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PubMed1996

[Ataxia telangiectasia and genetic predisposition to cancer].

Ataxia telangiectasia (AT) is a genetic disorder with an autosomic recessive transmission. Occurring during childhood, it affects different organs and/or systems. Physiopathology is still unclear. The first clinical signs are evident early in childhood and evolution always leads to death. The secondary cause of mortality in 10 to 15% of the affected is the development of cancers. Genetic predisposition to cancer for homozygotes, as well as for heterozygotes, is one of the most remarkable aspects of this disease. For heterozygotes the risk of cancer is three times that of the norm. The gene responsible for the disease has been cloned. Its function may resolve some questions, and provide the link between degenerative process, cancer susceptibility and immunodeficiency evident in AT patients.

Ataxia Telangiectasia↗
PubMed1999

Genetic predisposition, environment and cancer incidence: a nationwide twin study in Finland, 1976-1995.

Twin studies integrate genetic and environmental (including physical environment and life-style) information by comparing monozygotic and dizygotic twins for the occurrence of disease. Our objectives were to compare cancer incidence in twins with national rates and to estimate both the probability that co-twins of affected twins may develop cancer and the importance of genetic predisposition and environment in cancer development. The nationwide record linkage of the Finnish Twin Cohort Study, the Finnish Cancer Registry and the Central Population Register allowed the follow-up of 12,941 same-sexed twin pairs for incident primary cancers from 1976 to 1995. Zygosity was determined by use of a validated questionnaire in 1975. Methods included calculation of standardized incidence ratios and concordances and fitting of structural equation models. A total of 1,613 malignant neoplasms occurred in the cohort. The overall cancer incidence among twins resembled that among the general population. Monozygotic co-twins of affected twins were at 50% higher risk than were dizygotic co-twins. Based on genetic modeling, inherited genetic factors accounted for 18% (95% confidence interval 4-32%) of the liability in inter-individual variation in the risk of overall cancer, while non-genetic factors shared by twins accounted for 7% (0-16%) and unique environmental factors for 75% (65-85%). Our results appear to exclude a contribution greater than one-third for genetic predisposition in the development of cancer in the general population, thus pointing to the earlier confirmed substantial role of environment.

Adult↗
PubMed2002

Bilateral angiosarcoma of the breast after conservative treatment of bilateral invasive carcinoma: genetic predisposition?

AIMS: In view of the increasing application of breast-conserving therapy (BCT) for early breast cancer during the last decades, the number of BCT-associated angiosarcomas is likely to increase. Their aetiology is not completely clear. The aim of this study was to examine the potential role of genetic predisposition for development of this rare tumour. METHODS: The authors report on a case of consecutive bilateral development of angiosarcoma of the breast 6 and 12 years after BCT for bilateral invasive breast carcinoma. The literature was reviewed and the potential role of genetic predisposition was examined. RESULTS: Such a case of bilateral BCT-induced breast angiosarcoma has not been previously reported in the international literature. The change on development of such a tumour bilaterally is 0.25-2.6 per million women who underwent bilaterally BCT with radiotherapy for invasive carcinoma. The case history and the literature review suggest that gene mutations are likely to play a role in development of post-radiation angiosarcoma of the breast. CONCLUSIONS: It is assumed that genetic predisposition may play a role in the development of angiosarcoma after BCT. When such a predisposition is known, one might decide to avoid BCT in favour of mastectomy.

Aged↗
PubMed1993

Genetic predispositions for the immunological features of chronic active hepatitis.

To assess the frequency and genetic predispositions of concurrent immunological diseases and immunoserological markers in autoimmune hepatitis and chronic viral hepatitis, we assessed 185 patients prospectively, including 122 patients with autoimmune hepatitis and 63 patients with viral disease. Human leukocyte antigens were determined in all patients. Sixty patients (32%) had concurrent immunological diseases, and the majority of the diseases (68%) had known human leukocyte antigen associations. Although patients with autoimmune hepatitis had concurrent immunological diseases more commonly than those with viral disease (38% vs. 22%; p = 0.04), the nature of the diseases was similar in both groups, as were the frequencies of human leukocyte antigen-DR4 (42% vs. 39%; p = 0.7). The presence of human leukocyte antigen-DR4 was associated with the concurrence of immunological diseases in both autoimmune (62% vs. 33%; p = 0.01) and viral hepatitis (75% vs. 29%; p = 0.009). In autoimmune hepatitis, human leukocyte antigen-DR4 was also associated with the expression of smooth muscle antibodies and high-titer antinuclear antibodies. We conclude that concurrent immunological diseases and immunoserological markers are common in autoimmune and chronic viral hepatitis. Both conditions have a common genetic predisposition for concurrent immunological disease associated with human leukocyte antigen-DR4. The expression of smooth muscle antibodies and high-titer antinuclear antibodies is associated with human leukocyte antigen-DR4 in autoimmune hepatitis only, suggesting that this response is associated with triggering antigens and immune recognition systems that are different from those in viral disease.

Antibodies, Antinuclear↗
PubMed2000

Urinary creatinine excretion in children from families with Balkan endemic nephropathy: evidence for genetic predisposition to the disease.

Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial kidney disease prevalent in Serbia, Bosnia, Croatia, Bulgaria and Romania. Genetic studies have supported the genetic predisposition to BEN, and some studies in Bulgaria and in the Kolubara region of Serbia have revealed abnormalities of the urinary tract in up to 46% of children from families with BEN. In the present study, urinary excretion of creatinine, an index of muscle mass, was studied in 703 healthy children from endemic and non-endemic areas around the South Morava River. The survey covered a three-year period, and the children were studied three times a year: in the spring, autumn and winter. A urine sample for the period corresponding to 7-10 a.m. was collected during each study period. Evidence has been presented that children from families with BEN excrete significantly less creatinine than those from families without BEN living in the same area, or than children living in villages outside the endemic region or in the city of Nis. This study supports the view that genetic predisposition to BEN is indicated by a smaller muscle mass, although the effect of living conditions and nutrition may also contribute to this.

Adolescent↗
PubMed2006

[The influence of psychosocial factors in developments of ischemic heart disease and arterial hypertension in persons with genetic predisposition].

The purpose of the work was to investigate the influence of psychosocial factors on the development of ischemic heart disease and arterial hypertension in persons with genetic predisposition to cardiovascular disease. Three groups of patients were investigated: 72 patients with AH, 175 patients with IHD (74 with angina pectoris and 101 with angina pectoris and myocardial infarction) and 164 patients with IHD and AH. In nearest relation of 283 (69/03%) patients from 410 were found the presence of high arterial hypertension, myocardial infarction, diabetes and obesity. In this persons reliable relationship were found between psychosocial and genetic factors (in persons with genetic predisposition to cardiovascular disease were found high rate of anxiety, frequent stressful situations at work and in family, psychoemotional overloads). On the basis of our investigations it may be concluded that the genetic and psychosocial factors together play important role in the development of IHD and AH, that perhaps caused from influence of genetic factors on capable of to overcome the stress.

Adult↗
PubMed2004

Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma.

Germline anomalies of the INK4a-ARF and Cdk4 genes were sought in a series of 89 patients suspected of having a genetic predisposition to melanoma. Patients were selected based on the following criteria: (a) familial melanoma (23 cases), (b) multiple primary melanoma (MPM; 18 cases), (c) melanoma and additional unrelated cancers (13 cases), (d) age at diagnosis less than 25 years (21 cases), and (e) nonphoto-induced melanoma (NPIM; 14 cases). Mutations of INK4a-ARF and Cdk4 were characterised by automated sequencing, and germline deletions of INK4a-ARF were also examined by real-time quantitative PCR. Seven germline changes of INK4a-ARF, five of which were novel, were found in seven patients (8%). Four were very likely to be pathogenic mutations and were found in three high-risk melanoma families and in a patient who had a pancreatic carcinoma in addition to melanoma. Three variants of uncertain significance were detected in one MPM patient, one patient <25 years, and one NPIM patient. No germline deletion of INK4a-ARF was found in 71 patients, and no Cdk4 mutation was observed in the 89 patients. This study confirms that INK4a-ARF mutations are infrequent outside stringent familial criteria, and that germline INK4a-ARF deletions are rarely involved in genetic predisposition to melanoma.

Adolescent↗
PubMed2006

Update on evidence for a genetic predisposition to cerebral vasospasm.

Considerable evidence links cerebral vasospasm to the decreased bioavailability of endothelial nitric oxide synthase (eNOS) after aneurysmal subarachnoid hemorrhage (SAH). In recent studies from the cardiology literature, researchers have suggested that a genetic predisposition to coronary vasospasm might develop as the result of a T-786C single nucleotide polymorphism (SNP) in the eNOS gene. The authors of this study attempted to determine if there may be a similar genetic predisposition toward cerebral vasospasm. The authors prospectively identified 28 patients with Fisher Grade 3 SAH from a group of 51 consecutive patients with ruptured intracranial saccular aneurysms. Genomic DNA was isolated from a peripheral blood sample obtained with permission from each patient. Gene microarray technology was used to assay the samples for the presence and distribution of certain key eNOS gene polymorphisms. Clinical, radiological, and genomic data were analyzed. The finding of eNOS T-786C SNP could be used to significantly differentiate between the presence and severity of cerebral vasospasm (p = 0.04). The findings from this preliminary study support similar findings in the coronary vasospasm literature as well as the hypothesis that a predisposition toward cerebral vasospasm may be related partially to genetic factors, which needs to be confirmed in a larger study. Such gene-based information may be important in rapidly identifying patients at increased risk of vasospasm after SAH, independent of their Fisher grade. In this article, the authors review key studies in this area.

Animals↗
PubMed2003

Association between pepsinogen C gene polymorphism and genetic predisposition to gastric cancer.

AIM: To identify a molecular marker for gastric cancer, and to investigate the relationship between the polymorphism of pepsinogen C (PGC) gene and the genetic predisposition to gastric cancer. METHODS: A total of 289 cases were involved in this study. 115 cases came from Shenyang area, a low risk area of gastric cancer, including 42 unrelated controls and 73 patients with gastric cancer. 174 cases came from Zhuanghe area, a high-risk area of gastric cancer, including 113 unrelated controls, and 61 cases from gastric cancer kindred families. The polymorphism of PGC gene was detected by polymerase chain reaction (PCR) and the relation between the genetic polymorphism of PGC and gastric cancer was examined. RESULTS: Four alleles, 31 0bp (allele 1), 400 bp (allele 2), 450 bp (allele 3), and 480 bp (allele 4) were detected by PCR. The frequency of allele 1 was higher in patients with gastric cancer than that in controls. Genotypes containing homogenous allele 1 were significantly more frequent in patients with gastric cancer than that in controls (0.33, 0.14, chi(2)=3.86, P<0.05). There was no significant difference between the control group of Zhuanghe and the group of gastric cancer kindred. But the frequency of allele 1 was higher in control group of Zhuanghe area than that in control group of Shenyang area and genotypes containing homogenous allele 1 were significantly more frequent in the control group of Zhuanghe area than those in control group of Shenyang area (0.33, 0.14, chi(2)=4.32, P<0.05). In the group of gastric cancer kindred the frequency of allele 1 was significantly higher than that in control group of Shenyang area (0.5164, 0.3571, chi(2)=4.47, P<0.05). Genotypes containing homogenous allele 1 were significantly more frequent in the group of gastric cancer kindred than those in control group of Shenyang area (0.36, 0.14, chi(2)=4.91, P<0.05). CONCLUSION: These results suggest that there is some relation between pepsinogen C gene polymorphism and gastric cancer, and the person with homogenous allele 1 predisposes to gastric cancer than those with other genotypes. Pepsinogen C gene polymorphism may be used as a genetic marker for a genetic predisposition to gastric cancer. The distribution of pepsinogen C gene polymorphism in Zhuanghe, a high-risk area of gastric cancer, is different from that in Shenyang, a low risk area of gastric cancer.

Alleles↗
PubMed2006

Detecting genetic predisposition for complicated clinical outcomes after burn injury.

Sepsis, septic shock and organ failure are common among patients with moderate to severe burns. The inability of demographic and clinical factors to identify patients at high risk for such complications suggests that genetic variation may influence clinical outcome. Moreover, the genetic predisposition to death from infection has been estimated to be greater than for cardiovascular disease or cancer . While it is widely accepted that genetic factors influence many complex disease processes, controversy has emerged regarding the most appropriate methods for detection and even the validity of many published allelic associations . This article will review the few studies of genetic predisposition that have been conducted in the setting of burn injury, then discuss some of the obstacles and potential approaches for the discovery of additional allelic associations.

Burns↗
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&#xa0;=&#xa0;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↗
PubMed2000

An animal model for the study of genetic predisposition in the pathogenesis of middle ear inflammation.

OBJECTIVES: Chronic otitis media with effusion (COME) is the most prevalent inflammatory disease in children and is associated with numerous adverse long-term sequelae. Many factors have been associated with an increased risk of developing COME, one of which may be a genetic predisposition to the disease. To study the role that genetics play in the pathogenesis of COME, we used an animal model to compare the middle ear inflammatory responses in two different strains of rats (Lewis and Fisher). METHODS: In earlier studies, we demonstrated that exposure of the middle ear to endotoxin caused early extensive exudation and, later, goblet cell hyperplasia and mucin hypersecretion. In the present study, the animals were divided into six groups. In each group the animals were given transtympanic injection with gram-positive bacterial cell wall product (peptidoglycan-polysaccharide [PG-PS]). The middle ear bullae were studied at 1 week and 3 weeks after infection, and after systemic reinfection. Comparisons were made of the quantity of mucin exudate by enzyme-linked immunosorbent assay and by histological evaluation of the middle ear epithelial thickness. RESULTS: Our data demonstrate a statistically significant difference in middle ear inflammation and effusion formation between the two genetically different strains of rats. CONCLUSIONS: These data support the hypothesis that the middle ear response to PG-PS may be genetically determined and therefore suggest that genetic predisposition may play a role in the pathogenesis of COME.

Acute Disease↗
PubMed2003

[Agenesis of inferior vena cava combined with multiple genetic predisposition in the case of deep venous thrombosis in a young male].

Deep venous thrombosis in the young age may be a complication of the rare congenital abnormality of the vena cava inferior. Genetic factors predisposing to thrombophilia in coincidence with vena cava malformation put the patients at much higher risk to develop thrombosis. The authors report a case of a 25-year old male who suffered from a massive deep venous thrombosis derived from the vena poplitea involving the vena iliaca communis. The molecular genetic examination of the patient revealed his combined genetic predisposition to venous thrombosis (Heterozygosity for Factor V. Leiden, Heterozygosity for prothrombin G20210A). Authors conclude that it is essential to perform all the relevant molecular genetic examinations to identify the presence of thrombophilic vulnerabilty and radiological imaging procedures in all cases of young patients with deep venous thrombosis if the suspicion of vascular malformation arises. The review of the literature revealed that the vena cava malformation in association with genetic factor predisposing to thrombophilia is an infrequent condition. In the authors knowledge this is the first report presenting a multiple combined genetic predisposition of risk factors in deep venous thrombosis.

Adult↗
PubMed1999

Relationship between a genetic predisposition to hypertension, blood pressure levels and pain sensitivity.

INTRODUCTION: The aim of this study was to determine whether the degree of blood pressure elevation and/or a genetic predisposition to hypertension have a major role in determining a reduced pain perception in hypertensives. The reasons underlying the relationship between blood pressure elevation and pain perception mechanisms are not completely understood. METHODS: One hundred and four untreated hypertensive patients (65 subjects with and 39 without a positive parental history of hypertension) together with a control group of 42 subjects (20 normotensive offspring of normotensive parents, and 22 normotensive offspring of hypertensive parents) were submitted to standard blood pressure evaluation, 24-h blood pressure monitoring and dental pain perception evaluation. RESULTS: Both pain threshold and tolerance were found to be higher in hypertensive than normotensive subjects (P < 0.0001 and P < 0.015, respectively). Positive significant correlations were found between both 24-h systolic and diastolic pressure and the pain perception variables. When a 2 x 2 ANOVA test was performed, factoring for the effects of both blood pressure status and family history of hypertension on pain sensitivity, a significant effect was revealed only for blood pressure status. Moreover, after controlling for blood pressure by a covariate analysis, no significant difference was found between the subjects with or without hypertensive parents as regards pain perception variables. CONCLUSIONS: Pain sensitivity is correlated to blood pressure levels whereas the parental history of hypertension per se does not affect the pain perception pattern. Thus, the degree of blood pressure elevation, more than a genetic predisposition to hypertension may influence the mechanisms leading to hypalgesia in hypertension.

Adult↗
PubMedDate not supplied

Evaluation of a shared decision making program for women suspected to have a genetic predisposition to breast cancer: preliminary results.

BACKGROUND: Women suspected to have a genetic predisposition to breast cancer face the difficult choice between regular breast cancer screening and prophylactic mastectomy. The authors developed a shared decision making program (SDMP) to support this decision. OBJECTIVES: To evaluate the SDMP in terms of practicality, beneficial effects, and patient satisfaction. DESIGN: A one-group pretest-posttest design was used. MEASURES: Decision uncertainty, decision burden, subjective knowledge, and risk comprehension were assessed before and after the SDMP. Additional measures were obtained for concepts related to breast cancer concern, desire to participate in the program, satisfaction, program acceptability, and emotional reaction to the program information. RESULTS: Seventy-two women, most of whom were awaiting the genetic test results, participated. Decision uncertainty (effect size d = 0.37) and decision burden (d = 0.41) were reduced by the SDMP. Subjective knowledge (averaged d = 0.94) and risk comprehension were improved. The women were satisfied with the SDMP and found its rationale acceptable. Women who had strong emotional reactions to the information benefited less from the SDMP, whereas women with strong desires to participate in the decision benefited more. CONCLUSIONS: There is a need to give patients more information, especially about prophylactic mastectomy and among gene carriers. Beneficial effects were observed irrespective of whether genetic status was known, suggesting that information concerning treatment options should be made available as soon as DNA testing begins. The better psychological outcomes of women with stronger desires to participate may arise because the desire to participate is characteristic of emotional stability.

Adult↗
PubMed1998

Contribution of HLA genes to genetic predisposition in diffuse panbronchiolitis.

Diffuse panbronchiolitis (DPB) in East Asia is a distinctive chronic obstructive pulmonary disease of unknown etiology. We hypothesize that the disease susceptibility is due to genetic predisposition unique to Asians. Association between human leukocyte antigen (HLA)-Bw54 and the disease was previously reported. In the present study, using newly developed polymerase chain reaction (PCR)- based methods, we directly analyzed HLA class I and II alleles in 76 Japanese patients. HLA-A, -B, and -C antigens were screened by the conventional typing method, and then B22-group alleles including HLA-B54 were genotyped by single-strand conformation polymorphism analysis. Alleles of HLA-DRB1 gene were fully determined by the microtiter plate hybridization method. Thirty-seven percent of the patients possessed HLA-B*5401 allele conserved predominantly in East Asians, as compared with 15% of 110 healthy volunteers (chi2 = 12.4, p = 0.0004). In addition, 4% of the patients possessed B*5504 also unique to Asians but a rare allele which was not found in normal control subjects in this study. Typing of HLA-DRB1 class II gene did not demonstrate strong positive association with the disease. A33, B44, and DRB1*1302 showed negative association with the disease. We conclude that distinctive molecular structure of HLA-B alleles or a closely linked gene in the HLA region contributes to genetic predisposition in diffuse panbronchiolitis. This may partly explain why this disorder is found primarily in Asians.

Alleles↗
PubMed2002

The effect of bacillus Calmette-Guérin immunization depends on the genetic predisposition to Th2-type responsiveness.

The aim of this study was to investigate whether the effect of bacillus Calmette-Guérin (BCG) immunization on ovalbumin-induced allergic inflammation in a rat model depends on the genetic predisposition to react with a T helper cell (Th) 2-type cytokine response. This study was performed in an inbred Th2-predisposed "asthma prone" rat strain (brown Norway [BN]) and in an outbred nonpredisposed strain (Sprague Dawley [SD]), to differentiate between genetic and environmental factors. BCG decreased numbers of lung eosinophils and macrophages in the SD rat. This effect was not seen in the BN rat. In the BN rat, but not in the SD rat, BCG downregulated levels of total serum IgE. No significant differences were found with respect to frequencies of IFNgamma- or interleukin-4-producing cells in the lung in both rat strains. These results indicate that the degree and pathway of immunomodulatory effect of BCG in two genetically different rat strains is dependent on the genetic predisposition to develop a Th2-type response. Therefore, differences in genotype in relation to environment may result in difference in involvement of contributing pathogenic factors and thus different responsiveness to therapeutic strategies.

Animals↗