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PubMed1999

Recent developments in the genetics of schizophrenia.

Schizophrenia, which is also called "split personality," is a complex and multifactorial mental disorder with variable clinical manifestations. It perhaps represents several diseases and occurs throughout the world. It is a more-prevalent disorder among homeless people and is clinically characterized by hallucinations and delusions. The pathophysiology of schizophrenia is not localized to a single region of the brain and the etiology of this illness is not understood. Because of its complex pattern of inheritance, genetic techniques are not readily applicable in identifying the genes responsible for this disorder. Family, twin, and adoption studies, however, provide strong but indirect support for genetic components in the etiology of schizophrenia. Extensive linkage analyses now suggest that susceptibility genes may be present on chromosomes 5q, 6p, 8p, 13q, 18p, and 22q. Identification and characterization of these and other genes, as well as non-genetic factors, is one of the greatest challenges in biomedicine. This may ultimately lead to the development of a new line of effective and safe drugs or treatments for its prevention or cure.

Genetic Linkage↗

PubMed1998

Gene defect behind APECED: a new clue to autoimmunity.

The molecular background of human autoimmunity is poorly understood. Although many autoimmune diseases have a genetic basis, the actual disease appearance results from a complex interplay between genes and environment and thus these diseases represent typical multifactorial diseases. Even with molecular tools provided by the Human Genome Project, it still remains a challenge to identify the predisposing DNA variants behind such multifactorial traits. Two strategies have been suggested to provide short-cuts to the dissection of the genetic background of complex autoimmune diseases: (i) identification of genes in rare human diseases with a strong autoimmune component or (ii) unravelling loci causing phenotypes resembling autoimmune diseases in inbred mice strains. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic autosomal disease with a recessive inheritance pattern, characterized by multiple autoimmune endocrinopathies, chronic mucocutaneous candidiasis and ectodermal dystrophies. Since it is the only known human autoimmune disease inherited in a Mendelian fashion, it provides an excellent model to analyse the genetic component of human autoimmunity. The causative gene for APECED was isolated recently by a traditional positional cloning strategy by two independent groups. The cDNA for the APECED gene proved to originate from a novel gene, AIRE , which is expressed prevalently in thymus, pancreas and adrenal cortex. Multiple mutations in AIRE have been identified in APECED patients. The predicted proline-rich AIRE polypeptide harbours two PHD-type zinc finger motifs and contains a putative nuclear targeting signal suggesting its involvement in the regulation of transcription. In the future, functional analysis of the AIRE protein both in vitro and in vivo will provide valuable insight not only into the molecular pathogenesis of APECED but also into the aetiology of autoimmunity in general.

Animals↗

PubMedDate not supplied

Pharmacogenetics in HIV therapy.

Administration of standard doses of most antiretroviral drugs results in significant variations in plasma drug concentrations among different individuals, as well as different rates of drug-associated toxicity. The reasons for the large interindividual variability in drug levels are multifactorial, and involve differences in gender metabolism, concomitant medications, drug compliance, underlying diseases, and genetic factors. Pharmacogenetics is the discipline that analyses the genetic basis for the interindividual variation in the body disposition of drugs. One of the main goals is to give grounds to individualized therapy. The majority of pharmacogenetic traits so far have involved drug metabolism. An example of this is the inherited variation in the pharmacokinetics and pharmacodynamics of drugs such as hydralazine or isoniazid. This variation is due to polymorphisms in the N-acetyltransferase-2 (NAT2) gene, which may split the population into three categories: slow, intermediate, and fast metabolizers. Pharmacogenetic studies conducted so far with antiretrovirals have focused on metabolizing enzymes and transporter proteins in the cell membrane. Herein, we review the genetic polymorphisms known to be associated with altered pharmacokinetics of antiretrovirals, which may influence the efficacy and toxicity of these drugs.

Anti-HIV Agents↗

PubMed2002

Genetics of osteoporosis.

Osteoporosis is a common multifactorial disorder of reduced bone mass. The disorder in its most common form is generalized, affecting the elderly, both sexes, and all racial groups. Multiple environmental factors are involved in the pathogenesis. Genes also play a major role as reflected by heritability of many components of bone strength. Quantitative phenotypes in bone strength in the normal population do not conform to a monogenetic mode of inheritance. The common form of osteoporosis is generally considered to be a polygenic disorder arising from the interaction of common polymorphic alleles at quantitative trait loci, with multiple environmental factors. Finding the susceptibility genes underlying osteoporosis requires identifying specific alleles that coinherit with key heritable phenotypes in bone strength. Because of the close correspondence among mammalian genomes, identification of the genes underlying bone strength in mammals such as the mouse is likely to be of major assistance in human studies. Identification of susceptibility genes for osteoporosis is one of several important approaches toward the long-term goal of understanding the molecular biology of the normal variation in bone strength and how it may be modified to prevent osteoporosis. As with all genetic studies in humans, these scientific advances will need to be made in an environment of legal and ethical safeguards that are acceptable to the general public.

Animals↗

PubMed1998

Genetics of hypertension. Therapeutic implications.

Essential hypertension affects approximately 20% of the adult population, and has a multifactorial origin arising from an interaction between susceptibility genes and environmental factors. The understanding of the molecular basis of essential hypertension may provide us with new and more specific pharmacological agents, and perhaps the ability to individualise treatment and maximise the reduction in risk of morbidity and mortality from cardiovascular disease. Hypertension due to single gene abnormalities is very rare; however, it follows a Mendelian model of inheritance and therefore can be identified successfully using family linkage studies. Since clear Mendelian models of inheritance cannot readily be assigned in essential hypertension as there may be variable penetrance of susceptibility genes, other studies with designs based on affected sibling pairs, family-based association studies and case-control studies have been performed. The renin-angiotensin system (RAS) plays an integral part in the control of blood pressure, and genetic polymorphisms within this system and their effect on the response to antihypertensive therapy are now being studied. Polymorphisms of the angiotensin converting enzyme (ACE) gene, although associated with left ventricular hypertrophy, do not appear to have a clear association with hypertension. Studies on the association of genotype with response to antihypertensive therapy are less consistent for genetic polymorphisms of the RAS. Although some of the results are positive, patient numbers have been small in the studies completed to date. Genetic polymorphisms of the adrenergic receptors have been associated with blood pressure variation in African-Americans, White Americans and African-Caribbeans. A beta 2-adrenoceptor polymorphisms exhibits agonist-mediated receptor downregulation which may lead to enhanced peripheral vasoconstriction. Therapeutic studies have not yet been completed on patients with this genotype. A further polymorphism of the alpha-adducin gene has been associated with essential hypertension. This may influence blood pressure response to sodium loading/depletion and response to long term treatment with a thiazide diuretic, but further studies are needed to clarify this. Antisense oligonucleotides targeted against genes of the RAS, e.g. angiotensinogen and the angiotensin type 1 receptor, are being modified to improve targeting and thereby reduce toxicity. However, gene therapy is unlikely to replace pharmacological therapy in the foreseeable future. The immediate goal should be to enhance our understanding of the genetic nature of essential hypertension based on the interaction of genetic makeup with the environment, with a view to individualising antihypertensive therapy.

Antihypertensive Agents↗

PubMedDate not supplied

George Lyman Duff Memorial Lecture. Multifactorial etiology of hypercholesterolemia. Implications for prevention of coronary heart disease.

This review underlines the concept that multiple factors are responsible for hypercholesterolemia in the American public. Dietary factors (cholesterol, saturated fatty acids, and obesity) clearly raise the cholesterol level, and they are important causes of borderline-high cholesterol. Still, the unexplained decline of LDL receptor activity with aging contributes importantly to borderline-high levels and cannot be ignored. The loss of estrogen-stimulated LDL receptor synthesis after menopause is an important contributor to elevated cholesterol in postmenopausal women. In addition, several genetic defects inherited singly appear to be responsible for moderate hypercholesterolemia. Some of these defects may represent genetic hypersensitivity to diet, and dietary therapy alone may provide adequate cholesterol lowering. Other defects impart resistance to dietary control, and use of a single cholesterol-lowering drug may be required. With the exception of heterozygous FH, most cases of severe hypercholesterolemia appear to be the result of the coexistence of at least two defects in LDL metabolism, and as a rule, they can be treated successfully only by using cholesterol-lowering drugs in combination.

Cholesterol↗

PubMed1981

Retinoblastoma: mutational mosaicism or host resistance?

Carlson and Desnick's [1979] proposals of multiple allelism and mutational mosaicism to account for the observed variability in penetrance and expressivity in retinoblastoma do not seem to give a clear-cut explanation for the facts that 1) a bilaterally affected patient could have an unaffected carrier child who in turn would produce bilaterally affected offspring, and 2) carriers of the retinoblastoma gene are prone to nonradiogenic osteosarcoma irrespective of their phenotypes. However, these observations are readily explained by assuming that inherited host resistance plays an important role in the manifestation of a single major gene for retinoblastoma. Based on their model, Carlson and Desnick offer recurrence risk figures for genetic counseling, but their figures concerning the transmissible types of retinoblastoma do not seem more accurate, as assumed by them, than those previously estimated from the family data. We present evidence that host resistance may be regarded as a multifactorial threshold character with high heritability, and we propose that tissue-specific genes, which we presume to be involved in normal differentiation of retinoblasts and osteoblasts, play a crucial role in malignant transformation. Two lines of suggestions are made for future studies: one, to search for polymorphic genes associated with retinoblastoma, and the other, to see whether the principle of synchronous appearance of multiple tumors in persons at high risk applies to other cancers as well.

Adolescent↗

PubMed2006

Overview of the pharmacogenetics of HIV therapy.

The administration of standard doses of most antiretroviral drugs results in significant variations in plasma drug concentrations among different individuals, influencing antiviral activity as well as incidence of drug-related toxicities. The reasons for this large inter-individual variability in drug levels are multifactorial, and involve differences in metabolism related to gender, concomitant medications, drug compliance, underlying diseases and genetic factors. Pharmacogenetics is the discipline that analyses the genetic basis for the inter-individual variation in the body disposition of drugs. One of its main goals is to give grounds to individualized treatment. The majority of pharmacogenetic traits so far have involved drug metabolism. This is the case for the inherited variation in the pharmacokinetics and pharmacodynamics of drugs such as hydralazine or isoniazid, which is due to polymorphisms in the N-acetyltransferase-2 (NAT2) gene, which allows splitting the population into three categories: slow, intermediate, and fast metabolizers. Pharmacogenetic studies conducted so far with antiretroviral drugs have focussed on metabolizer enzymes at the liver and on transporter proteins on cell membranes. Herein, we review the most relevant metabolizer enzymes and protein transporters, along with the genetic polymorphisms, which seem to influence the pharmacokinetics of antiretroviral drugs, ultimately determining its efficacy and toxicity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1992

Role of genetic factors in breast cancer susceptibility.

Hereditary breast cancer is common and accounts for approximately 10-14% of all breast cancers. Knowledge of a family history of breast cancer may significantly influence diagnosis and therapy. Genetic heterogeneity has been demonstrated in familial breast cancer. Recently inherited mutations in the tumor suppressor gene p53, have been shown to be the underlying defect in the Li-Fraumeni syndrome. We have shown that defects in this gene also play a role in the predisposition to other familial breast cancers. The gene responsible for early onset familial breast and ovary cancer has recently been mapped to chromosome 17q21. For most of the sporadic breast cancers a multifactorial model, including variable genetic and environmental factors, has been considered. Two genetic risk factors which may predispose for a considerable portion of breast cancers are the gene causing ataxia telangiectasia (AT) and the gene that gives rise to proliferative breast disease (PBD). Identification of distinct genes enhancing the risk of breast cancer will give us the opportunity to identify high risk individuals. Such individuals may benefit from periodic examination affording the possibility of early diagnosis and treatment.

Ataxia Telangiectasia↗

PubMed1988

Opportunities for cancer prevention and early detection among children.

The tumors of infants, children, and adolescents are generally deep seated rather than superficially located cancers of epithelial structures. Appropriate mass screening techniques (i.e., pap smear, mammogram, hemoccult test, or chest radiograph) have not been available for the early detection of childhood tumors. It is widely believed that the tumors of children are not suitable for mass screening tests. Therefore, they are diagnosed most often at an advanced stage. An inexpensive urine test has been found to be effective in detecting neuroblastoma at an early, preclinical stage in infants as young as 6 months. The tumors detected in this manner have a high rate of curability. This test appears to be suitable for wide application and has been shown to be both cost-effective and medically effective. Much less is known about the possible causes of the cancers of children than about the cancers of adults, so preventive measures are less well defined. Children in whom cancer develops are more likely to have a genetic predisposition due to one of the rare but numerous heritable genetic defects associated with more than 100 such known syndromes or an acquired genetic defect. Such children are predisposed to cancer because they already have an inherited or acquired somatic genetic lesion and are more susceptible to another genetic insult that results in neoplasia. Such children should be screened regularly for the early detection of cancer. They also constitute a special population to which maximal preventive efforts should be applied, both because they are at high risk and because they constitute a unique population for testing the effectiveness of proposed preventive measures. Cancer is a multifactorial, multistep process that results in the highest incidence of cancer among older adults after a lifetime of exposure to known and presumed cancer risks. Current efforts at cancer prevention are aimed primarily at adults. A greater challenge, which should be even more effective, is to motivate children, their parents, and teachers to prevent the cancers of adults during childhood.

Child↗

PubMed1988

Association between equine leucocyte antigens (ELA) and equine sarcoid tumors in the population of Swedish halfbreds and some of their families.

The distribution of equine leucocyte antigens (ELA) in Swedish Halfbreds affected by sarcoid tumors was determined and compared with that of control horses of the same breed. ELA-haplotype A3W13 appeared more frequently in affected horses, resulting in a chi 2 value of 4.45 (P = 0.034) for A3 and 9.05 (P = 0.0026) for W13, respectively. The relative risk factor (RR) could be estimated to 2.13 and 3.00 for A3 and W13, respectively. The etiology fraction (EF) was calculated to 28% and 37% for A3 and W13, respectively. Thus, in the population of Swedish Halfbreds approximately 40% (at least) of the disease appeared to be associated with the genetic background of the affected horse. Family studies established that ELA are codominantly expressed and inherited as simple Mendelian traits and that sarcoids among offspring are significantly associated with one of the parental haplotypes (P = 0.00942). This parental haplotype does not always include A3W13. These results confirm and extend previous results from other breeds and strongly suggest the existence of a predisposition for sarcoids among horses, that is due to an autosomal, dominant, ELA-linked gene with incomplete penetrance. In extension, this indicates a multifactorial etiology of equine sarcoids (additional non-MHC gene(s) and/or environmental factors).

Animals↗

PubMed1983

Family resemblance for fasting blood glucose in a population of Japanese Americans.

The pattern of inheritance of fasting blood glucose was examined in a Japanese cohort of 500 nuclear families living in Hawaii. A principal component of glucose was defined to improve the ranking of diabetics and individuals receiving treatment (medication and/or diet) for hyperglycemia, thereby allowing as well as possible for inability to determine untreated levels in patients. Results from path and segregation analysis show that family resemblance for glucose is low in this population. The additive variation can be explained by a cultural model of inheritance without introducing intergenerational differences, a maternal-paternal effect, or even genetic parameters. Heritability is approximately 0.125. Complex segregation analysis provides no convincing evidence for a major gene, with preliminary support based upon leptokurtic outliers in five families disappearing on further analysis by partial truncation. A claim by other workers of a major recessive gene for hyperglycemia may be due to their failure to allow for treatment, skewness, and multifactorial heritability. In future, the search for major loci acting on liability to hyperglycemia should use multiple determinations of fasting glucose or be addressed to more primary and repeatable variables than fasting blood glucose.

Adult↗

PubMed2001

Genetic components of perinatal morbidity and mortality.

The authors summarize the perinatal effects of the main genetic disorder groupings. Diseases of autosomal dominant inheritance are usually less severe and postnatal life is possible. Diseases of autosomal recessive inheritance are serious in most cases, causing severe symptoms in postnatal life. Diseases of X-linked recessive inheritance manifest themselves in male embryos and may be mild or serious; the more severe forms may influence the perinatal outcome. Diseases of X-linked dominant inheritance occur less frequently and manifest themselves in both sexes: in some cases the life expectancy is not favorable. Chromosomal anomalies, unbalanced rearrangements and autosomal trisomies may cause severe multiplex malformation syndromes and mental retardation. The diseases are serious in most cases and intrauterine mortality is high. Conversely, in cases of numerical differences of the sex chromosomes perinatal mortality does not increase remarkably, except in X-monosomy. Diseases of multifactorial origin lead to isolated malformations, but many civilization diseases originate from similar causes. In a few cases, severe diseases (i.e. congenital heart defects and neural tube defects) occur which may influence the outcome of the pregnancy. In terms of teratogenic effects, taking medication or undergoing X-ray examination or infections during early pregnancy indicates only a small risk in most cases. The authors emphasize that genetic centers significantly influence the perinatal outcome of pregnancies with their complex activity and their role in prenatal diagnostics.

Chromosome Aberrations↗

PubMed1990

Clinical and pathologic study of familial dilated cardiomyopathy.

To evaluate the occurrence of familial cases of dilated cardiomyopathy (DC), 165 consecutive patients were studied. Diagnosis of myocardial disease was based on clinical, hemodynamic, bioptic, postmortem or a combination of these criteria. Twelve patients (7% of cases) showed evidence of myocardial disease in greater than or equal to 1 relative; 27 patients with myocardial disease were detected in the 12 families, but a suspected history of myocardial involvement was present in a further 16 cases. In 6 families proband and relatives were affected by DC (total 14 cases); in 1 of these families the disease began with an atrioventricular block. In 4 families the relatives showed the presence of myocarditis at the endomyocardial biopsy. In 2 families the relatives presented a right ventricular cardiomyopathy. The mode of inheritance was autosomal dominant in 7 families, recessive in 4; X-linked pattern may be hypothesized in 1. Nine patients died under the age of 45 years: 2 of sudden death, 6 of chronic heart failure and 1 of cerebral embolism. Familial transmission is not rare. Different modes of genetic transmission (autosomal dominant, recessive and X-linked) and different forms of myocardial disease suggest that familial DC may be a multifactorial disease.

Adolescent↗

PubMed1996

Genetic screening, testing and treatment: how far can we go?

Treatment comes in three forms: care, control, cure; each will be part of any new development in the management of genetic disease, either Mendelian or complex. Diagnosis recognizes three states of disease: impairment, disability, and handicap when the disease is symptomatic and has manifestations. Genetics in health care has the potential to prevent these manifestations by interventions at the presymptomatic stage. Wherever cause of disease involves genotypic variation that undermines homeostasis, genetic testing and screening could play a predictive role. The area of greatest interest will be the common multifactorial diseases. While some persons worry that geneticists have taken society too fast and far along the road to ruin, it is closer to the truth that we have actually gone rather slowly and not very far along the road to better personal and collective health. With wisdom and caution the new opportunities for genetic testing or screening will become part of health care; and sooner rather than later when better treatments for our inherited infirmities are found.

Genetic Diseases, Inborn↗

PubMed1996

Genetic mapping of the human homologue (T) of mouse T(Brachyury) and a search for allele association between human T and spina bifida.

We describe a genetic analysis of the human homologue (T) of the mouse T (Brachyury) gene; human T was recently cloned in our laboratory. The protein product of the T gene is a transcription factor crucial in vertebrates for the formation of normal mesoderm. T mutant Brachyury mice die in midgestation with severe defects in posterior mesodermal tissues; heterozygous mice are viable but have posterior axial malformations. In addition to its importance in development, T has intrigued geneticists because of its association with the mouse t-haplotype; this haplotype is a variant form of the t-complex and is characterized by transmission ratio distortion, male sterility and recombination suppression. We have identified a common polymorphism of human T by single strand conformation polymorphism (SSCP) and used this in mapping studies and to re-investigate the idea that human T is involved in susceptibility to the multifactorial, neural tube defect, spina bifida. Our mapping data show that human T maps to 6q27 and lies between two other genes of the t-complex, TCP1 and TCP10. These data add to the evidence that in man the genes of the t-complex are split into two main locations on the short and long arms of chromosome 6. We have used an allele association test which is independent of mode of inheritance and penetrance to analyse data from the spina bifida families. Using this test we find evidence for a significant (p = 0.02) association between transmission of the TIVS7-2 allele of the human T gene and spina bifida.

Alleles↗

PubMed1994

Mitochondrial DNA sequence variation in human evolution and disease.

Germ-line and somatic mtDNA mutations are hypothesized to act together to shape our history and our health. Germ-line mtDNA mutations, both ancient and recent, have been associated with a variety of degenerative diseases. Mildly to moderately deleterious germ-line mutations, like neutral polymorphisms, have become established in the distant past through genetic drift but now may predispose certain individuals to late-onset degenerative diseases. As an example, a homoplasmic, Caucasian, tRNA(Gln) mutation at nucleotide pair (np) 4336 has been observed in 5% of Alzheimer disease and Parkinson disease patients and may contribute to the multifactorial etiology of these diseases. Moderately to severely deleterious germ-line mutations, on the other hand, appear repeatedly but are eliminated by selection. Hence, all extant mutations of this class are recent and associated with more devastating diseases of young adults and children. Representative of these mutations is a heteroplasmic mutation in MTND6 at np 14459 whose clinical presentations range from adult-onset blindness to pediatric dystonia and basal ganglial degeneration. To the inherited mutations are added somatic mtDNA mutations which accumulate in random arrays within stable tissues. These mutations provide a molecular clock that measures our age and may cause a progressive decline in tissue energy output that could precipitate the onset of degenerative diseases in individuals harboring inherited deleterious mutations.

Amino Acid Sequence↗

PubMed1999

Gene-environment and gene-gene interaction studies in the molecular genetic analysis of asthma and atopy.

Asthma is a complex trait for which genetic predisposition is fundamental in disease aetiology, but poorly understood. Unravelling the genetic aetiology is complicated by the tremendous influence of the environment over disease expression. For this reason, asthma is multifactorial, in that disease expression is influenced by interactions between multiple major and minor genes, and modulated by interacting non-genetic factors (e.g. environment). 'Parent of origin' effects may be both genetic and environmental in aetiology, and have been observed in a number of population studies on asthma. The primary focus of this review is to evaluate the current approaches used in identifying the interrelationship between (1) certain environmental factors (e.g. allergen exposure, maternal inheritance) and genetic susceptibility to asthma and its associated phenotypes; and (2) candidate genes in chromosomal regions that have been linked to asthma and atopy in ongoing, molecular genetics studies.

Asthma↗