Pseudocholinesterase deficiency

The human genome project was initiated in 1990 to study the structure and characteristics of human DNA that are important for understanding gene functions and their relation to diseases. The large-scale genome research has driven the technology advancement in genetic testing, drug design, gene therapy, and other genetic related areas such as pharmacogenetics. Although the project reveals potential benefits, it raises ethical, legal, and social issues. The outcomes of individuals' genetic information disclosure may lead to confidentiality and genetic discrimination issues. In addition, clinical relevance of genetic testing and psychological effect from the results are debatable. This article discusses the potential benefits and risks from the human genome project. Key Words: Human genome project; Public policy

INTRODUCTION

THE HUMAN GENOME project was launched in 1990 by a joint commission between the Department of Energy (DOE) and the National Institutes of Health (NIH) to identify all of the estimated 80000 genes in human DNA and to determine the sequences of the three billion chemical bases that make up human DNA, store this information in databases, and develop tools for data analysis. It is a 15-year initiative to provide detailed information about the structure and characteristics of human DNA that are critical to understanding the functions of genes and their relation to etiology of diseases (1). More than 60 disease-linked genes have been identified and are believed to be advantageous to gene-based therapy development when the study of human genetics is completed. Potential implications of genetic information and issues raised from the use of that knowledge are discussed in this article.

THERAPEUTIC IMPLICATIONS

Why the Human Genome Project (HGP)?

There are several rationales endorsing the intensive investment and endeavor in the HGP. First, researchers will obtain benefits from economy of scale. In general, the estimated cost of searching for an inherited disease gene (eg, cystic fibrosis) is more than $100 million (2). The total cost of finding all of the human genes, one at a time, according to the estimated cost would be astronomical and prohibitive. The systematic finding approach (all at once), however, helps reduce the cost of finding all genes to $3 billion, or $30,000 per gene. The second reason is to improve the technology for DNA mapping and sequencing, and data manipulation. Major goals of informatics development are to improve data management, analysis, and distribution. Focus has been placed on accessibility and user-friendly tools to organize and interpret a large amount of data. The largescale genome research approach has driven the technology advancement toward enhancing capacity and reducing size. The first fiveyear plan has shown a development in sequencing DNA at reducing cost and increasing rate. The original 1996 goal of $0.50/ base pair has been met, and an additional annual budget of $100 million will be devoted to develop sequencing technology in order to achieve the entire human genome sequences by 2005 (3). A decreased cost of only one cent per base pair could save $30 million in sequencing the entire human genome (2). In addition, the "chromosome painting" technology developed by this project in 1995 was licensed to a private company for research or disease detection in many chromosomal abnormalities such as Down's syndrome and cancers (4). Moreover, the Advanced Technology Program of National Standards and Technology has funded several companies to engage in developing diagnostic DNA arrays and adapting diagnostic tools for analyzing human tissues. Other projects that are developed as high potential diagnosis and treatment tools include applications of DNA "superchip" technology that have a capacity of rapid sequencing, and industrial and environmental monitoring.

Genetic Testing

Who Would Benefit from Genetic Testing? If genetic testing becomes effective and available in the near future, there would be potential benefits to patients, patients' families, physicians, insurance companies, business, society, and government (5). For instance, patients can decide upon an appropriate treatment and life planning while physicians make the best use of time and medical resources to treat patients due to more accurate diagnosis and testing. Some genetic screenings of newborns are very useful for treatment of disease that can be successfully treated. Insurance companies will have good profiles of medical procedures in each disease state, which will help provide for expected long-term complication actuary and coverage. Business and society would benefit from having a healthy and productive population and the government could effectively allocate funds for detecting and treating diseases as demanded by citizens.

The HGP has reformed traditional epidemiological research by providing a better understanding and more precise etiology of genetic disease, especially chronic diseases. It augments the understanding by mapping the genes responsible for the diseases and develops models to predict onset of chronic disease with late onset (6). In addition, the offspring's impending disease from the carriers of recessive genes for untreatable diseases could be avoided by providing genetic counseling about reproductive options. Examples of such tests are Tay-Sachs, HbS, and betathalassemia (7).

The HGP contributes to a better understanding of etiology and risk factors of breast cancer. It reveals that genetic predisposition and environmental factors play more significant roles than the previous hypothesis of environmental carcinogens and hormonal influences (8). As age is one of the risk factors for breast cancer, the identification of breast cancer susceptibility genes and development of testing for breast cancer will reduce the mortality of women who undergo annual mammography. Breast cancer screening and therapy have been improved dramatically in the past decade. Recently, tamoxifen has been approved by the Food and Drug Administration as a preventive medicine for certain types of breast cancer. Early identification of high-risk women will help design strategies for prevention and intensive surveillance.

The Pharmaceutical Industry

Since the Human Genome Project was launched in 1990, a group of outstanding scientists related to the pharmaceutical industry discussed the trend and potential breakthrough for drug design and therapeutic-based pharmaceutical development at the September 30, 1990 satellite meeting, Genome Sequencing Conference II (9). It is estimated that more than 50000 genes will be identified as potential targets for pharmacological intervention. The HGP will help scientists understand the etiologies of multigenic diseases including heart disease, diabetes, hypertension, and cancer. Thus, applying the genomic data will facilitate pharmaceutical interventions in alleviating or even eradicating these diseases. As a part of such a drug design revolution, information from the project databases will expedite the design of oligonucleotide drugs that modulate target DNA transcription. In addition, utilizing the DNA sequencing database to predict threedimensional protein structure and function is substantially advantageous to protein-based drug design. Moreover, the HGP will assist in identification and evaluation of potential chemopreventive agents in cohorts at genetic risk, and will help develop strategies for specific drug targeting (10).

Pharmacogenetics

Although a wide variety of drug categories that work at different target organs are available, they fall behind their maximum effectiveness partially due to the variability in individual genetic differences that have a great impact on drug metabolism. In the past, researchers had observed and experienced the consequences of responses to drugs from different ethnic groups and people who have impaired metabolism for those drugs. In the late 1930s and early 1940s, monitoring sulfonamide blood levels was recognized as a tool to assure the effectiveness of antibacterial therapy. The observation of isoniazidinduced neuritis that is selective among individuals had demonstrated the significance of inter-individual differences in the metabolic fate of the drug (11). In addition to therapeutic failure and drug toxicity due to variation in drug metabolism, genetic polymorphism also plays a role in disease susceptibility as seen in G6PD deficiency. Previously, the pivotal role of pharmacogenetics relied on the limited information on genetic markers for traits and the use of family history, and racial and ethnic background. The new technology of physical mapping and `functional cloning' will enhance the understanding of an aberrant metabolic pathway, that is, an insight into the relevant gene(s) encoding the aberrant protein products (12).

The genetic polymorphisms that have the most clinical relevance are enzymes related to C-oxidation by cytochrome P450 (CYP2D6) and 2Cmeph, acetylation by Nacetyltransferase, S-methylation by thiopurine methytransferase, and ester hydrolysis by pseudocholinesterase (13). Metoprolol poor metabolism is a prototype of the debrisoquine/separteine polymorphism that embraces a broad list of drugs acting on either the central nervous system or cardiovascular system. The livers of poor metabolizers lack active CYP2D6 enzyme due to mutations, resulting in potentiation of adverse drug reactions. Other prototypes involved in genetic polymorphism include mephenytoin, isoniazid, sulphadiazine, 6-Mercaptopurine, and suxamethonium. The mephenytoin metabolic deficiency was initially observed and studied in a family who had unusual sedation after regular doses of mephenytoin (14). It appears that the genetic polymorphism presents in 2-6% of Caucasians, and 14-22% of populations in Far Eastern countries such as Japan, China, or India.

The therapeutic/toxic consequences of polymorphic enzymes, however, impinge on the pharmacokinetic and pharmacodynamic outcomes. The determinative factors for the significance of polymorphic enzymes include the effectiveness of the parent drug or its primary metabolite or both, the overall contribution of the impacted pathway, and the availability and efficiency of an alternative clearance pathway. Nonetheless, the knowledge obtained from genetic studies would lead to allele-specific DNA amplification tests and genotyping, and provide a benchmark for drug dosing and toxicity prevention, especially for low therapeutic index drugs.

Gene Therapy

Gene therapy is a challenge for 21st century health care professionals. It involves the transfer of genes, mostly in a form of an expression cassette, into patients who have "defective genes." The transfer of an expression cassette into target cells could be accomplished via ex vivo (isolate the target cells and transfer the expression cassette in laboratory), or in vivo (directly introduce the expression cassette into target cells within the individual) (15). Human gene therapy is an ongoing research area, and is being developed for a wide variety of diseases such as genetic disorders, cancer, and AIDS. Genetic-based diseases using bone marrow hematopoietic stem cells that are currently in clinical trials include hemophilia B, severe combined immunodeficiency, familial hypercholesterolemia, cystic fibrosis, Gaucher disease, and cancer vaccine. Examples for current gene transfer tools are retroviral vectors, adenovirus and adeno-associated viral vectors, mammalian artificial chromosomes, and cationic lipids and liposomes. In many cases, if temporary expression or transduction is more favorable, only the introduction of DNA or RNA into the cells is sufficient without incorporation of genes into the host genome. This method is considered safer because it avoids insertional mutagenesis, and the DNA or RNA is ultimately eliminated from the host cells. Preparation and administration of gene delivery systems could be an attractive opportunity for health care practitioners, especially pharmacists when special care is required for product delivery in forms of a liposomal system, freeze-dried plasmid, and/or a preparation of unstable virus (16).

RISKS

Ethical, Legal, and Social Issues

Deciphering the entire blueprint of the human genome may raise ethical, legal, and social issues when the genetic information becomes available. The HGP has pondered these potential emerging issues and devoted 3-5% of the genome project budget for ethical, legal, and social issues study. The study concerns five major areas:

1. Genetic testing,

2. Fairness in the use of genetic information,

3. Privacy and confidentiality,

4. Clinical application, and

5. Professional and public education.

Although genetic testing has potential benefits to society, it leads to other issues and concerns regarding who should have access to the genetic information and how it is interpreted, clinical relevance, and the psychological outcomes from the tests.

Privacy and Confidentiality

It is important that the privacy of genetic testing is assured. In other words, individuals who undergo genetic testing have the ability to control, restrict, or refuse unauthorized access to their information (17). If genetic information becomes part of a patient's health history and medical record, however, it will be accessible by insurance companies (18). It is possible that once the genetic information is revealed, patients may receive discrimination in employment and insurance coverage. Employers would prefer the most efficient employees who have few sick days, and no expected serious illness that may lead to increased insurance premiums. The provisions of the Americans with Disabilities Act of 1990 for the relevance of the HGP to the emerging legal, empirical, and policy implications are discussed by Blanck and Marti (19). It is very likely that persons with known onset of disease and potential complications of disease would receive higher premium or coverage denial because of "preexisting conditions."

Clinical Relevance

Manifestation of genetic diseases is varied at different ages from prenatal life to old age (18). For example, Alzheimer's disease, Huntington's disease, Parkinson's disease, and breast and ovarian cancers become more prevalent in advanced age. Children, however, are the most vulnerable population affected by the social risks of genetic testing. The impact of testing results is primarily imposed on the children's families, especially the parents, due to anxiety, guilt, psychological distancing, over-protectiveness, and financial investment for a child with a possibly limited life span (20). In most cases, parents are the decision makers for genetic testing. Therefore, it is important that the competency for medical decision making and understanding of genetic information are addressed. Despite the fact that informed consent intends to emphasize the voluntary nature of testing, occasionally it lacks sufficient information for the participant to make an appropriate decision by weighing the risks and benefits of participation, hence pretest genetic counseling is essential (21). Undoubtedly, there is no necessity to perform genetic tests in children on the late onset genetic susceptible diseases if there is no therapeutic implication or surveillance available. For example, the 1990 committee of the International Huntington Association and the World Federation of Neurology did not recommend a test for Huntington's disease for children under the age of 18 due to the lack of benefit from testing (20). Likewise, breast cancer genetic screening in children should not be performed with the absence of appropriate surveillance recommendations from routine procedures such as mammograms, Pap smear, or PSA test.

The impact of genetic information influencing women's decisions on reproduction, that is, decisions to continue or terminate a pregnancy, is the most challenging issue emerging from the HGP while the treatment of unborn abnormal fetuses is not yet available. At present, the only treatment for many fetal genetic abnormalities pursuant to prenatal diagnosis is abortion (22). It seems worthless for prenatal genetic testing for individuals who would continue the pregnancy regardless of the results (23) unless the information would allow preparation for the caregivers of the child. Moreover, low income and minority women are at risk of being denied access to genetic technology hence, suffering an increased incidence of bearing children with genetic diseases (24). Ideally, genetic counseling should be provided before any testing is performed. Ironically, Medicaid programs in some states provide prenatal genetic tests without providing counseling and coverage for abortion (22).

The Psychological Effect

Although most single-gene disorders probably have a strong genotype-phenotype relationship, the genes are not insulated from others nor can they be influenced by other genetic influences such as their immediate sequence environment or other gene loci. For example, precise genetic abnormalities information in sickle-cell anemia (homozygous parents with beta-globin gene lesion) fails to predict the exact clinical phenotype (25). The variability in severity of the disease is due to the effects of genetic variation either within the regulatory regions that are linked to the gene or the far upstream regions. In addition, other factors also account for the difficulty in predicting the phenotype, including the proportion of cells bearing the lesion (mosaicism), the activity state of the chromosome carrying it (X-inactivation and imprinting), the effects of other loci and their protein products (epistasis), the status of the other allele, and the variable expression of the wild type or mutant allele. Clearly, it is more difficult to achieve perfect manifestation patterns of multifactorial genetic diseases such as heart diseases, familial hypercholesterolemia, cancers, and Alzheimer's disease. Therefore, the result of genetic testing can lead to devastating psychological effects rather than benefits to patients in terms of therapy. Genetic testing outcomes could result in worries about one's health, marital problems, anxiety, sorrow, depression, and even suicidal thoughts (26). Thus, it is pointless to have genetic testing for a disease with late onset and no available therapy. Salkovskis (26) requests an urgent study on the likely type and intensity of psychological reactions to different types of testing. In addition, a study of sensitivity and specificity of genetic testing is warranted prior to any public policy implementation. The ultimate goal of genetic disease treatment involves the restoration of functional homeostasis. Metaanalysis of 65 selected inborn metabolic errors, however, demonstrated that only eight of the errors were cured while the remainder were far from treatment or experienced only partial treatment (27). The stigma of carrying a genetic disease could be a life-long calamity and disgrace for those who lack distinction in knowledge of genotype and phenotype.

CONCLUDING REMARKS

There are a wide variety of benefits that are potentially gained from the HGP on the premise of a genetic revolution. Improvement in mapping and sequencing technologies, and data manipulation will lead to the era of informatics and its use in health care. The study of the entire human genome provides insight into how differences in genetic make up influence manifestations of geneticlinked diseases. In addition, the pharmaceutical industry will benefit from applying the genome project information and introducing new pharmaceutical interventions. Before the genetic information is available, however, researchers need to prepare for emerging issues in the advent of the HGP. In light of preventing, ameliorating, and eradicating diseases, there are prices related to those interventions and the problem is who will pay? Currently, the growth of health care expenditures is exceeding the inflation rate partially due to an introduction of high-cost new therapeutic interventions.

Moreover, the use and misuse of the `informatics' will have a huge impact on individuals and society as a whole. Studies of the ethics, legal, and social issues (ELSI) have been initiated in the hope of addressing potential emerging issues. Prior to applying any informatics to health insurance and public access, the ELSI should exhaustively explore the issues as well as provide a wellestablished set of guidelines and regulations that are ready to approach all of the potential issues. Public education is the primary and crucial foreground to be considered, especially genetic counseling.

In general, most multifactorial geneticlinked diseases are not solely caused by inherited susceptibility. A positive test does not indicate that person will develop the disease and vice versa, a negative result does not guarantee a disease-free future because the risk remains the same as that of the average population such as in the case of cancer. It is still an ongoing dilemma whether the environment or genetics play a more important role in triggering onset of certain diseases even for those caused by a single-gene mutation. Paradoxically, there is a concern for potential malpractice suits for failure to inform about genetic risk regarding a wrongful birth. Therefore, there is a real need for a method to design meaningful genetic testing in medical practice. In addition, focus should be meticulously placed on the employment provisions of the American with Disabilities Act ( 1990) with regard to genetic discrimination. Similar acts will be necessary in order to prevent adverse selection by insurance companies and discrimination by social institutes. In summary, public health policy development needs to address all issues in the arena of informatics and its impact prior to implementing population-based programs designed to minimize morbidity and mortality associated with genetic susceptibility diseases.

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SUVARA WATTANAPITAYAKUL, MS

Doctoral Candidate, Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio JON C. SCHOMMER, PHD

Associate Professor, Department of Pharmaceutical Care and Health Systems, College of Pharmacy, University of Minnesota

Reprint address: Suvara Wattanapitayakul, Division of Pharmacology, College of Pharmacy, The Ohio State University, 500 W. 12th Ave., Columbus, OH 432101214, e-mail: wattanapitayaku1.1@osu.edu.

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