- Ichiro Matsuda, M.D.
Ezuko Institution for Developmental Disabilities
Hokkaido Health Science University
Postal address: 862-0947 Ezumachi, Kumamoto City, Japan
Eubios Journal of Asian and International Bioethics 13 (2003), 57-58.
A critical review from standpoints of ethical, legal and social implications (ELSI) is required to properly develop and distribute genetic services, including genetic testing. In addition to assure analytical validity, clinical validity and clinical utility of the testing, public opinion and perceptions of the community regarding implementation of the testing are important for obtaining informed consent prior to testing. Otherwise, the testing could be done on only limited numbers of community members. Development of effective inversion in clinical practices and regulation to provide confidentiality of all genetic information should bolster the attitude of the community. Education of the public and mass media is the most important factor if progress is to be made in the clinical application of human of human genome research, and to avoid "genohype".
Genetic services in Japan will become much more readily available in the near future. However, the attitude of the general public and their perceptions will be scarcely changed. Generally speaking, the Japanese people are more concerned with society or family conventions than with respecting individual rights, and they have been reluctant to discuss genetic services. The former is related to traditional Japanese culture (1), and the latter related to the relative lack of major genetic diseases, such as thalassemia, cystic fibrosis, Sickle cell anemia and others (2). For example, since the Organ Transplantation Act was established in Japan in 1997, fewer than 30 organ transplantation have been done using cadavers, yet these are over 200 cases of liver transplantation operations involved living family members, mostly parents, including subjects with genetic diseases such as ornithine transcarbamylase (OTC) deficiency, Wilson disease and amyloid polyneuropathy. Even for individuals who gave consent before their death to be a donor for organ transplantation, the procedure is not allowed without additional agreement of bereaved family members. This idea is unacceptable from the viewpoint of western bioethics and respecting autonomy (3). This ignores the individual "advance directive" which depends on the "death-alive-concept" and family convention of the Japanese people.
In the Guidelines of Genetic Research proposed by the Japanese Government in 2000 informed consent is necessary to be obtained from both individual and his/her parents, even though individuals are 18 to 20 years of age,with regard to sampling of biological materials, and such is not necessary in western societies (4). By contrast, this conservative idea involves maternal serum marker testing. The Japanese people are circumspect about population based screening, even now when the birth rate of babies with Down syndrome is on the increase (2,5).
2. Genetic testing for disease susceptibility
Testing for common diseases will lead to several possibilities as stated by Sander (6), " Let us look at how an imaginary patient will benefit from this revolution. Shortly after a person is born, her genotype is recorded at her physician's office, and the information is transmitted to a secure database". Here, the definition of genotype is the presence or absence of specific variations in genes known to be relevant for assessing disease susceptibility and predicting response to a known drug type, but not the genotype of catastrophic monogenic disorders. This might be acceptable when information on genotype is reliable and will prevent the disorders by changing individual life styles, or is treatable with specified drugs. Colorectal cancer (CRC) rates for Japanese migrants to the United State rapidly increased to surpass the level of the host population (7). CRC rates for the Japanese in Hawaii and California are now the highest in the world (8). Even in Japan, rates for CRC have increased, perhaps related to increased consumption of western style food, in addition of several relevant genotypes, such as NAT2, and CYP1A (7). However, 10 years or longer will be required to prove a definite gene-environmental interaction.
For known cancer genes involving hereditary tumor (e.g. BRCA1, BRCA2), essential parameters evaluating the testing such as positive predictive value and negative predictive value (9) are lacking, a lower rate of familial tumors compared to other populations being one reason (10). However, again it will take a longer period to define effective measures to prevent cancer manifestation in a certain genotype positive population. The idea also applies to other common diseases.
Even if preventing measures are available, at what age should one initiate genetic testing? If the measures taken do not benefit until an early adult age, the testing should not be considered for newborns (11). The susceptibility factor, similar to monogenic diseases, could lead to discrimination or stigmatization. What one can do and what one has to be considered differ. Validity and efficacy of testing, careful ethical evaluation and correct social policies are keys to resolve these issues.
3. Prenatal testing
According to a survey in 1996 (1,518 individuals), for all individuals regardless of medical professionals, non-medical professionals or patients plus family members over 85% said that they would accept a prenatal diagnosis, if available and if there is a possibility that the fetus has a (severe) genetic diseases (12). In the surveys of the general public by Macer similarly high levels are observed (23). Under the condition that the disease of the affected fetus is less severe and treatable, 81% would choose a live birth. When the fetal disease is severe and untreatable, though the term of "severe" is open to discussion, 22% of women wanted a child. However, in another survey of prenatal diagnosis in 1997, 89% of those diagnosed with fetal abnormalities, mostly chromosomal abnormalities, terminated the pregnancy. It is unclear whether this 10% difference is due to different populations surveyed or to other factors. Prenatal diagnoses of pregnant women over age 35 years were given to only 4% of the Japanese in 1997 (2), with over 50% in Germany in 1989 (13) and 60% in France in 1991(over age 38 years) (14). The large difference between reply in the above survey and numbers of tested cases may be because Japanese women are reluctant to accept a prenatal diagnosis only because of advanced age or to insufficient information given by obstetricians. There may be a difference, of course, between prospectively proposed (1996) and actual rate of the testing (1997). Fetal disorders, including several chromosomal abnormalities can be determined using ultrasonic tests (15) and the testing is most common in obstetric clinics. Fetal cells circulating in the maternal blood stream will be widely used for prenatal testing (16). The rate of acceptance of the prenatal testing may change in the near future as non-invasive measures become available.
Prenatal diagnosis can yield useful information to determine early effective treatments in some cases. In OTC deficiency, specific gene mutations are relevant to a mild or moderate clinical course and early treatment can be effective. In our experience, of 21 cases of prenatal monitoring for OTC deficiency, one male fetus with Arg129His and two male fetuses with Arg40His were diagnosed based on molecular analysis of amniotic cells (17). They enjoy normal school life as treatment was initiated immediately after birth. Neonates with adenosine-deaminase deficiency have benefited from gene therapy. (18). Further progress in therapies, including effective gene therapy and drug development targeted to specific inherited diseases could influence the future of prenatal diagnoses in Japan. There remains a large discrepancy between advances of diagnosis with molecular analysis and a shortage of effective therapies for subjects with severe monogenic diseases.
Concerning pre-implantation diagnosis, no case has been reported in Japan, even though the technology is sufficent. Ethical Committees of Japan Society of Obstetrics and Gynecology held back on approval in the first case of pre-implantation diagnosis of Duchenne muscular dystrophy, since technical conditions proposed were insufficient. Similar to the case of organ-transplantation, parents who a want pre-implantation diagnosis will go to other countries where the diagnosis is readily available.
4. Genetic service system and education of clinical genetics
Today, the genetic counseling system is still at a premature stage in Japan. Board examinations for clinical geneticists were established in 1994 by Japan Society Human Genetics (JSHG) and 103 doctors were certified by 2001. In addition, there are 267 doctors certified as "Clinical Genetists", depending on their history of genetic training. Recently, JSHG proposed to unify these 370 clinical geneticists and 67 "Genetic Counselors" certified by the Japan Society of Clinical Genetics (22 have both certifications). Also they stated, "there should be opportunities for training future medical genetic personnel, not only doctors, but also for co-medical staff such as nurses and public health nurses to better meet the needs of users" in the "Guidelines of genetic testing" in 2000 (19). The greatest disadvantage in promoting a genetic counseling system in Japan is the cost, as governmental health care insurance does not cover the costs. In addition, clinical genetic curricula in medical schools and residency training to enable all physicians to recognize genetic risk factors in patients and families is not well developed in Japan. Genetic counseling will in future be more targeted to genetic risks for common diseases, and depending on the circumstances a center of genetic services needs to be established in each prefecture. JSHG proposed in the "Caution in genetic testing by commercial laboratories" in 2000 (20), that a careful evaluation of each genetic testing by authorized facilities, and cross-talk between medical facilities and commercial laboratories conducting rational testing should be established.
The public and mass media must be careful to avoid "genohype" (21). The necessity to educate the general public was proven in cases for the genetic screening programs of Tay Sachs disease in Ashkenazi Jews and _-thalassemia in Cypriotes (22).
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