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Results for “genetic predisposition”

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PubMed1989

The genetic predisposition to cancer.

The multi-stage nature of cancer, and the interaction of the host and environment in the origin of cancer, both suggest multiple ways in which genetic predisposition to cancer might operate. A role for genetic variation has already been demonstrated in many instances and it is likely that still more examples of genetic predisposition will be uncovered. In some individuals genetic predisposition operates interactively with environment. Much of human cancer may occur in persons of this interactive oncodeme. Other persons have a very strong susceptibility to cancer because they have inherited a mutation on the path to cancer; they belong to a "purely" genetic oncodeme. The population of target cells itself is known to be affected by some environmental agents. Genetic factors may also operate, as in the X-linked lymphoproliferative syndrome with its predisposition to Burkitt lymphoma. Somatic mutation plays a critical role in carcinogenesis. Numerous environmental agents can increase the probability that somatic mutation will occur. Host genes can interact with these factors in two general ways. One concerns the ability to repair the damage caused by the agent. Most of the damage is repaired in normal persons, but much more is not repaired in persons with certain recessively inherited disorders, known as DNA-repair deficiencies. The other general way concerns the delivery of the critical agent. For example, the albino absorbs such excessive amounts of sunlight that even a normal DNA-repair mechanism is stressed. Similarly, some individuals metabolize certain chemical compounds in such a way that the concentration of an active mutagen is abnormally high, again overcoming the DNA-repair mechanism. The stages of promotion, progression, and metastasis are much less well understood, and clear examples of a role for genetic factors in them are not available. However, there are multiple ways in which heredity could be interacting, as with a genetic control of hormone production. Finally, the genetic targets of mutation, the "cancer genes," can play a role in cancer. Although no heritable mutations for oncogenes are yet known in man, there are reasons to believe that they could occur. On the other hand, heritable mutations of anti-oncogenes are well known and apparently account for much, or all, of dominantly heritable cancer in humans. In toto, the contribution of genetic predisposition to the burden of cancer could be considerable, because of the potentially large size of the interactive oncodeme. Identification of such susceptible persons could have important consequences in preventive oncology.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Transformation, Neoplastic↗

PubMed1987

Cleft lip with or without cleft palate: identification of sporadic cases with a high level of genetic predisposition.

Previous studies have suggested that asymmetry for certain bilaterally represented features may be an indicator of genetic predisposition to cleft lip with or without cleft palate and may therefore be of value in the individual assessment of recurrence risk, particularly for sporadic cases. An asymmetry score has been devised that may be of use in identifying those with a high level of genetic predisposition. Stepwise logistic regression selected nine variables that together correctly classified 85% of familial cleft patients and unrelated non-cleft controls. Applying the same regression equation to sporadic cases, 26% fell into the range occupied by the majority of familial patients, suggesting that these had a high level of genetic predisposition.

Adolescent↗

PubMed2026

Perceived partner substance use, genetic predispositions, and their associations with problematic alcohol use, emotional well-being, and relationship quality.

BACKGROUND: Romantic relationships are important contexts for substance use and emotional well-being. We tested the hypotheses that (i) genetic predispositions for alcohol consumption would be positively associated with partner substance use, (ii) partner substance use would moderate genetic influences on one's own alcohol outcomes, and (iii) partner discordance in substance use would be associated with lower emotional well-being and relationship quality. METHODS: Analyses included 2,357 participants (Mage = 51.4, 58.2% female) from the Collaborative Studies on the Genetics of Alcoholism. Focal measures included participants' reports of their own and their current partner's past-year substance use (frequencies of alcohol use, heavy drinking, drunkenness, cannabis use, and nicotine use), emotional well-being, and relationship quality. Participants' genetic predispositions were indexed with genome-wide polygenic scores for alcohol consumption (PGSAlc). Participant-partner substance use discordance was calculated as the difference between the participant's and their partner's use for each substance use measure, separately. RESULTS: Participant PGSAlc was not significantly associated with partners' perceived substance use. Frequent perceived partner alcohol use and heavy drinking significantly amplified the association between PGSAlc and alcohol use or drunkenness. Frequent perceived partner drunkenness and cannabis use significantly attenuated the association between PGSAlc and heavy drinking or frequency of alcohol use. Participant-partner discordance for several substance use measures was significantly associated with lower emotional well-being and relationship quality, controlling for participant and partner substance use main effects. CONCLUSIONS: The results highlight the importance of partner substance use in etiological models of alcohol use, emotional health outcomes, and relationship quality.

Humans↗

PubMed1991

The role of genetic predisposition to type I (insulin-dependent) diabetes mellitus.

The aetiology of insulin-dependent diabetes (IDDM) involves genetic predisposition, a major component of which has been mapped in the HLA complex, near to or identical with genes encoding class II molecules. In Caucasian populations IDDM is strongly associated with the serologically defined HLA-DR3 and DR4 antigens, which are widely recognised as markers of susceptibility. The particularly high risk of DR3/DR4 heterozygotes suggests that susceptibility is determined by two genes acting synergistically. The development of recombinant DNA technology has allowed a finer description of the class II region and provided evidence that DQ rather than DR determinants may primarily influence IDDM susceptibility. The search for specific structural changes of the DQA and DQB genes has shown that susceptibility correlates with the absence of aspartic acid at position 57 on the DQ beta chain (DQ beta 57 Asp--) and/or the presence of arginine at position 52 on the DQ alpha chain (DQ alpha 52 Arg+). In Caucasians the formation of a putative DQ susceptibility molecule (DQ alpha 52 Arg+, DQ beta 57 Asp-) accounts best for the disease associations when transcomplementation molecules consisting of DQ alpha and beta chains encoded by different haplotypes are postulated to explain the excess risk of heterozygotes. The HLA-IDDM associations in the Japanese, however, are not explained by this model. These and other unresolved questions indicate that other residues of the DQ alpha and beta chains or other class II molecules (DR beta chains), as well as non-MHC genes, may also contribute to the susceptibility.

Diabetes Mellitus, Type 1↗

PubMed1992

Immunotherapy of rheumatic diseases based on understanding genetic predisposition to the development of these diseases.

During the past two decades, investigators have made great inroads in understanding markers of genetic predisposition to the development of rheumatic diseases. An important question that must be addressed by investigators and clinicians is whether this knowledge will ultimately benefit patients, either through genetic counseling or predictions for beneficial therapeutic intervention. This article discusses various disease mechanisms and modes of immunotherapy such as anti-CD4, major histocompatibility complex blockade, and T-cell receptor-based and determinant-induced responsiveness.

CD4 Antigens↗

PubMed2025

Genetic Predisposition to Low-Density Lipoprotein Cholesterol and Incident Type 2 Diabetes.

IMPORTANCE: Treatment to lower high levels of low-density lipoprotein cholesterol (LDL-C) reduces incident coronary artery disease (CAD) risk but modestly increases the risk for incident type 2 diabetes (T2D). The extent to which genetic factors across the cholesterol spectrum are associated with incident T2D is not well understood. OBJECTIVE: To investigate the association of genetic predisposition to increased LDL-C levels with incident T2D risk. DESIGN, SETTING, AND PARTICIPANTS: In this large prospective, population-based cohort study, UK Biobank participants who underwent whole-exome sequencing and genome-wide genotyping were included. Participants were separated into 7 groups with familial hypercholesterolemia (FH), predicted loss of function (pLOF) in APOB or PCSK9 variants, and LDL-C polygenic risk score (PRS) quintiles. Data were collected between 2006 and 2010, with a median follow-up of 13.7 (IQR, 12.9-14.5) years. Data were analyzed from March 1 to November 1, 2024. EXPOSURES: LDL-C level, LDL-C PRS, FH, or pLOF variant status. MAIN OUTCOMES AND MEASURES: Cox proportional hazards regression models adjusted for age, sex, genotyping array, lipid-lowering medication use, and the first 10 genetic principal components were fitted to assess the association between LDL-C genetic factors and incident T2D and CAD risks. RESULTS: Among the 361 082 participants, mean (SD) age was 56.8 (8.0) years, 194 751 (53.9%) were female, and mean (SD) baseline LDL-C level was 138.0 (33.6) mg/dL. During the follow-up period, 22 619 (6.3%) participants developed incident T2D and 17 966 (5.0%) developed incident CAD. The hazard ratio for incident T2D was lowest in the FH group (0.65; 95% CI, 0.54-0.77), while the highest risk was in the pLOF group (1.48; 95% CI, 1.18-1.86). The association between LDL-C PRS and incident T2D was 0.72 (95% CI, 0.66-0.79) for very high LDL-C PRS, 0.87 (95% CI, 0.84-0.90) for high LDL-C PRS, 1.13 (95% CI, 1.09-1.17) for low LDL-C PRS, and 1.26 (95% CI, 1.15-1.38) for very low LDL-C PRS. CAD risk increased directly with the LDL-C PRS. CONCLUSIONS AND RELEVANCE: In this cohort study, LDL-C and T2D risks were inversely associated across genetic mechanisms for LDL-C variation. Further elucidation of the mechanisms associating low LDL-C risk with increased risk of T2D is warranted.

Humans↗

PubMed1986

Genetic predisposition to diabetes mellitus is associated with impaired humoral immunity to coxsackievirus B4.

Experiments were performed to determine whether genetic predisposition to diabetes mellitus (DM) or clinical DM or both exert an influence on the production of neutralization antibodies to coxsackievirus B4 (CB4). The homozygous diabetic mutant mouse db+/db+, on the inbred C57BL/KsJ genetic background, develops a diabetes-like disease when maintained on ad libitum diet but restriction of excess food intake prevents overt disease. The doubly heterozygote db+/+m or the homozygote +m/+m misty coat color mutant, on the C57BL/KsJ genetic background, do not develop DM and served as controls. Animals infected with one-half a previously determined LD50 of CB4 were bled prior to infection and at 3, 5, 7, 14, 21 days and at 1, 2, 3, 4 and 5 months after infection. Serum neutralization antibody (NA) levels were determined from the percent CB4 plaque reduction. Until 2 months following infection, NA levels were not significant in either of the homozygous diabetic mutant groups, db+/db+. In the diabetic mutant group db+/db+, without overt disease, neutralization of CB4 when observed, was low, short-lived, and apparently not specific. However, in the homozygous diabetic mutants with spontaneous diabetes, CB4 NA became evident at 2 months after infection. By 3 months post-infection, serum NA levels were sufficient to cause 90% virus plaque reduction. These observations demonstrate that hereditary DM as characterized by the mutation diabetes, db, in the C57BL/KsJ mouse, is associated with a marked impaired humoral immune response to a diabetogenic human CB4. Specifically, there is an inability to develop an adequate level of anti-CB4 antibodies. The type and degree of immunological impairment are apparently different prior to and after onset of diabetes mellitus.

Animals↗

PubMed1976

Genetic predisposition and stress-induced hypertension.

When chronically exposed to an approach-avoidance conflict, rats with a genetic susceptibility to hypertension showed persisten elevations in systolic blood pressure, but rats with a genetic resistance to hypertension did not. Hence, psychic stress is selectively efficacious in producing hypertensive effects depending on genetic predisposition of the animal.

Animals↗

PubMed1985

Analysis of DNA haplotypes suggests a genetic predisposition to trisomy 21 associated with DNA sequences on chromosome 21.

To test the hypothesis that there is a genetic predisposition to nondisjunction and trisomy 21 associated with DNA sequences on chromosome 21, we used DNA polymorphism haplotypes for chromosomes 21 to examine the distribution of different chromosomes 21 in Down syndrome and control families from the same ethnic group. The chromosomes 21 from 20 Greek families with a Down syndrome child and 27 control Greek families have been examined for DNA polymorphism haplotypes by using four common polymorphic sites adjacent to two closely linked single-copy DNA sequences (namely pW228C and pW236B), which map somewhere near the proximal long arm of chromosome 21. Three haplotypes, +, +---, and - with respective frequencies of 43/108, 24/108, and 23/108, account for the majority of chromosomes 21 in the control families. However, haplotype - was found to be much more commonly associated with chromosomes 21 that underwent nondisjunction in the Down syndrome families (frequency of 21/50; X2 for the two distributions is 9.550; P = 0.023; degrees of freedom, 3). The two populations (control and trisomic families) did not differ in the distribution of haplotypes for two DNA polymorphisms on chromosome 17. The data from this initial study suggest that the chromosome 21, which is marked in Greeks with haplotype - for the four above described polymorphic sites, is found more commonly in chromosomes that participate in nondisjunction than in controls. We propose an increased tendency for nondisjunction due to DNA sequences associated with a subset of chromosomes 21 bearing this haplotype.

Base Sequence↗

PubMed1992

Tumor necrosis factor and interferon gamma: relevance for immune regulation and genetic predisposition to autoimmune disease.

The role of TNF-alpha and IFN-gamma in various models of autoimmune disease were analyzed. These include murine models of lupus, type 1 diabetes in NOD mice and the adjuvant arthritis model in rats. Rather than being involved mainly in the effector arm of the inflammatory process of autoimmune organ destruction, our data suggest a primary involvement of these cytokines in some of the basic mechanisms of the autoimmune process. Evidence has been presented that emphasizes the possibility of the involvement of TNF-alpha in the genetic predisposition to SLE. Based on the data presented, one should be cautious in extrapolating the effects of these cytokines in various in vitro systems to the in vivo situation.

Animals↗

PubMed1985

HLA and genetic predisposition to lupus erythematosus and other dermatologic disorders.

Human leukocyte antigen (HLA) associations with different clinical and serologic subsets of lupus erythematosus are providing important clues to genetic predisposition and pathogenesis. The evolving complexity of the HLA-D region is described, and currently recognized HLA-region associations with systemic lupus erythematosus, subacute cutaneous lupus erythematosus, homozygous C2-deficient lupus, Sjögren's syndrome, and the neonatal lupus syndrome are reviewed. The striking relationship between the Ro/SSA-La/SSB antibody responses and HLA-DR2 and DR3 are emphasized. Other dermatologic conditions associated with HLA are also noted.

Adult↗

PubMed1985

Assessment of genetic predisposition to alcoholism in male alcoholics.

Association between the history of alcoholism in different relatives with the development of alcoholism in male probands was analysed using the rate of development of alcoholism as a marker of genetic predisposition. It was found that a history of alcoholism in parents, grandparents and siblings of parents was associated with an accelerated rate in the development of alcoholism while a history of alcoholism in siblings and children of probands was not. The rate of development of alcoholism was positively associated with the number of generations of the proband's family in which alcoholism occurred.

Adult↗

PubMed1975

The mechanism of genetic predisposition in congenital dislocation of the hip.

The important role of polygenic acetabular configuration and monogenic joint laxity has again been proved in the aetiology of congenital dislocation of the hip. According to the findings reported these two genetic predispositions seem to be unrelated. The time of diagnosis in accetabular dysplasia type and joint laxity type did not differ, thus the neonatal and late-diagnosed cases do not seem to be two clear-cut entities.

Acetabulum↗

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↗

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↗

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↗