© 1998 American Heart Association, Inc.
Editorial |
Clinical Criteria Versus DNA Diagnosis in Heterozygous Familial Hypercholesterolemia
Is Molecular Diagnosis Superior to Clinical Diagnosis?
From the Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Humboldt University of Berlin, Berlin, Germany.
Correspondence to Dr Herbert Schuster or Prof Friedrich C. Luft, Franz-Volhard-Klinik, am Mas-Delbruck-Centrum, Wiltbergstrasse 50, D-13122 Berlin, Germany. E-mail luft{at}fvk-berlin.de
Key Words: familial hypercholesterolemia • molecular genetics • lipid disturbances
More than half of all deaths in Western society are related to arteriosclerotic cardiovascular diseases. Approximately 5% of coronary artery disease (CAD) before the age of 55 years is attributable to familial hypercholesterolemia (FH), an autosomal-dominant disease.1 In contrast to population hypercholesterolemia, FH typically leads to a twice-normal LDL cholesterol level for age and sex and to heart attacks in early middle age. The frequency of FH is estimated to be 1 in 500, roughly half a million in the United States and >10 million persons worldwide. FH is also a very heterogeneous disease; worldwide, at least 300 mutations involving several genes divide the clinical disease into two major entities, namely, LDL receptor defects and apoB-100 defects (see Day and Humphries at the World Wide Web site http://www.ucl.ac.uk\/fh for up-to-date information). However, the number of mutations within certain populations varies, due to genetic drift, founder effects, and consanguineous marriages. In the apoB gene, the arginine 3500 to glutamine mutation is also common and affects about one in 600 people.2 This mutation seems to be of central European origin and could not be identified in other Europeans, such as Finns and Russian.
Traditionally, the diagnosis of FH is based on clinical findings, an autosomal-dominant family history pattern of early CAD, and elevated LDL cholesterol levels. In some cases, cholesterol deposits ("xanthomata") in the skin and tendons suggest the diagnosis. However, phenotypes overlap and family studies are complicated to perform. A genetic test for FH has utility in several applications. The FH test provides a simple yes/no answer in terms of FH diagnosis. Cholesterol concentrations, after all, are a continuous variable. The FH test is a definitive tool for family tracing. The FH test is useful in the differential diagnosis of high-risk patients. Finally, there may be some prognostic value for FH testing, in that "cholesterol-years" is a more accurate predictor of risk than is the early identification of carriers with milder mutations. However, indirect DNA diagnosis is complicated by locus heterogeneity and the high frequency of hypercholesterolemia.
In the November 1997 issue, Vuorio et al4 have
made use of the unique geographic and historical situation of the
Finnish population, comprising 180 000 individuals in North Karelia
province, to perform a genetic epidemiological study to delineate the
impact of FH as a determinant of CAD risk in a high-incidence area. The
mean age of onset of symptomatic CAD was 42 years for men
and 48 years for women. The corresponding ages at the time of first
acute myocardial infarction were 47 and 59 years, respectively. The
investigators also assessed the effectiveness of molecular genetic
techniques in diagnosis. Their goal was the complete recruitment of
patients in this population. Extensive genealogical studies by the
investigators showed that one specific mutation, termed FH-North
Karelia, which is characterized by a deletion of seven
nucleotides from exon 6 in the LDL receptor gene, accounts
for 
90% of all FH cases in this population. DNA samples were
available in 95% of this group. Most important, the authors showed
that FH is responsible for the relatively high incidence of CAD in
Finland by demonstrating its presence in 9% of young patients with CAD
in North Karelia. Interestingly, the variation in onset of CAD was
mainly due to nonlipid factors, such as age, sex, and smoking habits.
DNA analysis avoided the 2% false-negative and 7%
false-positive diagnoses that occur with clinical criteria. These data
provide the scientific background to develop case-finding programs and
primary prevention strategies to decrease morbidity and mortality. They
are particularly applicable in Finland, which has a well-organized
public health services.
An increasingly important issue in health care systems is cost-effectiveness. In general, the efficacy of any test system is based on its sensitivity, specificity, and prognostic value. A second factor that is often ignored is pretest probability. In genetic disorders, pretest probability is generally low (1 in 500 for FH). Therefore, specificity is more important than sensitivity. Specificity is defined as the ability of a test to identify as "positive" only those individuals who actually have the disease. The test must avoid false-positive results to avoid treatment of unaffected individuals. In a situation with a high pretest probability, identification of healthy individuals as healthy is important to avoid missing the diagnosis and treatment of sick individuals. This attribute is called the sensitivity of a test. Most clinical tests are compromises between sensitivity and specificity. The main advantage of DNA diagnostics is its very high specificity compared with clinical criteria. Currently, determining the cost of DNA diagnostic tests is difficult. None of the high-throughput automated methods have been applied in those populations where FH is prevalent and all the mutations are known. As with any other diagnostic test, the costs will decrease considerably with full automation and application in reference laboratories and when large sample numbers are examined. Currently, in a research environment the cost of a test is similar to the cost of a single month's drug treatment. Since the test needs to be done only once in a lifetime, its cost-effectiveness seems assured. The new tools in DNA diagnostics will particularly benefit subsets of patients at high risk for premature atherosclerosis and coronary heart disease, namely, those with a positive family history.
We have recently established a new DNA assay, an oligonucleotide ligation assay , based on both the polymerase chain reaction and oligonucleotide ligation methods.3 We have successfully modified this assay to identify multiple mutations and to handle large numbers of samples simultaneously. The test uses mobility modifiers, which allow the method to be adapted to automated genotyping systems, thereby making it useful for analysis of large numbers of samples. The oligonucleotide ligation assay method could allow the identification of as many as 200 separate mutations in a reasonable amount of time. Because of its automation, reference laboratories will be in a position to provide this service for large numbers of patients at a reasonable price. Despite the fact that this technology needs expensive equipment, its high degree of automation is very cost-saving in terms of personnel and space.
Three recent studies have indicated that heart attacks can be reduced
by one third and deaths related to heart attacks by 40% with drug
treatment in high-risk individuals.5 6 7 The
definition of high risk is important, because serum
cholesterol levels included in this category overlap the
normal range. Thus, current guidelines for managing
hypercholesterolemia are likely to
change.8 Whereas treatment regimens for secondary
prevention are no longer under discussion, primary prevention is the
important issue for the future. Since cholesterol lowering
has been shown to be effective in almost all individuals, effectiveness
is entirely dependent on risk. Consequently, cost-effectiveness of
treatment considerations should be based on proper risk assessment.
There is a need for primary prevention, since at least 30% of
individuals with CAD never get any chance for intervention or secondary
prevention because of their high, 30% sudden death rate. Currently,
testing procedures for risk assessment rely on total
cholesterol, LDL cholesterol, HDL
cholesterol, and triglyceride determinations
and other cardiovascular risk factors like
hypertension, diabetes, and left ventricular
hypertrophy. These tests and diagnoses are not able to
provide any genetic information. We predict that genetic
diagnostic screening will be of major importance in the
future. In Finland the future is now.
Received December 1, 1997; accepted December 1, 1997.
References
1.
Brown MS, Goldstein JL. A receptor mediated
pathway for cholesterol homeostasis.
Science. 1986;232:34–47.
2.
Hansen PS, Defesche JC, Kastelein JJ, Gerdes LU, Fraza
L, Gerdes C, Tato F, Jensen HK, Jensen LG, Klausen IC, Faergeman O,
Schuster H. Phenotypic variation in patients heterozygous for familial
defective apolipoprotein B (FDB) in three European countries.
Arterioscler Thromb Vasc Biol. 1997;17:741–747.
3. Baron H, Fong S, Aydin A, Bähring S, Luft FC, Schuster H. A novel oligonucleotide ligation assay for the diagnosis of familial hypercholesterolemia. Nat Biotechnol. 1996;14:1279–1282.[Medline] [Order article via Infotrieve]
4.
Vuorio AF, Turtola H, Kontula K. Neonatal diagnosis of
familial hypercholesterolemia in newborns born
to a parent with a molecularly defined heterozygous familial
hypercholesterolemia. Arterioscler Thromb
Vasc Biol. 1997;17:3332–3337.
5. The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389.[Medline] [Order article via Infotrieve]
6.
The West of Scotland Coronary Prevention Study
Group. Prevention of coronary heart disease with
pravastatin in men with
hypercholesterolemia. N Engl J
Med. 1995;333:1301–1307.
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average cholesterol levels. N Engl J
Med. 1996;335:1001–1009.
8. Ramsy LE, Haq IU, Jackson PR, Yeo WW, Pickin DM, Payne JN. Targeting lipid-lowering drug therapy for primary prevention of coronary disease: an updated Sheffield table. Lancet. 1996;348:387–388.[Medline] [Order article via Infotrieve]
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