Genetic factors in multiple sclerosis

OBJECTIVE: To evaluate the role of candidate genes in the susceptibility to multiple sclerosis (MS) and describe the role of T-cell receptor (TCR) gene rearrangements in the MS brain lesion in identifying a major target of the immune response in this disease. DATA SOURCES: MEDLINE, bibliography review of published data, and unpublished studies. STUDY SELECTION: Published studies using novel molecular approaches to analyze the role of the major histocompatibility complex (MHC) and TCR gene complexes, as well as other candidate genes, in susceptibility to MS. We analyze epigenetic events involving TCR genes in individuals with MS and describe recent clinical trials in which immunotherapy has been attempted. DATA SYNTHESIS: Consistent with a polygenic model for disease predisposition, MHC and TCR gene associations with MS are relatively weak. Despite intensive research, no other putative "MS genes" have been firmly established. The analysis of TCR rearrangements in the brain lesion has helped to identify a major target of the immune response in MS. CONCLUSION: Understanding the genetic basis for autoimmune demyelination will offer new possibilities for the treatment of this illness.     

Molecular pathogenesis and prognostic factors in testicular tumor

Aim of this review article was to critically analyse the recently described zytogenetic and molecular markers for testicular germ cell tumors with regard to their clinical utility. The isochromosome i(12p) represents the most common and characteristic cytogenetic finding which already appears in testicular carcinoma in situ. A number of proto-oncogenes (Cyclin D and PTHLH) as well as putative tumor suppressor genes are localized on 12p; however, their role in pathogenesis and prognosis of testicular germ cell tumors has not been defined yet. Clinical characteristics of patients with familial testicular germ cell tumors indicate a genetic background for the development of testicular tumors. Although a number of chromsomal loci encoding potential testicular tumor susceptibility genes have been identified, the genetic basis of testicular cancer pathogenesis is still unknown. With regard to molecular prognostic risk factors most of the reported data on proliferation markers, tumor suppressor genes, proteases and adhesion molecules have to be confirmed in prospective randomized trials prior to their widespread clinical use. Based on the available data on prospective studies percentage of embryonal carcinoma and vascular invasion appear to be the most significant prognosticators. Investigation and identification of those factors determining the aggressive biologic behavior of embryonal carcinoma compared to all other histological components appear to be most promising in research for prognosticators of metastatic disease. In conclusion, the increasing knowledge of molecular genetic events involved in pathogenesis and prognosis of testicular germ cell tumors will not only help to better understand development and progression of testicular cancer, but it also will define new approaches to classification and management of germ cell tumors.     

Modification of pentasaccharide core of surface N-glycans during differentiation of HL-60 cells

Graves' disease (GD) is generally thought of as a multifactorial disorder in which genetic susceptibility interacts with environmental and endogenous factors to cause disease. The importance of genetic factors is suggested by the clustering of GD within families and by a higher concordance rate for disease in monozygotic than dizygotic twins. This has, however, recently been shown to be less pronounced than previously thought. During the last decade, much effort has been put into characterization of the genetic background of GD. Until recently most studies have examined associations between GD and the human leukocyte antigen (HLA) region, but recent advances in molecular techniques have opened the way for whole-genome screening. A number of HLA and non-HLA candidate genes have been proposed, but despite several large investigations within multiplex families no major susceptibility genes have been identified. This brief review discusses relevant articles published from 1940 through 1997 regarding the influence of genetic factors in the etiology of GD. Ongoing studies will focus on whole genome screening in multiplex families as well as population based twin studies. However, the possibility of GD being a heterogeneous disease without a single well-defined genotype and phenotype should be left open.     

The genetics of human noninsulin-dependent (type 2) diabetes mellitus

Familial aggregation and concordance in monozygotic and dizygotic twins argue strongly for a genetic etiology to noninsulin-dependent diabetes (NIDDM). Nonetheless, studies of pathways implicated by the known physiology have failed to identify gene defects that can explain the genetic susceptibility. In contrast, studies of early onset dominant diabetes have revealed three major loci resulting in diminished insulin secretion. Recently, studies have taken a new approach to map the genes causing typical NIDDM using large numbers of families or sibling pairs. The first reports of these studies have suggested possible loci on chromosomes 1, 2 and 12, but no report has been confirmed. Other studies have examined the quantitative defects that may be precursors of clinical NIDDM such as hyperinsulinemia, hyperglycemia, insulin response to glucose and obesity. These studies have suggested additional loci that may contribute to NIDDM susceptibility, but the genes responsible for most of these loci remain unknown. Studies of NIDDM susceptibility and the role of obesity genes in that susceptibility have entered an exciting new phase, but the challenges of complex disease genetics in humans will have to be conquered to translate this research into preventive or therapeutic benefits.     

Cancer susceptibility genes and molecular carcinogenesis. American Association for Cancer Research Special Conference: Cancer Susceptibility Genes and Molecular Carcinogenesis

As elaborated by Nobel Laureate Harold Varmus (Director of the National Institutes of Health, Bethesda, MD, USA) in his Keynote address, future studies must not only continue to expand our repertoire of genetic determinants of cancer susceptibility by identifying new cancer susceptibility genes, but most also now begin to address the function of these genes and their roles in the process of tumor development. Key areas for future investigation in this field, identified at the meeting, were: (1) understanding how susceptibility genes are altered in cancer cell physiology, (2) elucidating the function of these genes in the biochemistry of cellular signaling pathways; and (3) improving our ability to use this information to extrapolate basic oncology research to the clinic. At this meeting, the fields of molecular carcinogenesis, DNA repair and human genetics were very successfully integrated. These fields have converged in the areas of cell cycle control and genetic susceptibility, and this meeting capitalized on this convergence to highlight recent progress in these areas. Key areas for future research were also emphasized, including the need to apply the rapidly emerging information from these fields towards developing novel therapeutic modalities to treat and prevent cancer.     

Schizophrenia genetics at the millennium: cautious optimism

As the new millennium approaches, research into the genetic aspects of schizophrenia has already made an impressive start toward an integrated model which is discovering roles for genetic agents, environmental agents and experiences, and chance factors. The best model follows that proposed for understanding such complex diseases as coronary artery disease and diabetes. Genetic information has come from both genetic epidemiology and molecular genetics. Evidence for gene regions on 6p and 8p gives the strongest support for harboring schizophrenia susceptibility genes, based on international collaborative studies that "generally" replicate one another; evidence for regions on 3p, 5q, 9p, 20p, and 22q, while less compelling, will encourage focused work. Determining the steps between the regions and the phenotype will challenge the next generation of scientists.     

Genetic susceptibility to visceral obesity and related clinical implications

This paper reviews evidence supporting the notion that genetic factors may have an influence on the determination of body fat distribution, particularly emphasizing the genetic susceptibility of visceral adipose tissue (AT) accumulation. The potential contribution of genetic susceptibility to the development of metabolic alterations in visceral obese individuals will also be reviewed. The contribution of genetic factors to the variation in body fat distribution is supported by studies in which racial differences in body fat distribution were reported. These ethnic differences suggest that body fat distribution may be influenced by some components of the genetic background which are shared among individuals of a given race. Furthermore, the familial aggregation and the resemblance between monozygotic twins that have been observed for anthropometric measurements of body fat distribution and for visceral AT accumulation measured by computed tomography, also suggest that genetic factors are involved in the determination of body fat distribution. Genetic susceptibility may also influence the relationship between visceral AT accumulation and the development of metabolic alterations. In this regard, it has been reported that the polymorphism of some genes (for example, the apolipoprotein (apo) E, apo B100 and lipoprotein lipase genes) is altering the relationship between visceral obesity and plasma lipoprotein-lipid levels. In conclusion, results presented in this paper suggest that genetic factors seem to have a significant influence on the propensity to accumulate AT in the visceral depot and that genetic factors also seem to affect the associations commonly reported between visceral obesity and the development of metabolic alterations.     

Lesions of the posterior insular cortex impair water maze performance in the rat

This special issue of Patient Education and Counseling on genetic education and counseling provides an overview of studies and findings in this field. It features a mixture of papers dealing with five different topics related to several psychosocial aspects of genetic education and counseling. Attention is paid to new issues in counseling for hereditary cancer and Huntington Disease. Articles are presented on information recall of counseled individuals, the use and impact of genetic services on counselees (acceptance of testing; knowledge of inherited cancer susceptibility; risks of genetically testing children). Also topics are addressed with respect to the counselor (neutral attitude; understandable language; information recall; satisfaction with the services provided by the genetic counselor). Furthermore, recommendations are discussed for screening practices for women with a family history of breast cancer, and in addition, the effectiveness of genetic counseling is addressed. In conclusion several suggestions for future research are given.     

Androgen receptor and mating-induced fos immunoreactivity are co-localized in limbic and midbrain neurons that project to the male rat medial preoptic area

The repair of DNA damage protects the genome of the cell from the insults of cancer causing agents. This was originally demonstrated in individuals with the rare genetic disease, xeroderma pigmentosum, the prototype of cancer genes, and subsequently in the relationship of mismatch repair to colon cancer. Recent studies suggest that individuals with less dramatic reductions in the capacity to repair DNA damage are observed at polymorphic frequency and these individuals have an increased susceptibility to several types of cancer. Screening of individuals for DNA sequence variation in the exons of 9 DNA repair genes has resulted in identification of 15 different polymorphic amino acid substitution variants. Although the studies to relate these variants to reduced DNA repair capacity and cancer status have not been completed, the available information is sufficient to suggest that DNA repair genes should be incorporated into molecular epidemiology and cancer susceptibility studies. The availability of molecular epidemiology data presents exciting opportunities for refinement of risk estimation models and identification of individuals at increased risk of disease, with resultant opportunities for effective surveillance and early intervention and treatment. The opportunities to acquire susceptibility data are associated with possible perils for establishment of regulations for permissible exposures to carcinogenic agents and also stigmatization of 'at risk' individuals that may result in decreased access to employment opportunities and health care.     

Personality and the inheritance of smoking behavior: a genetic perspective

In contrast to the extensive research effort to understand the genetic contribution to alcoholism risk, there has been little research directed at understanding genetic influences on smoking behavior. Data from large twin studies in Scandinavia and Australia are consistent with a major genetic influence on the probability that an individual will become a smoker ("initiation") and will persist in the smoking habit once smoking has started ("persistence"). We use data from the 1988/1989 follow-up survey of the Australian NH&MRC twin panel to determine to what degree personality measures (Tridimensional Personality Questionnaire, Eysenck Personality Questionnaire--Revised) and attitudinal and sociodemographic variables (social and political conservatism, education, religious involvement) might account for genetic or environmental influences on smoking. While we find significant phenotypic associations between these variables and smoking, these are too modest to account for much of the genetic variance. Possible mechanisms by which this genetic variance may arise are discussed.     

The role of ethnicity in cancer susceptibility gene polymorphisms: the example of CYP1A1

Individual susceptibility to cancer from environmental agents may be influenced by polymorphic metabolic genes such as CYP1A1. The CYP1A1 gene contains four major polymorphisms identified to date. A modern nomenclature system, used with other genes, is presented to clarify the identity of these polymorphisms. The various CYP1A1 alleles exhibit population frequencies that depend on ethnicity. The association of these alleles with cancer at several sites has also been found to depend on racial or ethnic origin of the study population. Statistical considerations, such as the need for large studies when the power to detect a rare polymorphism is low, and ethnic differences in genetic linkage disequilibrium are among possible reasons for ethnic-specific effects on cancer susceptibility related to metabolic gene polymorphisms. New efforts to determine population frequencies of such polymorphisms are essential for future research in this area.     

Joe Doupe Young Investigators Award. The Human Genome Project: tools for the identification of disease genes

In the first phase of the Human Genome Project, new and ingenious tools have made it possible to map all the individual nucleotides that make up the 23 human chromosomes. During the next 5 years, the 3 billion DNA bases and the 50,000 to 100,000 genes will be sequenced. This knowledge will have widespread applications in biology, medicine and industry. The genetic research community currently has access to abundant DNA markers, detailed chromosome maps, extensive online databases as well as rapid DNA analysis technologies, all of which can be used to identify disease-causing genetic mutations. In the next 15 to 20 years, the Human Genome Project is expected to identify defective genes causing thousands of hereditary diseases, including common diseases such as heart disease, diabetes, asthma and cancer. The hope is that these discoveries will lead to better understanding of the causes of these diseases, and to better approaches to diagnosis, prevention and treatment of human genetic disorders.     

Dissecting the genetics of type 1 diabetes: relevance for familial clustering and differences in incidence

A combination of genetic and environmental factors is most likely the cause of Type 1 diabetes. Results from twin data, familial clustering of the disease and difference in incidence according to ethnicity infer the presence of specific disease genes. The genetic component of Type 1 diabetes cannot be classified according to a classical model of inheritance but is due to an interaction between different genes and environmental factors. The major genes are within the HLA region that are responsible for 40% of the genetic susceptibility, although other genes are important (non-HLA genes). To date, more than 10 specific loci have been localized on different chromosomes. The gene involved has been characterized only for two of such loci, IDDM1 and IDDM2, while in the other cases the presence of some susceptibility genes can be envisaged and their identification represents the goal of genetic research in coming years. Fine mapping of the loci will certainly increase our understanding of the genetics of Type 1 diabetes; the limitation in detecting some of the remaining genes by linkage studies can be overcome by association studies. That is possible via the collection of a large number of affected families (over 1000) in homogeneous populations.     

Gamma-heavy chain disease associated with MALT lymphoma of the duodenum

BACKGROUND: Glutathione S-transferases (GSTs) are encoded by a superfamily of genes and play a role in the detoxification of potential carcinogens. In a nested case-control study, we investigated associations between genetic variability in specific GST genes (GSTM1, GSTT1, and GSTP1) and susceptibility to breast cancer. METHODS: In 1989, a total of 32 898 individuals donated blood samples to a research specimen bank established in Washington County, MD. Genotypes of blood specimen DNA were determined for 110 of 115 women with incident cases of breast cancer diagnosed during the period from 1990 through 1995 and up to 113 of 115 control subjects. Associations between specific genotypes and the development of breast cancer were examined by use of logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The GSTM1 homozygous null genotype was associated with an increased risk of developing breast cancer (OR = 2.10; 95% CI = 1.22-3.64), principally due to an association with postmenopausal breast cancer (OR = 2.50; 95% CI = 1.34-4.65). For GSTP1, the data were suggestive of a trend of increasing risk with higher numbers of codon 105 valine alleles (compared with isoleucine alleles); a 1.97-fold increased risk of breast cancer (95% CI = 0.77-5.02) was associated with valine/valine homozygosity. The risk of breast cancer associated with the GSTT1 homozygous null genotype was 1.50 (95 % CI = 0.76-2.95). The risk of breast cancer increased as the number of putative high-risk genotypes increased (P for trend <.001) (OR = 3.77; 95% CI = 1.10-12.88 for a combined genotype of GSTM1 null, GSTT1 null, and either GSTP1 valine heterozygosity or GSTP1 valine homozygosity). CONCLUSIONS: Our findings suggest that genetic variability in members of the GST gene family may be associated with an increased susceptibility to breast cancer.     

Early cancer detection programmes for women at high risk for breast and ovarian cancer: a proposal of practical guidelines

Women from families with multiple breast and/or ovarian cancers may be at increased risk to develop breast/ovarian cancer themselves. Due to personal experience with family members having these diseases they are anxious and ask for specific prophylactic measurements or treatment. The detection of two susceptibility genes, BRCA1 and BRCA2, has given insight into the genetic background of part of the familial breast/ovarian cancer syndromes. This has led to an increased demand in genetic counselling, testing, and early cancer detection programmes. Prospective data from early cancer detection programmes in this high risk population are yet not available. Based on data from epidemiological risk studies, breast and ovarian screening programmes and follow up data from breast cancer trials recommendations for an early cancer detection programme have been summarized. At the present these recommendations are tested in a prospective trial.     

Academic pediatrics: the view of New York City a century ago

Multifactorial diseases such as coronary heart disease, cancer, and osteoporosis are of increasing public health concern. Such diseases have a complex etiopathogenesis involving genetic and environmental factors and interactions between these factors. Nonhuman primates are uniquely suited as animal models for complex human diseases because of their close evolutionary relationship to humans. We present the rationale for using nonhuman primates as animal models in research designed to assess the genetic determinants of multifactorial diseases. Strategies and current approaches for the use of nonhuman primate models in genetic research on complex diseases are reviewed.     

Long-term effects of amyloid enhancing factor: clinical and experimental implications

The aim of our study was to assess Polish women's attitudes and possible acceptance of genetic tests for breast cancer susceptibility. The research was carried out in 1995-1996 and enrolled 200 women of different age, education and professional status who were asked to answer the questions included in a questionnaire. We estimate the percentage of women presenting different attitudes towards breast cancer genetic testing: 77% of women accepted genetic tests for breast cancer (BRCA) and 48% of women accepted informing their close relatives of the genetic tests results.     

Emerging strategies in the management of cancer

PURPOSE/OBJECTIVES: To review advances in understanding the biology of cancer that will lead to new prognostic indicators and approaches for treating cancer and its metastases and to explore the implications of these developments for oncology nurses. DATA SOURCES: Published papers, abstracts, research result, package inserts, books, and personal experience. DATA SYNTHESIS: Understanding is evolving that cancer is a genetic disease that occurs when a single cell and its progeny are remarkably changed by a series of genetic mutations. A new paradigm for managing cancer is emerging that is based on new prognostic indicators, intracellular and intercellular communication, and biologic control. Potential new therapeutic strategies include gene-directed therapy, control of cellular proliferation, exploitation of cell death, inhibition of metastasis, and reversal of multidrug resistance. Many of these therapies are only beginning to enter phase I/II clinical trials. CONCLUSIONS: With continued progress, doctors will be able to identify patients with the highest likelihood of experiencing recurrent or progressive disease and formulate therapeutic strategies specific for their disease and even for their individual genetic makeup. IMPLICATIONS FOR NURSING PRACTICE: To remain abreast of these new and increasingly sophisticated treatments, oncology nurses must be knowledgeable about cell and cancer biology, human genetics, the immune system, a how advances in these fields are forming the foundation for new therapies. Nurses with creativity and drive will continue to lead the way in developing management strategies for patients receiving these new therapies.     

Genetic dissection of murine susceptibilities to liver and lung tumors based on the two-stage concept of carcinogenesis

Inbred mouse strains exhibit strain-specific susceptibilities to spontaneous and induced tumors, indicating that the individual risks for neoplastic development are largely under genetic control. Recent advances in linkage analysis have made it routine to chromosomally map the mouse genes responsible for the strain variations in tumor susceptibility using segregating crosses. It is also possible to characterize their biological functions using the positional information. These types of studies are still severely hampered for human cases due to the remarkable genetic heterogeneity and impossibility of experimental crosses. In this article, previous work on genetic susceptibility to mouse liver and lung tumors is reviewed in view of the classical two-stage concept of carcinogenesis. According to this central concept, the tumor susceptibility genes should affect either the first stage, 'initiation', or the second stage, 'promotion', or both. At least some genes seem to be specifically involved in initiation or promotion, in line with the fact that initiation and promotion are due, to a certain extent, to independent mechanisms. This notion should be also applicable to human carcinogenesis and may provide important clues for prevention of initiation and promotion in populations with a genetic predisposition for cancer development.     

Gene therapy: ovarian carcinoma as the paradigm

The delineation of the molecular basis of cancer in general, and of ovarian carcinoma in particular, allows for the possibility of specific intervention at the molecular level for therapeutic purposes. To this end, three main approaches have been developed: mutation compensation, molecular chemotherapy, and genetic immunopotentiation. For each of these conceptual approaches, human clinical protocols, including those specific for ovarian carcinoma, have entered phase I clinical trials to assess dose escalation, safety, and toxicity issues. However, major problems remain to be solved before these approaches can become effective and commonplace strategies for the treatment of cancer. In this regard, an examination of the applications of gene therapy for ovarian carcinoma can exemplify the rationality and the problems observed in the development of gene therapy, and may illustrate prospects for their solution that are being refined, including current efforts in our laboratory. An overriding obstacle is the basic ability to deliver therapeutic genes quantitatively, and specifically, into tumor cells. As vector technology fulfills these requirements, it is anticipated that promising results already observed in preclinical studies will translate quickly into the clinical setting for amelioration of this life-threatening disease in women.