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Results for “Genetic predisposition”

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PubMed2000

The expression frequency of common fragile sites and genetic predisposition to colon cancer.

The expression frequency of common fragile sites induced by aphidicolin (Apc), bromodeoxyuridine (BrdU), and caffeine was evaluated on prometaphase chromosomes obtained from the peripheral blood lymphocytes of 32 patients with colon cancer, 30 of their clinically healthy family members and 30 age-matched normal controls. The proportion of damaged cells (P < 0.001), the mean number of chromosomal aberrations and the expression frequencies of fragile sites were significantly higher in the patient and relative groups compared to the control group. Our findings show an increased genetic instability in patients with colon cancer and their first-degree relatives. In addition, common fragile sites can be used as a suitable marker for determining genetic predisposition to cancer.

Adenocarcinoma↗

PubMedDate not supplied

The role of environmental carcinogens, viruses and genetic predisposition in the pathogenesis of mesothelioma.

Mesothelioma is one of the most aggressive human cancers and kills approximately 2500 people per year in the US. This cancer was almost unknown until the second half of the 20th century, and its rapid increase has been linked to the widespread use of asbestos. In spite of an enormous research effort, the mechanisms of asbestos carcinogenicity have remained an enigma. Why only a fraction of individuals exposed to high levels of asbestos develop mesothelioma while individuals with low to no asbestos exposure also develop this cancer remains unknown. Recently, simian virus 40, a DNA tumor virus known to preferentially cause mesotheliomas in hamsters, and genetic factors have been linked to mesothelioma development. Therefore, a new research front has been opened in mesothelioma, a cancer that appears to be caused by the environmental carcinogens asbestos and erionite, viruses, and genetic predisposition. The challenge for future research is to establish how these apparently very different factors interact to cause mesotheliomas.

Animals↗

PubMed2005

The TGF-beta 1 gene codon 10 polymorphism contributes to the genetic predisposition to nephropathy in Type 1 diabetes.

AIMS: We hypothesize that transforming growth factor-beta (TGF-beta), a multifunctional growth factor which plays a key role in the development of tissue fibrosis, may be involved in the pathophysiology of diabetic nephropathy. Our aim was to examine three polymorphisms within the TGF-beta 1 gene, in codons 10, 25 and 263, for association with nephropathy in Type 1 diabetes. METHODS: We conducted a large case-control study using cases with Type 1 diabetes and clinical nephropathy. Controls were Type 1 diabetic subjects who have been injecting insulin for at least 50 years and have extremely low risk of nephropathy. Genotyping was by polymerase chain reaction with sequence-specific primers. RESULTS: There was a significant difference in the frequency of the TGF-beta 1 codon 10 genotypes in the diabetic nephropathy group (n = 420) when compared with the controls (n = 410, P = 0.007). There were no significant differences when the frequencies of the TGF-beta1 codons 25 and 263 genotypes in the diabetic nephropathy group were compared with the control group. CONCLUSIONS: In our study the TGF-beta 1 codon 10 polymorphism is associated with nephropathy in Type 1 diabetes and variation in this gene may contribute to the genetic predisposition to this complication in Type 1 diabetes.

Adult↗

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↗

PubMed2004

Complex genetic predisposition in adult and juvenile rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) are complex multifactorial diseases caused by environmental influences and an unknown number of predisposing genes. The present study was undertaken in order to investigate association of polymorphisms in candidate genes with RA and JRA in German subjects. RESULTS: Up to 200 unrelated German RA and JRA patients each and 300-400 healthy controls have been genotyped for HLA-DRB1, TNFa, TNFA -238a/g, TNFA -308a/g, TNFA -857c/t, TNFR1 -609g/t, TNFR1 P12P, TNFR2 del 15bp, IKBL -332a/g, IKBL -132t/a, IKBL C224R, CTLA4 -318c/t, CTLA4 T17A, PTPRC P57P, MIF -173g/c, the MIF and IFNG microsatellites as well as for D17S795, D17S807, D17S1821 by polyacrylamide gel electrophoresis, single-strand conformation polymorphism analysis, restriction fragment length polymorphism analysis or allele specific hybridization. None of the investigated genetic markers is associated with both, RA and JRA, but there are some statistically significant differences between patients and controls that have to be discussed sensibly. CONCLUSIONS: The difficulty in investigating the genetics of complex disorders like RA and JRA may arise from genetic heterogeneity in the clinically defined disease cohorts (and generally limited power of such studies). In addition, several to many genes appear to be involved in the genetic predisposition, each of which exerting only small effects. The number of investigated patients has to be increased to establish the possibility of subdivison of the patients according their clinical symptoms, severity of disease, HLA status and other genetic characteristics.

Adaptor Proteins, Signal Transducing↗

PubMed2005

[Chronic pulmonary berylliosis: a model of interaction between environment and genetic predisposition (Part 1). Mineralogy, toxicology, epidemiology and risk factors].

INTRODUCTION: The physico-chemical properties of beryllium (Be) are crucial for high technology industries. The inhalation of beryllium may cause, in certain individuals, a specific sensitisation (BeS) and lead, in some of them, to a pulmonary granulomatosis called chronic pulmonary berylliosis (CPB). BACKGROUND: Although there is no linear relationship between the level of exposure to Be and the risks of BeS and CPB, the highest exposures are associated with an increased risk. The specific influences of the chemical composition, the solubility and different types of Be on the risk of BeS an CPB are poorly understood. Insoluble particles of small diameter are probably associated with an increased risk. Many studies have reported the role of a genetic predisposition in the risk of BeS and CPB. At present the role of HLA-DPB1 Glu69 in sensitisation to Be is the best studied. CONCLUSION: Sensitisation to Be and CPB result from the combination of exposure and predisposing genetic polymorphisms. CPB is a model for the understanding of the pathology of certain ideopathic pulmonary granulomatoses such as sarcoidosis.

Berylliosis↗

PubMed1997

Interactions between genetic predisposition and environmental toxicants for development of lung cancer.

Significant interindividual variations in health outcome may be caused by the inheritance of variant polymorphic genes, such as CYP2D6 and CYP2E1 for activation, and GSTM1 and GSTT1 for detoxification of chemicals. However, mechanistic studies linking the inheritance of predisposing genes with genotoxic effects towards cancer have yet to be systematically conducted. We have studied 54 lung cancer patients and 50 matched normal controls, who have been cigarette smokers, to elucidate the role of polymorphic genes in cancer. Our data indicates that the inheritance of unfavorable CYP2D6, CYP2E1, and GSTT1 genes in strongly correlated with the smoking-related lung cancer. For heavy cigarette smokers (> 30 pack-years), the smoking habit is the strongest predictor of lung cancer risk irrespective of the inheritance of unfavorable metabolizing genes. For moderate to light smokers (< 30 pack-years), the genetic predisposition plays an important role for the risk (odds ratio = 3.46; 95% Cl = 0.46-40.2). Using a subgroup of the study population, we observed that cigarette smokers having the defective GST genes have significantly more chromosome aberrations as determined by the fluorescence-in-situ-hybridization (FISH) technique than smokers with the normal GST genes (P < 0.001). In conclusion, our study provides data to indicate that individuals who have inherited unfavorable metabolizing genes have increased body burden of toxicants to cause increased genetic damage and to have increased risk for cancer. Studies like ours can be used to understand the basis for interindividual variations in cancer outcome, to identify high risk individuals and to assess health risk.

Adenocarcinoma↗

PubMed2000

The influence of genetic predisposition on the prevalence of atopic diseases in Carinthian school children.

The reasons for the origin and increasing rise in incidence of atopic diseases such as bronchial asthma, allergic rhinoconjunctivitis and eczema in many countries are still unknown. Our survey carried out within the frame of the ISAAC protocol comprised three districts in the Austrian province of Carinthia. A complete study of first and second year elementary school children was done in order to uncover a relationship between "presumed exposure" to different possible risk factors with that of an atopic disorder (i.e. asthma, hay fever, eczema). The results show a significant association between the occurrence of atopic disorders and genetic predisposition and the fact that a carpet which had previously been present in the child's bedroom, had been removed due to the presence of an allergic disease in a family member. The logistic regression model explains a very small part of the overall variability (R2 = 7.32%).

Air Pollution, Indoor↗

PubMed2006

The TGFbeta1 gene codon 10 polymorphism contributes to the genetic predisposition to high myopia.

PURPOSE: Transforming growth factor-beta (TGFbeta), a multifunctional growth factor that plays a key role in the remodeling of scleral tissue, may be involved in the predisposition and pathophysiology of high myopia. Our aim was to examine the association between myopia and the polymorphisms within codon 10 of the TGFbeta1 gene. METHODS: This was a case control study. The study group contained participants who had high myopia and a spherical equivalent greater than -6.00 D. The control group was composed of medical students whose spherical equivalent was less then -0.5 D. All volunteers in this study were over 16 years old and had never undergone ocular surgery. Genotyping was conducted by restriction fragment length polymorphism, and the results were compared between myopia patients and control subjects. RESULTS: The frequency of the CC genotype in TGFbeta1 codon 10 differed significantly between patients in the high myopia group (n=201) and individuals in the control group (n=86; p<0.001). People with either the CT or TT genotype had a lower probability of having high myopia with a spherical equivalent greater than -6.00 D than those with the CC genotype. Furthermore, there was a higher frequency of the C allele in the high myopia group than with the control group (p<0.001, OR=1.83, CI=1.27-2.63). CONCLUSIONS: The frequency of the CC homozygote in the high myopia group was much higher than in the control group, indicating people with the CC homozygote may be at a higher risk of developing high myopia. Varied expression of this gene may contribute to the genetic predisposition to high myopia in Chinese Taiwanese.

Adolescent↗

PubMed1998

Inversion of genetic predisposition to carcinogenesis in liver of two lines of mice selected for resistance (Car-R) or susceptibility (Car-S) to skin carcinogenesis.

Two lines of mice, one resistant (Car-R) and one susceptible (Car-S) to skin carcinogenesis, were produced by bi-directional selective breeding. To see whether the characteristics of susceptibility or resistance to tumorigenesis were also expressed in the liver and lung, the two lines were submitted comparatively to treatment with 5,9-dimethyl dibenzo[c,g]carbazole (DiMeDBC), a potent hepatocarcinogenic derivative of the ubiquitous heterocyclic carcinogenic pollutant, 7H-dibenzo[c,g]-carbazole (DBC). An inversion of genetic predisposition to carcinogenesis in liver was observed. Car-R animals displayed rapid tumorigenesis in 100% of cases while Car-S mice were remarkably less sensitive, showing a 4-fold lower mean tumor multiplicity and a 4-month longer latency time. In parallel adduct formation by DiMeDBC and DBC in liver DNA was analyzed by the 32P-postlabeling method, showing a remarkably higher level in Car-R mice than in Car-S animals. These data indicate that tissue-specific sensibility in carcinogenesis may involve gene expression at various levels.

Animals↗

PubMed2001

HLA class I and class II are both associated with the genetic predisposition to primary Sjögren syndrome.

Primary Sjögren syndrome (pSS) is an autoimmune disease characterized by progressive destruction of the exocrine glands leading to mucosal and conjunctival dryness. It is marked by lymphocytic infiltration of the glands and the accumulation of several types of autoantibodies such as rheumatoid factor (RF), antinuclear, anti-SS-A (anti-Ro) and anti-SS-B (anti-LA) autoantibodies. The susceptibility to pSS and/or the presence of SS-A/SS-B autoantibodies in pSS patients is associated with DRB1*03-DQB1*02 and DRB1*02-DQB1*06 haplotypes, whereas no associations have been described with any HLA class I allele. To define the impact of HLA class I alleles in predisposition to pSS, 46 patients responding to the European criteria and 222 healthy unrelated Caucasians were analyzed for their HLA class I and class II haplotypes. Our results confirm the association of the DRB1*03-DQB1*02 haplotype with SS-A/SS-B autoantibodies positive pSS and demonstrate a significant association of the HLA-A24 with the disease. Moreover, HLA-A24 is more often associated with DRB1*11-DQB1*0301 and/or DRB1*0301-DQB1*02 in pSS patients than in the controls. The novel association of HLA class I alleles with susceptibility to pSS provides new insights to the genetic predisposition to this disease and subsequently to its physiopathology.

Adult↗

PubMed1996

Genetic predisposition to organ-specific endpoints of alcoholism.

Medical records of the 15,924 twin-pairs in the National Academy of Sciences-National Research Council (NAS-NRC) twin registry were collected for an additional 16 years through 1994 when the surviving twins were aged 67 to 77 years. Compared with earlier analyses (Hrubec, Z, and Omenn, G. S., Alcohol. Clin. Exp. Res., 5:207-215, 1981), when subjects were aged 51 to 61, there were 23% more diagnoses of alcoholism (34.4 per 1,000 prevalence), 32% more diagnoses of alcoholic psychosis (5.4 per 1,000), and 25% more twins with liver cirrhosis (17.7 per 1,000). Overall, 5.3% of the cohort had at least one of the diagnoses related to alcoholism. Probandwise concordance rates (%) were: alcoholism-26.7 monozygotic (MZ), 12.2 dizygotic (DZ) (p < 0.0001); alcoholic psychosis-17.3 MZ, 4.8 DZ (p < 0.05); and cirrhosis-16.9 MZ, 5.3 DZ (p < 0.001). Concordance for any diagnosis related to alcoholism was 30.2 MZ, 13.9 DZ (p < 0.0001). Maximum-likelihood modeling indicated that approximately 50% of the overall variance was due to additive genetic effects; in all diagnosis categories, a totally environmental model gave a significantly poorer fit to the data. Bivariate and trivariate genetic analyses indicated most of the genetic liability for the organ-specific endpoints of psychosis and cirrhosis was due to the shared genetic liability for alcoholism. Once the shared variance with alcoholism was considered, there was no further shared genetic liability for psychosis and cirrhosis. Our results confirm Hrubec and Omenn's conclusion that there was significantly greater concordance in MZ twins-pairs for alcoholic psychosis and cirrhosis in the NAS-NRC twins, and concordance rates remained similar to those reported 16 years earlier. In contrast, we found most of the genetic liability to organ-specific complications of alcoholism was shared with the genetic liability for alcoholism per se; only a small portion of the genetic variance of the individual complications was independent of the genetic predisposition for alcoholism.

Aged↗

PubMed1999

CYP2C19 genotype does not represent a genetic predisposition in idiopathic systemic lupus erythematosus.

BACKGROUND: The aetiology of systemic lupus erythematosus (SLE) is still unknown. In several cases, however, chemicals or drugs were identified as aetiological agents and associations with certain phenotypes of drug metabolising enzymes have been reported. The purpose of this study was to discover if there is an association between CYP2C19 polymorphism and susceptibility to SLE. METHODS: Racemic mephenytoin (100 mg orally) was given to healthy volunteers (n = 161) and SLE patients (n = 37) and then S-mephenytoin and R-mephenytoin were determined in eight hour urine samples. A 10 ml blood sample was obtained from healthy volunteers (n = 80) and SLE patients (n = 69) for genotypic assay. Each blood sample was tested for the detection of CYP2C19*1 and CYP2C19*2 (formerly wt and m1 respectively) by oligonucleotide ligation assay. RESULTS: The ratio of S/R-mephenytoin ranged from < 0.1 to 1.293 in healthy subjects and from < 0.1 to 1.067 in SLE patients. PM phenotype was observed in 2 of 37 patients with idiopathic SLE (5.4%) and 6 of 161 healthy subjects (3.7%). There were no significant differences in the frequency of PM phenotypes between the groups (Fisher's exact test, p = 0.64) or in the frequency distribution profiles of ratios of S-mephenytoin to R-mephenytoin. No significant differences in distribution of overall genotypes and in allele frequencies were observed between the two groups. No significant relation was found between clinical features and the overall genotype. CONCLUSION: The results of this study indicate that CYP2C19 genotype does not represent a genetic predisposition in idiopathic SLE patients.

Adult↗

PubMed2002

Chromosomal fragile sites and relationship between genetic predisposition to small cell lung cancer.

Fragile sites are non-staining gaps and breaks on mammalian chromosomes. Several investigators have pointed out that these sites may act as factors that predispose to specific chromosomal rearrangements that are present in some cancer cases. The expression of common fragile sites induced by aphidicolin (Apc) was evaluated on prometaphase chromosomes obtained from the peripheral blood lymphocytes of 15 patients with lung cancer, 20 of their clinically healthy family members, and 20 age-matched normal controls. As a result of cytogenetic evaluation carried out by the High Resolution Banding (HRB) technique, 1q21, 2q33, 3p14, 7q32, 13q13, 16q23, 17q21, and 22q12 are defined as fragile sites in patients and relatives. The rate of total fragile sites and 2q33, 3p14, and 16q23 are statistically significant in both patients and relatives when compared with the control group. Therefore, our results showed that common fragile sites might be unstable factors in the human genome and they can be used as suitable markers for genetic predisposition to lung cancer.

Adolescent↗

PubMed1993

Genetic predisposition to hypertension facilitates blood pressure elevation in hemodialysis patients treated with erythropoietin.

PURPOSE: This study investigated the hypothesis that a genetic predisposition to hypertension is involved in the etiology of the elevation in blood pressure induced by human recombinant erythropoietin (rHuEPO). PATIENTS AND METHODS: Blood pressure changes after 10 weeks of treatment with rHuEPO were compared between 26 patients with a positive family history of hypertension and 27 with a negative family history. RESULTS: Mean blood pressure was significantly increased in patients with a positive family history of hypertension (+8.8 mm Hg, p < 0.001). In contrast, the change was not significant in those whose family history was negative (+1.8 mm Hg, not significant). The mean blood pressure of 14 of 26 patients with a positive family history of hypertension increased by more than 10%, whereas such an increase occurred in only 2 of 27 patients with a negative family history (p < 0.001). The two groups were similar in terms of the total dose of rHuEPO given, the degree to which their anemia improved, and their basal blood pressures. CONCLUSION: It appears that hemodialysis patients with a positive family history of hypertension are susceptible to developing hypertension during treatment with rHuEPO.

Antihypertensive Agents↗

PubMed2003

SCCA2-like serpins mediate genetic predisposition to skin tumors.

Reasons for early onset skin cancer are poorly understood. Microarray analysis revealed overexpression of the Scca2 gene in the 12-O-tetradecanoylphorbol-13-acetate-treated skin of Car-S mice, or line phenotypically selected for high susceptibility to two-stage skin carcinogenesis, as compared with 12-O-tetradecanoylphorbol-13-acetate-treated skin of Car-R mice, which is resistant. A human skin squamous cell carcinoma cell line (NCI-H520) transfected with mouse Scca2 or a related gene, Scca2-rs1, both expressed in the skin, showed significantly increased tumor growth as compared with controls when injected in nude mice. Immunohistochemical analysis of samples from two independent series of Italian and Korean patients with squamous cell carcinoma of the skin indicated a significant association between SCCA2 protein expression and younger age at tumor onset. These findings provide evidence that SCCA2-like serpins mediate genetic predisposition to skin cancer in a mouse model and in humans.

Adult↗

PubMed2007

Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients.

OBJECTIVE: To test for an association between apolipoprotein E (APOE) genotypes and duration of intensive care unit delirium. DESIGN: Prospective, observational cohort study. SETTING: A 541-bed, community-based teaching hospital. PATIENTS: Fifty-three mechanically ventilated intensive care unit patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patients were managed with standardized sedation and ventilator weaning protocols as part of an ongoing clinical trial and were evaluated prospectively for delirium with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). DNA was extracted from whole blood samples obtained on enrollment, and APOE genotype was determined using polymerase chain reaction followed by restriction enzyme digestion by investigators blinded to the clinical information. Delirium occurred in 47 (89%) patients at some point during the intensive care unit stay. Of the 53 patients, 12 (23%) had an APOE4 allele (APOE4+) and 41 (77%) had only APOE2 or APOE3 alleles (APOE4-). APOE4+ patients were younger (53.2 +/- 21.9 vs. 65.4 +/- 13.4, p = .08) and less often admitted for pneumonia (0% vs. 29.3%, p = .05) compared with APOE4- patients, yet they had a duration of delirium that was twice as long: median (interquartile range), 4 (3, 4.5) vs. 2 (1, 4) days (p = .05). No other clinical outcomes were significantly different between the APOE4+ and APOE4- patients. Using multivariable regression analysis to adjust for age, admission diagnosis of sepsis or acute respiratory distress syndrome or pneumonia, severity of illness, and duration of coma, the presence of APOE4 allele was the strongest predictor of delirium duration (odds ratio, 7.32; 95% confidence interval, 1.82-29.51, p = .005). CONCLUSIONS: APOE4 allele represents the first demonstrated genetic predisposition to longer duration of delirium in humans.

Aged↗

PubMedDate not supplied

Assessment of the time-tradeoff values for prophylactic mastectomy of women with a suspected genetic predisposition to breast cancer.

BACKGROUND: Female carriers of the breast-cancer-susceptibility genes BRCA1 and BRCA2 are at high risk for breast cancer (85%). They face the choice between prophylactic mastectomy (PM) and breast cancer screening. For this treatment choice, a shared-decision-making program was developed. In this program, the time tradeoff (TTO) was used to assess preferences for PM. PURPOSE: Assessment of the feasibility, constant proportional tradeoff, and reliability of using the TTO for this purpose. METHODS: Fifty-four women suspected to carry the BRCA1/2 mutation were provided with comprehensive relevant information. Their preferences for PM were assessed on two occasions. Discrepancies between preferences indicated by the two tests were resolved by testing a third time. The preferences assessed on the last occasion were used for individual decision analyses. In order to test constant proportional tradeoff, the TTO consisted of four items with different numbers of life years. RESULTS: Forty-two women (78%) completed the TTO twice and nine women (17%) performed the test a third time. Three women (5%) completed the TTO only once. The mean TTO value for PM at the last replication was 0.69 (SD=0.30). Violations of constant proportional tradeoff were significant: the largest tradeoffs were recorded for the shortest durations. Pearson's correlation coefficient between the TTO values for the two last sessions was 0.96. CONCLUSION: Assessment of individual preferences by the TTO in this patient group is feasible and reliable. Therefore, the TTO can be used in clinical settings to elicit treatment preferences of women proven or suspected to have a genetic predisposition to breast cancer.

Adult↗