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PubMed1997

Interstitial lung disease: basic mechanisms and genetic predisposition.

Diffuse (interstitial) lung disease comprises a wide variety of relatively uncommon conditions, which present with characteristic clusters of clinical features and often with aberrant lung function. These diseases cause major morbidity and mortality due to lung injury and fibrosis. Some of these diseases are of known aetiology, whereas others are not. It has been suggested that the environment is a major contributing factor in this group of diseases. However, since not all individuals exposed to a common environment develop interstitial diseases, we can hypothesize that there is a genetic predisposition to their development. Therefore, if we can identify individuals who are genetically predisposed to develop diseases characterized by lung injury and fibrosis, then management strategies can be designed which will attempt to identify early disease and, in the longer term, to develop targeted genetic interventional approaches to treatment.

Female↗
PubMed1989

Genetic predisposition to drug hepatotoxicity: role in hepatitis caused by amineptine, a tricyclic antidepressant.

Amineptine-induced immunoallergic hepatitis is unpredictable. It may be related to its oxidation into a reactive metabolite acting as hapten. We have looked for a possible genetic predisposition involving drug oxidation capacity and/or cell defense mechanisms in nine patients with previous amineptine hepatitis. Drug oxidation capacity was assessed using dextromethorphan, a test compound recently proposed as a substitute for debrisoquine. The eight patients tested had the extensive metabolizer phenotype. The susceptibility to amineptine metabolites was studied by an in vitro test assessing the destruction of the patients' lymphocytes by reactive metabolites generated from amineptine by a standardized oxidation microsomal system. Lymphocyte death increased with the dose of amineptine (1 to 2.5 mM); it was increased by preincubation with trichloropropene oxide, but was absent when amineptine was omitted or when the oxidation system was not operating. Mean lymphocyte death was twice higher in the nine patients with amineptine hepatitis than in 17 healthy controls. In contrast, when the test was performed with acetaminophen (3 to 10 mM), lymphocyte death was similar in controls and in patients. Basal epoxide hydrolase activity toward benzo[a]pyrene-4,5-oxide and glutathione concentration was similar in lymphocytes from controls and patients. Family studies showed an increased susceptibility to amineptine metabolites in lymphocytes from several first-degree relatives of two patients. These results show that amineptine hepatitis occurs in patients with extensive dextromethorphan oxidation capacity but with an increased susceptibility to amineptine reactive metabolites, probably related to a genetic deficiency in a cell defense mechanism.

Adolescent↗
PubMed1990

[Evaluation of genetic predisposition and acquired risk factors in development of essential hypertension and its acute complications].

The authors studied a population of 4.023 subjects from several rural and urban communities selected on the basis of age, work tasks and social class. Genetic predisposition to essential hypertension was evaluated by determining intraerythrocyte sodium levels in all subjects with essential hypertension and their families. The authors also verified the behaviour of some biohumoral factors (PRA, aldosterone, ANP, intraerythrocyte, Na) as possible markers of essential hypertension and the role of some acquired risk factors in the development of the disease and its cerebrocardiovascular complications. The hypertense subjects were divided into groups and treated with diet alone or diet associated with drugs depending on the prevalence of pathogenetic factors. The results were evaluated after 1, 3, 6 and 12 months.

Erythrocytes↗
PubMed1991

[Genetic predisposition to hypercholesterolemia and coronary heart disease. DNA polymorphism in the apolipoprotein B gene as a possible cause].

It has been demonstrated in numerous studies that hypercholesterolemia is an important independent risk factor for the development of coronary heart disease. Besides exogenous factors like diet and physical exercise genetic predisposition is a major determinant of serum cholesterol levels. Apolipoprotein B-100 (apo B-100) is the protein constituent of LDL which serves as ligand to the LDL-receptor. A hypervariable region containing repetitive elements adjacent to the apo B gene was used as marker to study the role of genetic variation in this gene in the development of elevated serum lipid levels and premature coronary heart disease. A group unrelated patients with severe coronary heart disease and normal controls were studied. Using a high resolution method we could identify 14 different alleles. Alleles with a large number of repetitive elements were associated with coronary heart disease. The same alleles were weakly associated with elevated levels of serum levels of cholesterol, triglycerides and apolipoprotein B.

Alleles↗
PubMed1994

Transient hepatic dysfunction in two brothers receiving heparin and streptokinase: a genetic predisposition?

Two brothers with acute myocardial infarction are presented. Subsequent to a standard thrombolysis treatment with streptokinase and heparin, both developed abnormal liver tests, with elevated transaminases only. This liver dysfunction resolved promptly. The occurrence of such side-effects in two siblings raises the question of genetic predisposition to the otherwise uncommon hepatic complications of thrombolysis treatment.

Alanine Transaminase↗
PubMed1988

Study of possible genetic predisposition to endemic goitre among the Fur and Baggara tribes of the Sudan.

The overall prevalence rate of endemic goitre among the Fur and Baggara tribes of Western Sudan was found to be 74%. Family studies in 60 nuclear families showed a significantly higher incidence of endemic goitre among the offspring of affected parents than among the offspring of normal parents. This suggests a possible genetic predisposition to endemic goitre. The proportion of phenylthiocarbamide (PTC) non-tasters was found to be 13% among the goitrous subjects compared to 17.5% among the non-goitrous subjects. However, the association with PTC as well as with 6 blood-genetic markers, was not statistically significant.

Blood Proteins↗
PubMed1995

[Genetic predisposition to cancer].

This review focuses on the genetics of inborn predisposition to the development of cancer. The gene defects responsible for the majority of the most common syndromes of inherited predisposition to cancer have been deciphered during the last five years. These discoveries have shown that the genetics of most of these inherited forms of cancer is remarkably simple: the mechanism underlying the risk of cancer is precisely the one proposed by Knudson to explain the inherited forms of retinoblastoma. Only a small minority of the cancers are imputable to inherited mutations causing a very high risk of cancer. However, low penetrance susceptibility genes, mainly acting as environmental risk modifiers, are probably involved in the development of the majority of cancers. As much as possible, we will consider the immediate and long term possible repercussions on everyday medical practice of these advances in basic understanding of genetic cancer risks.

Genetic Counseling↗
PubMed2001

Genetic predisposition to coronary artery disease.

Understanding the genetic basis of coronary artery disease (CAD) can improve management and prevention. Family and twin studies, animal models and gene association studies support a genetic basis for CAD. Genes contribute to CAD development and progression, and response to risk factor modification and lifestyle choices. Family history is the best indicator of a predisposition to CAD and further refinement is possible with biochemical and DNA testing. Many inherited cardiovascular risk factors can be modified, such as LDL cholesterol, homocysteine and lipoprotein(a). Early detection of CAD might lead to earlier intervention for genetically susceptible individuals. However, data are lacking regarding the efficacy of this approach in preventing clinical events. Despite this lack of evidence, knowledge of genetic CAD susceptibility has value in providing risk information and guiding decision making. Further research that investigates outcomes regarding genetic risk assessment for CAD is necessary.

Coronary Artery Disease↗
PubMed1985

Sibling pairs affected by chronic arthritis of childhood: evidence for a genetic predisposition.

Twelve families with a sibling pair affected by seronegative juvenile chronic arthritis (JCA) were studied. The ratio of HLA haplotype sharing was significantly different from that expected. No common haplotype was found. All 10 sibling pairs concordant for pauciarticular disease shared 2 haplotypes and the other 2 pairs shared one haplotype. These findings are evidence of a genetic predisposition to develop pauciarticular onset JCA in the families studied and suggest the presence of a disease susceptibility gene or genes within the major histocompatability complex.

Antibodies, Antinuclear↗
PubMed1986

Non-Hodgkin malignant lymphomas and Hodgkin's disease in first-degree relatives. Evidence for a mutual genetic predisposition?

The occurrence of malignant lymphomas in 3 siblings is described. The cases include the first report of Hodgkin's disease and non-Hodgkin malignant lymphoma in dizygotic twins. Another remarkable feature was the development of malignant lymphoma, when the siblings were at the same age. Although a transmissible agent or environmental factors cannot be excluded in this family, our observations may suggest a mutual genetic predisposition in Hodgkin's disease and non-Hodgkin malignant lymphoma.

Adult↗
PubMedDate not supplied

Personality, stress, smoking, and genetic predisposition as synergistic risk factors for cancer and coronary heart disease.

Risk factors for cancer have been found in the past to act synergistically in a number of studies. However, these studies were not always designed to test the hypothesis of synergism, and have sometimes failed to equate for important variables, which might influence the results. The present study tests the hypothesis that psychosocial variables and physical ones (personality/stress, smoking, and genetic predisposition) interact in a synergistic fashion in the causation of lung cancer and coronary heart disease (CHD).

Adult↗
PubMed1985

Testicular neoplasms occurring in four brothers. A search for a genetic predisposition.

Four brothers who developed testicular neoplasms, one bilaterally, are described. Histologic examination showed four of the tumors to be seminomas and one to be a mixed germ cell tumor. Three of the brothers are alive. Apart from a late-onset bladder carcinoma in their father and a pulmonary cancer in a maternal uncle, cancers were not recorded in the extended kindred. One patient, a sister, and the parents had normal frequency of sister chromatid exchange (SCE) and chromosome aberrations, whereas the two patients sampled after radiation showed increase in one or both. The father was found heterozygous in 12 and the mother in 8 genetic marker systems among 25 tested. For the blood group gene loci JK and MNSs, and the erythrocyte enzyme locus GPT the father had given the same allele to all three affected sons examined. The mother had given different alleles to the sons in all of her informative markers. On the model of a recessively acting susceptibility gene, only JK and GPT remained consistent with linkage without recombination. These investigations did not add support to a genetic etiology for the unusual family occurrence of testicular cancer. An apparent birth-order effect on time at onset/diagnosis in this and published families suggests time-limited environmental factors. Nevertheless, JK, MNSs, and GPT should be included in future testis cancer families to test the model of a "dominant" genetic predisposition.

Adult↗
PubMed1990

Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor alpha: relevance to genetic predisposition to systemic lupus erythematosus.

We report on the production of tumor necrosis factor (TNF)-alpha and TNF-beta by mitogen-activated peripheral blood lymphocytes or enriched monocyte subpopulations from human leukocyte antigen (HLA)-typed healthy subjects. The results indicate that HLA-DR2- and DQw1-positive donors frequently exhibit low production of TNF-alpha, whereas DR3- and DR4-positive subjects show high levels of TNF-alpha production. No correlation between TNF-alpha levels and HLA-A, -B, and -C genotype was found. The relevance of this quantitative polymorphism to the genetic predisposition to lupus nephritis in systemic lupus erythematosus (SLE) patients was investigated. DR2, DQw1-positive SLE patients show low levels of TNF-alpha inducibility; this genotype is also associated with an increased incidence of lupus nephritis. DR3-positive SLE patients, on the other hand, are not predisposed to nephritis, and these patients have high TNF-alpha production. DR4 haplotype is associated with high TNF-alpha inducibility and is negatively correlated with lupus nephritis. These data may help explain the strong association between HLA-DR2, DQw1 in SLE patients and their susceptibility to nephritis.

Alleles↗
PubMed1994

Persistent polyclonal lymphocytosis with binucleated B lymphocytes: a genetic predisposition.

Persistent lymphocytosis is usually associated with a malignant lymphoproliferative disease (MLPD). We report six female patients presenting a chronic, moderate lymphocytosis of 2-16 years duration with atypical binucleated lymphocytes on peripheral blood smears. Further investigation showed a polyclonal increase in serum IgM and HLA-DR7 phenotype in all patients. The B cells were polyclonal because Southern hybridization of DNA and polymerase chain reaction failed to demonstrate a clonal rearrangement of immunoglobulin heavy chain genes. Peripheral blood examination showed binucleated lymphocytes in a family member of two of the cases; taken together with the association with HLA-DR7 these data suggest a genetic predisposition. The identification of this benign syndrome is important in order to prevent its misdiagnosis as a MLPD.

Adult↗
PubMed1987

Evidence for genetic predisposition for some nasopharyngeal cancers by in vitro hyperdiploidy in human dermal fibroblasts.

A numerical alteration in chromosome complement in human dermal fibroblast cultures, hyperdiploidy with a normal occurrence of tetraploidy (IVH), has been reported to be associated with some hereditary single tumors including squamous carcinoma of the nasopharynx (NPC). Its incidence was compared in cultures derived from 39 NPC patients and 29 clinically normal subjects without a family cancer history by two different methods (percentage of numerically altered metaphases in chromosome preparations from nonconfluent monolayer Petri dish cultures in logarithmic growth, and by the distribution of DNA content of propidium iodide stained cells from plastic flask cultures in stationary growth phase as assayed by flow cytometry) to ascertain its usefulness in identification of such genetic predisposition. Concordance was observed between the two assays. There was a linear relationship between the percentage of hyperdiploid metaphases assayed in the chromosome preparations and the percentage of cells with a DNA index of greater than 1 as determined by flow cytometry. By metaphase assay, none of the 29 normals showed IVH. OF the 39 carcinoma of the nasopharynx patients studied, 19 had IVH and 20 did not. By flow cytometry there were significant differences in the flow cytometry DNA index (p less than 0.001) of IVH-negative (all normals and 20 carcinoma of the nasopharynx patients) and IVH-positive carcinoma of the nasopharynx patients. The percentage of cells with a DNA index of 2 and greater than 1 could be used to distinguish all IVH-negative from the IVH-positive subjects and, thus, were considered to be the parameters of choice in assaying IVH by flow cytometry. None of the subjects studied showed increased in vitro tetraploidy (IVT), which has been associated with some heritable colon cancer syndromes. Irrespective of family cancer history, approximately one-half of the NPC patients (19 of 39) had IVH, which has been reported to be associated with the in vivo expression of certain heritable tumors including carcinoma of the nasopharynx. The average age of carcinoma of the nasopharynx diagnosis was earlier (mean 52 yr) for the IVH-positive group than for the IVH-negative carcinoma of the nasopharynx group (mean 67 yr).

Adult↗
PubMed1984

Effects of changes in dietary sodium intake on normotensive subjects with and without a genetic predisposition to essential hypertension.

Twenty-two young normotensive male subjects, 12 with an established family history of essential hypertension, were put on a low-followed by a high-sodium diet. Plasma from each dietary period was tested for inhibitory activity on Na-K-ATPase using three different techniques: measurement of 22Na efflux rate, measurement of 3H ouabain binding characteristics and a bioluminescent adenosine triphosphate assay. The high-sodium diet was associated with a diminished ouabain-sensitive sodium efflux rate constant in the whole group; however, no circulating inhibitor could be detected in the plasma. Those with and those without a family history of essential hypertension were indistinguishable. The results suggest that young normotensive individuals with a genetic predisposition to essential hypertension do not produce a circulating inhibitor of sodium-potassium adenosine triphosphatase (Na-K-ATPase) in response to a high-sodium challenge.

Adenosine Triphosphate↗