of a mutation in one or another of at least 10 genes in the index patient is then used for family screening.5
There are historical reasons for the preference of genotypic diagnosis in lipidology. The current era of molecular medicine was begun by the discovery in 1973 of the LDL receptor,6 and for some years thereafter, we believed that deficiency or absence of the LDL receptor was synonymous with FH. In 1987, however, Innerarity et al.7 showed that deficiency of apolipoprotein B, one of the ligands for the LDL receptor, could cause hypercholesterolaemia clinically indistinguishable from that due to LDL receptor defects. Nevertheless, that disorder was given its own name, ‘familial defective apolipoprotein B’. Since then we have learned that mutations in the gene for PCSK9 (proprotein convertase subtilisin/kexin type 9) as well as mutations in the ARH gene (‘autosomal recessive hypercholesterolaemia’) and possibly still other genes can cause the clinical picture of FH. Indeed, the molecular background for FH, like that of many other genetically inherited disorders, has turned out to be heterogeneous and complex. Earlier work by the Dutch group of researchers has taught us, moreover, that the clinical picture depends as much on the environment as on DNA variations.8,9 None of this should surprise us, because heterogeneity, complexity, and contingency are invariable properties of all of biology, and the concept of a perfect match between a particular variation in our genes on the one hand, and a particular clinical picture on the other is an illusion.
The question of diagnosis and definition of disease is obviously important for routine clinical decisions. According to the ‘European Guidelines on Cardiovascular Disease Prevention in Clinical Practice’,10 for example, FH patients should be treated as patients with established cardiovascular disease. Studies from many countries, consistent with the current study from the Netherlands, have shown that approximately half of patients with the clinical picture of FH do not have a demonstrable mutation in the LDL-receptor gene. Nevertheless, the risk of cardiovascular disease is increased to about the same degree in patients with and without demonstrable mutations,11 and in clinical practice, therefore, no one should be comfortable in excluding patients with an unknown genotype from effective preventive treatment. Even in the absence of demonstrable mutations in the index patient, it is also necessary to screen relatives for hypercholesterolaemia, because the genetic and environmental background for heritability of hypercholesterolaemia and cardiovascular risk is almost certain to extend beyond what we currently can detect and understand, even in the best of molecular genetic laboratories.
There is no fully satisfactory solution to the problem addressed by van Aalst-Cohen et al., the imperfect match between genotype and phenotype, but there are arguments for the solution rejected by these authors: a clinical rather than a molecular genetic definition of disease. In a clinical or phenotypical definition of FH, the disorder would again be understood as hypercholesterolaemia (virtually always caused by high concentrations of LDL-cholesterol) occurring with high prevalence within families, often associated with deposition of cholesterol in skin, tendons, and arterial walls.
Defining FH phenotypically does not preclude full exploitation of the current potential of genetic testing. Thus, demonstration in an index patient of a mutation in the gene for the LDL-receptor, for apolipoprotein B, for PCSK9, or for other genes can be used in the examination of family members to confirm or rule out the particular cardiovascular risk associated with that particular mutation. But defining diseases by phenotype lessens the risk, for example, that a patient with the full-blown clinical picture of FH, but in whose DNA we are unable to find a mutation, is told that he does not have the disease.
Thus, analysis of genes can be very useful clinically, and, intellectually, it can be immensely satisfying. Nevertheless, the genetic background for disease has turned out to be more complex than we thought when the LDL receptor was discovered more than 30 years ago. Since then the prospect that an analysis of the DNA sequence could provide us with unequivocal answers to complex clinical issues has receded steadily. Messy as it is, it's the phenotype that matters, be it dyslipidaemia or cardiomyopathy, not the genotype, and, in diagnosing patients and making treatment decisions, there is no real substitute for good clinical judgment.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehl113 
References
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Related articles in EHJ:
- Diagnosing familial hypercholesterolaemia: the relevance of genetic testing
- Emily S. van Aalst-Cohen, Angelique C.M. Jansen, Michael W.T. Tanck, Joep C. Defesche, Mieke D. Trip, Peter J. Lansberg, Anton F.H. Stalenhoef, and John J.P. Kastelein
EHJ 2006 27: 2240-2246.[Abstract] [Full Text]
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