pp. 125-128 in Intractable Neurological Disorders, Human Genome Research and Society. Proceedings of the Third International Bioethics Seminar in Fukui, 19-21 November, 1993.

Editors: Norio Fujiki, M.D. & Darryl R.J. Macer, Ph.D.

Copyright 1994, Eubios Ethics Institute All commercial rights reserved. This publication may be reproduced for limited educational or academic use, however please enquire with Eubios Ethics Institute.

Genetic screening for prevention of common diseases

Hideo Hamaguchi
Professor, Department of Medical Genetics, Institute of Basic Medical Sciences, University of Tsukuba, JAPAN

Presymptomatic diagnosis for common diseases in which preventive measures and therapy are available is considered to be useful for the prevention of the diseases. Good examples include premature coronary artery disease where genetic and environmental factors contribute to risk. There is ample possibility to prevent premature coronary artery disease by dietary therapy, no smoking and medication. Among the genetic factors of premature coronary artery disease, it is possible to analyze the responsible genes, or their protein products, in the case of familial hypercholesterolemia due to the mutant low density lipoprotein (LDL) receptor gene and in the case of high plasma lipoprotein(a) (Lp(a)) concentrations due to genetically determined small size apolipoprotein(a) (apo(a)) genes (Table 1).
Table 1: Presymptomatic diagnosis for common diseases where intervention is possible

Example: Coronary artery disease

(1) Familial hypercholesterolemia due to the mutant LDL receptor gene
Large effects on the development of coronary artery disease are not common (frequency 0.2%)

(2) High plasma Lp(a) levels due to apo(a) isoforms and variability in gene sequence
Significant effects on the development of coronary artery disease are common (frequency 5-10%)

The risk for premature coronary artery disease is high for familial hypercholesterolemia, though the incidence of individuals is about 1/500, which is not very common, in most Caucasian populations and Japanese. Familial hypercholesterolemia is an autosomal dominant condition. Hypercholesterolemia due to high plasma LDL levels appears in the neonatal period and exists throughout life.

We have been detecting individuals with familial hypercholesterolemia from the family members of the patients with this disease who are under medical treatment, using clinical genetic methods. Then we lead or treat them for the prevention of coronary artery disease. Thus far we have detected 40 families with familial hypercholesterolemia. We also have detected various types of mutations in the LDL receptor gene among these families (1-4).

We have been carrying out genetic screening for familial hypercholesterolemia utilizing the school survey which is carried out by Ibaraki Prefectural Service Association (5,6). The subjects are 9 year old and 12 year old children. Prior to this genetic screening, we have obtained the approval from the P.T.A., school principals, and the local medical associations. After screening of hypercholesterolemic children by the Prefectural Health Service Association, we have explained the cause, preventive measures and therapy of hypercholesterolemia to the parents of hypercholesterolemic children. Then we have done voluntary genetic analysis of families of hypercholesterolemic children. We have obtained informed consent from the parents before conducting the tests for families.

We have detected 242 hypercholesterolemic children from 3453 screened. About half of the parents of the hypercholesterolemic children participated in our genetic screening and five families with familial hypercholesterolemia have been detected (Table 2). Almost all adults with familial hypercholesterolemia are under medical care. The mothers of children with familial hypercholesterolemia are eager to implement and maintain dietary therapy for their children. The social acceptance for this genetic screening is considerably good in this local community.

The reasons why our genetic screening for familial hypercholesterolemia is so well accepted, with good consequences locally include the following:
1) Availability of preventive measures and therapy for hypercholesterolemia, especially medication in the case of Japanese
2) No prejudice against hypercholesterolemia
3) The spread of education among the public for hypercholesterolemia
4) Positive cooperation of staff of the Prefectural Health Service Association, public health nurses and school nurses

Table 2: Genetic screening for familial hypercholesterolemia through a school survey

School age children screened 3457
Hypercholesterolemic children 242 (7%)
Parents participating in the test 230
Familial hypercholesterolemia 5 families

Recently it has been established that high plasma Lp(a) levels are an independent genetic risk factor for premature coronary artery disease. About 90% of individual differences in plasma Lp(a) levels have been reported to be determined by the genetic differences in the apo(a) gene, whose product is an important constituent of Lp(a). The individual difference in the apo(a) gene size is especially important for the determination of plasma Lp(a) levels. About 5 to 10% of individuals have the small size apo(a) genes that determine high plasma Lp(a) levels, and the frequency is high at least among Caucasian and Japanese populations. High plasma Lp(a) levels are thought to exert a significant effect on the development of premature coronary artery disease.

The frequency distribution of plasma Lp(a) levels in Japanese are very similar to that in most Caucasian populations. About 10% of individuals have high plasma Lp(a) levels above 30 mg/dl. There are at least 25 kinds of apo(a) which are genetically different in molecular weight (7). This means the presence of extreme differences in the apo(a) gene size among different individuals. There is a tendency that the lower the molecular weight of apo(a), the higher the Lp(a) levels. According to our data, about 70% of healthy subjects whose apo(a) molecular weights are smaller than 680 kDa have high plasma Lp(a) levels above 30 mg/dl (8).

In our studies on 369 Japanese patients with coronary artery disease and 389 healthy controls, the odds ratio for the disease was 2.7 in the case of high plasma Lp(a) levels and 2.8 in the case of apo(a) with molecular weights smaller than 680 kDa, respectively (9). This level of the risk seems to be similar to that of smoking and moderate hypercholesterolemia. Therefore I think genetic tests for plasma Lp(a) levels are important as a presymptomatic diagnosis for premature coronary artery disease on an individual and family basis. Genetic screening for Lp(a), however, might be premature, mainly because dietary therapy and medication are not useful and because the risk for the disease is not large.

Genetic screening for presymptomatic diagnosis of common diseases where medical intervention is possible will become more and more important, because Human Genome Project will promote the discovery of more and more disease susceptibility genes. In the genetic screening for common diseases, the following points should be considered:

1) Preventive measures and therapy
2) Prejudice against the disease in question
3) Levels of effects of the gene on the disease
4) Education of the public
5) Voluntary genetic screening coupled with genetic counseling
6) Informed consent
7) The duty of confidentiality to protect individual privacy

This year it was revealed that a common allele at the apolipoprotein E locus, E4 is an important susceptibility gene for common late-onset Alzheimer's disease. In many Caucasian populations, the frequencies of heterozygotes for E4 and homozygotes for E4 are 20 to 30% and 2 to 3%, respectively. According to our data, the frequencies of heterozygotes for E4 and homozygotes for E4 in the Japanese population are about 18% and about 1%, respectively (10). For part of a rare autosomal dominant early-onset form of Alzheimer's disease, the responsible gene has already been identified. Since no preventive measures and therapy for Alzheimer's disease are available at present, presymptomatic DNA analysis for this disease can not be coupled with medical intervention. The development of preventive measures and therapy are the prerequisite for genetic screening for common diseases. The development of preventive measures and therapy are also necessary to get rid of the prejudice against some common diseases such as schizophrenia.


1. Yamakawa, K. et al. (1989) Three novel partial deletions of the LDL receptor gene in familial hypercholesterolemia. Human Genetics 82: 317.
2. Yamakawa, K. et al. (1991) Family studies of the LDL receptor gene of relatively severe hereditary hypercholesterolemia associated with Achilles tendon xanthomas. Human Genetics 86: 445.
3. Yamakawa, K. et al. (1993) Two novel frameshift mutations associated with the presence of direct repeats of the LDL receptor gene in familial hypercholesterolemia. Human Genetics 92: 331.
4. Yamakawa-Kobayashi, K. et al., A novel complex mutation in the LDL receptor gene probably caused by the simultaneous occurrence of deletion and insertion in the same region. Human Genetics (in Press)
5. Yanagi, H. et al. (1990) Family studies of primary hypercholesterolemia in school children: The Tsukuba study. Jpn. J. Public Health 37: 585 (in Japanese with English abstract).
6. Yanagi, H. et al., Cardiovascular risk factors among Japanese school-age children: A screening system for children with high risk for atherosclerosis in Ibaraki, Japan. Jpn. J. Public Health (in Press), (in Japanese with English abstract)
7. Kikuchi, S. et al. (1993) High degree of genetic polymorphism in apolipoprotein(a) associated with plasma lipoprotein(a) levels in Japanese and Chinese populations. Human Genetics 92: 537.
8. Yanagi, H. et al. (1993) Frequent occurrence of familial aggregations of high lipoprotein(a) levels associated with small apolipoprotein(a) isoforms. Human Genetics 92: 547.
9. Kikuchi, H. et al., Role of apolipoprotein(a) size polymorphism and plasma lipoprotein(a) levels in coronary heart disease in Japanese. (submitted)
10. Hamaguchi, H. et al., Genetic risk factors for coronary heart disease in the Japanese population, pp. 110-126 in Berg, K. et al. (eds) Genetic approaches to coronary heart disease and hypertension (Springer-Verlag, Berlin-Heidelberg, 1991).

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