PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Genetic predisposition”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 361 records · Page 20Linked to original sources
PubMed2001

[The INK4a-ARF locus: role in the genetic predisposition to familial melanoma and in skin carcinogenesis].

The INK4a-ARF locus, localized on 9p21, encodes two tumor suppressor proteins, p16INK4a and p14ARF, acting respectively through the CDK4-pRb and the p53 pathways. Familial melanoma (comprising between 8 and 12% of all melanoma cases) is a genodermatosis transmitted as an autosomal dominant trait, often associated with clinically atypical moles (AN). Germline mutations of p16INK4a are found in up to 20-30% of melanoma prone families. Mutated families often contain more than three family members affected and/or comprise at least one relative with multiple melanomas. Most of these mutations have been shown to affect p16INK4a protein function (i.e. CDK4 binding or pRB phosphorylation). Germline mutations of p16INK4a are also found in a lesser extend in sporadic multiple melanoma and in familial pancreatic cancer. The INK4a-ARF locus plays also an important role in skin carcinogenesis. P16INK4a UV induced mutations (CC:GG > TT:AA tandem transition or C:G > T:A transition at dipyrimidic site) are found in 12% of sporadic skin carcinomas, mainly in epidermoid tumors, and seem to occur independently of p53 mutations. Xeroderma pigmentosum (XP) is characterized by an inheritable DNA repair defect (involving the nucleotid excision repair (NER) system) predisposing to skin carcinomas. In skin tumors from (XP) patients, p16INK4a UV induced mutations occur more frequently, are often multiple, and significantly associated with the presence of p53 mutations. Such data, which could be related to the XP genetic instability and indicates a possible cooperative effect of inactivation of these pathways in the tumoral process of XP skin tumors.

Cyclin-Dependent Kinase Inhibitor p16↗
PubMed1989

Possible role of genetic predisposition in multigeneration carcinogenesis.

A peculiar phenomenon in experimental transplacental carcinogenesis is that in certain animal species or strains, and with certain types of carcinogens, a tumorigenic risk is observed not only in the F1 generation but also in subsequent F2 and even F3 generations when only the P generation has been exposed to a carcinogen. Additionally, in many cases, specific types of organs tend to be involved. For example, lung tumours are most common in P, F1 and F2 generations of Swiss, ICR, MA and CD-1 mice after exposure of the pregnant P generation to 7,12-dimethylbenz[a]anthracene (DMBA), urethane, DMBA and diethylstilboestrol, respectively. In such mice, the mammary glands, lymphatic tissues and ovaries are also frequently involved. Recently, two-stage tumorigenesis in skin with a phorbol acetate as promoter was transmitted to F2 descendants born of F1 SHR mice exposed transplacentally to DMBA. In WKA, BD IV and BD VI rats, nervous tissues seem to be prone to tumour development in F2 and/or F3 descendants born of F1 exposed transplacentally to N-methyl-N-nitrosourethane, N-methyl-N-nitrosourea, N-ethyl-N-nitrosourea (ENU), respectively. In F344 strain rats, however, two-stage genesis of preneoplastic foci in the liver with 2-acetylaminofluorene (2-AAF) as the promoter failed to be transmitted to F2 and F3 generations from the F1 generation, which developed the preneoplastic hepatocellular foci after prenatal exposure to ENU followed by postnatal promotion by 2-AAF. Our own recent experiments with Syrian hamsters, in which multigeneration transmission of organ-specific (tracheal epithelium) tumorigenicity of N-nitrosodiethylamine was investigated, have also failed to show this phenomenon in F2 and F3 descendants. However, various field studies on pedigrees with frequently affected siblings indicate the existence of a heritable predisposition to tumour development over more than two generations. The organs involved include ovaries, mammary glands, stomach, lympho- and myelogenic systems, skin and nervous system. Interestingly, little or no such evidence has been found in the liver, respiratory tract (except for the nasopharyngeal region) or urinary tract. In the light of these experimental and human observations, the authors are currently inclined to hypothesize a heritable predisposition to tumour development in organs specific to animal species and strains, or certain families in human cases, for explaining the mechanisms underlying multigeneration transmission of chemical carcinogenicity.

Animals↗
PubMed2000

[Genetic predisposition to infective diseases in humans. Mendelian predisposition to mycobacterial infections].

Selective susceptibility to poorly pathogenic mycobacteria, such as bacille Calmette-Guérin (BCG) vaccine and environmental non-tuberculous mycobacteria (NTM), has long been suspected to be a mendelian disorder but its molecular basis has remained elusive. Recently, recessive mutations in the interferon gamma receptor ligand-binding chain (IFNgR1), interferon gamma receptor signalling chain (IFNgR2), interleukin 12 p40 subunit (IL-12p40), and interleukin 12 receptor beta 1 chain (IL-12Rb1) genes have been identified in a number of patients with disseminated BCG or NTM infection. Although genetically distinct, these conditions are immunologically related and highlight the essential role of interferon gamma-mediated immunity in the control of mycobacteria in man.

Genetic Predisposition to Disease↗
PubMed1998

Common fragile site expression and genetic predisposition to breast cancer.

The expression of common fragile sites induced by aphidicolin and caffeine was evaluated on prometaphase obtained from the peripheral blood lymphocytes of 35 women with breast cancer, their 35 clinically healthy female family members, and 20 sex- and age-matched normal controls. As a result of the cytogenetic and statistical evaluation, the number of damaged cells, chromosomal aberrations, and expression frequencies of fragile sites detected in patients with breast cancer and their first-degree relatives were found to be significantly higher than those in the control group. Our findings indicate an increased genetic instability in women with breast carcinomas and their relatives. Therefore, fragile sites may be used as a reliable marker for defining genetic susceptibility to cancer in general.

Aphidicolin↗
PubMed2025

Genetic predisposition and mediating pathways in ischemic stroke-induced cardiac arrhythmias: a genome-wide analysis.

INTRODUCTION: The clinical presentation of stroke-heart syndrome (SHS) underscores the interplay between the central nervous system and the cardiovascular system. While cardiac arrhythmia is the prevalent form of cardiac injury in SHS patients, the causal link between ischemic stroke and cardiac arrhythmia is still unclear. METHODS: Mendelian randomization analyses and genome-wide association studies data were used to investigate the causal role of ischemic stroke on cardiac complications. Mediation and colocalization analyses were used to identify potential pathways and shared genetic variants. Single nucleotide polymorphisms (SNPs) associated with arrhythmias and ischemic stroke were used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Gene expression omnibus (GEO) database from atrial fibrillation patients were used for validation. RESULTS: Mendelian randomization analyses showed a strong correlation between arrhythmias, including ventricular tachyarrhythmias and atrial fibrillation, with ischemic stroke. Diabetic microvascular (nephropathy, retinopathy) and macrovascular (cardiomyopathy, peripheral arterial disease) complications significantly mediated the effect of ischemic stroke on cardiac arrhythmias and atrial fibrillation, explaining 28.69 % and 20.48 % of the indirect effect, respectively. Colocalization analyses identified a shared causal variant in the Phosphodiesterase 3A (PDE3A) gene (rs11045239), providing genetic evidence for a shared pathogenic pathway between ischemic stroke and cardiac arrhythmias. Moreover, KEGG pathway enrichment analyses identified a role of the cyclic adenosine monophosphate (cAMP) signaling pathway in both ischemic stroke and arrhythmias. Validation using the GEO database confirmed a significant upregulation of the PDE3A gene expression in atrial fibrillation patients. CONCLUSION: This study demonstrated a causal link between ischemic stroke and cardiac arrhythmias, with diabetic complications as one mediating factor. The identification of a shared causal variant in the PDE3A gene and the role of the cAMP signaling pathway have the potential to improve prediction and management of SHS patients.

Humans↗
PubMed2005

PHOX2B mutations and genetic predisposition to neuroblastoma.

Neuroblastoma (NB) is a childhood malignancy originating from neural crest cells, which seldom occurs in association with other neurocristopathies. Owing to the rarity of familial NB cases, only a few linkage data are available and no mutations in candidate genes have been demonstrated up till now. Germline mutations in a small proportion of NB patients have been recently reported in the paired-like homeobox 2B (PHOX2B) gene, suggesting its role in NB predisposition. On the basis of this indication, we screened three Italian families with recurrence of NB and one family with occurrence of ganglioneuroblastoma and isolated Hirschsprung disease for PHOX2B defects. Our analysis did not show any mutation, excluding PHOX2B as the NB susceptibility gene in the families we analysed. Our findings combined with those derived from other PHOX2B mutation screenings and from genome-wide linkage analysis support a remarkable genetic heterogeneity of NB and suggest an oligogenic model of disease transmission. Furthermore, as PHOX2B mutations were mainly observed in some NB families with multifocal and syndromic NB, features that are missing in the families we have studied, we suggest they represent second-site modifications responsible for a specific phenotype rather than causal mutations of a major locus.

Female↗
PubMed2004

Genetic predisposition to colorectal cancer.

High-penetrance mutations in several genes have been identified that contribute to hereditary colorectal cancer. The role of these mutations in cancer pathogenesis is well understood and their detection is successfully used in clinical diagnosis. In stark contrast, our understanding of the influence of low-penetrance mutations that account for most of the remaining familial cases of colorectal cancer, as well as an unknown proportion of sporadic cases, is far less advanced. Extensive ongoing research into low-penetrance, multifactorial predisposition to colorectal cancer is now beginning to bear fruit, with important implications for understanding disease aetiology and developing new diagnostic, preventive and therapeutic strategies.

Adenomatous Polyposis Coli↗
PubMed1987

In vitro hyperdiploidy in head and neck cancer. A genetic predisposition?

The role of heredity in the cause of head and neck cancer has not been clarified. Contrary to the autosomal-dominant heritable cancer syndromes, there is no clear genetic pattern seen in oropharyngeal or laryngeal squamous cell carcinoma. Pedigree data demonstrating clusters of affected relatives suggest that some head and neck squamous cell cancers result from an interaction between environmental factors and germinal predisposition. Though no genetic marker has been described for head and neck epidermoid carcinomas, some heritable single tumor syndromes demonstrate increased amounts of hyperdiploidy (defined as a metaphase with more than 46 chromosomes exclusive of 92) in in vitro cultures of dermal fibroblasts. In the present study, dermal fibroblasts were cultured from 30 patients with biopsy-proved oropharyngeal and laryngeal squamous cell cancer. Compared with the percentage of cells with in vitro hyperdiploidy (IVH) of 0% to 1% in 155 clinically normal individuals without a family cancer history, 13 (43%) of these 30 patients had significantly elevated (7% to 12%) IVH. Six of the seven clinically affected women had IVH, a proportion significantly greater than that for the men. In vitro hyperdiploidy remained stable for each assayed cell line from the third through sixth passage. Each patient's IVH percentage of dermal and oropharyngeal fibroblasts remained nearly constant varying 0% to 1%. The stability of the hyperdiploid fraction independent of the biopsy site eliminates local factors as the sources of the elevated IVH.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

[The genetic predisposition in open-angle glaucoma].

The genealogic tree examination of a female patient with open angle glaucoma showed the presence of eight more cases of glaucoma in the same family. The transmission was autosomal predominant with a 75% penetration of the pathological gene. In the patient's family the affection appeared practically at the same age and evolved with the same specific feature.

Female↗
PubMed2006

[Genetic predisposition and children infectious disease].

The classic primary immunodeficiencies confer predisposition to multiple infectious diseases. However since ten years severe pediatric infections which were idiopathic have now molecular explanation. Indeed, defects in several genes confer a predisposition to infection with specific pathogenes in otherwise healthy individuals. These children present a new kind of hereditary immunodeficiency with severe and/or recurrent infections caused by only one microorganisms family, in opposition of others patients with "classic" primary immunodeficiency.

Child↗
PubMed2003

Effects of the C677T and A1298C polymorphisms of the MTHFR gene on the genetic predisposition for diabetic nephropathy.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is a regulatory enzyme of homocysteine metabolism. The C677T polymorphism of the MTHFR gene has been reported to be associated with elevated plasma homocysteine in patients with low folic acid intake. A recently reported second common polymorphism, A1298C, may increase homocysteine, but only in individuals carrying the T677 allele. This study aimed to investigate the influence of the C677T and A1298C polymorphisms of the MTHFR gene on the development of diabetic nephropathy in Caucasian patients with type 2 diabetes. METHODS: We genotyped 429 type 2 diabetic patients for the C677T and A1298C polymorphisms using standard PCR-based protocols, and divided them into three groups based on renal status: 159 patients with normoalbuminuria, 149 with microalbuminuria, and 121 with persistent proteinuria and chronic renal failure (CRF). The C677T and A1298C genotype frequencies were compared among the three groups. RESULTS: Although the frequencies of the CT and TT genotypes of the C677T polymorphism tended to increase with each stage of diabetic nephropathy (53, 56 and 63% in normoalbuminuria, microalbuminuria and proteinuria/CRF, respectively), these differences were not significant. When male and female patients were analysed separately, the effect was seen only in males. The CT + TT genotype was present in 46% of male patients with normoalbuminuria, in 57% with microalbuminuria and in 68% with proteinuria/CRF (OR = 2.46; 95% CI 1.13-5.38). There were no differ-ences in the A1298C polymorphism among the three groups. CONCLUSIONS: These findings indicate that the C677T polymorphism is a risk factor for diabetic nephrop-athy in male patients with type 2 diabetes.

Aged↗
PubMed2003

Genomic rearrangements of hMSH6 contribute to the genetic predisposition in suspected hereditary non-polyposis colorectal cancer syndrome.

BACKGROUND: Germline mutations in mismatch repair genes, mainly in hMLH1, hMSH2, and hMSH6, predispose to the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. A substantial fraction of these mutations exists in genomic rearrangements of hMSH2 and hMLH1. In contrast, genomic rearrangements have not been reported in hMSH6. METHODS: Out of 15 HNPCC or HNPCC-like patients who developed tumours with loss of hMSH6 protein expression, we selected three patients who still had no germline mutations after gene sequencing. Genomic DNA of these patients was analysed using PCR based relative quantification of hMSH6 fragments. Indicated exon deletions and amplifications were characterised by long range PCR and sequencing. RESULTS: Genomic rearrangements were identified in two of the three patients. Breakpoint analyses showed an Alu repeat mediated deletion of 13.0 kb affecting the promoter region, exon 1, and exon 2 in one patient, and a duplication of 4.9 kb containing 1.6 kb of the 3' end of exon 4 and exon 5, integrated into intron 5, in the other patient. CONCLUSIONS: Although genomic rearrangements of hMSH6 only play a small role in the spectrum of all mutations predisposing to HNPCC, our results suggest that up to 10-20% of patients with hMSH6 negative tumours harbour germline rearrangements in this gene.

Chromosome Breakage↗
PubMed1993

Early exposure to cow's milk and solid foods in infancy, genetic predisposition, and risk of IDDM.

Using a case-control study design, we examined the hypothesis that early exposure to cow's milk and solid foods increased the risk of IDDM. An infant diet history was collected from 164 IDDM subjects from the Colorado IDDM Registry with a mean birth year of 1973, and 145 nondiabetic population control subjects who were frequency matched to diabetic subjects on age, sex, and ethnicity. Early exposure was defined as exposure occurring before 3 mo of age. After controlling for ethnicity, birth order, and family income, more diabetic subjects were exposed early to cow's milk (OR 4.5, 95% CI 0.9-21.4) and solid foods (OR 2.5, CI 1.4-4.3) than control subjects. To examine this association while accounting for the genetic susceptibility to IDDM, we defined individuals as high and low risk by an HLA-DQB1 molecular marker. Early exposure to cow's milk was not associated with elevated risk for IDDM in low-risk individuals. Relative to unexposed low-risk individuals, early exposure to cow's milk was strongly associated in individuals with a high risK marker (OR 11.3, CI 1.2-102.0). Similar findings were observed for early exposure to solid foods. These data indicate that early exposure to cow's milk and solid foods may be associated with increased risk of IDDM. The inclusion of HLA-encoded risk in the analyses demonstrates the combined effect of genetic and environmental factors.

Adult↗
PubMed2003

Genetic predisposition to alcoholic chronic pancreatitis.

The mechanisms leading to alcoholic chronic pancreatitis in humans have remained elusive. Numerous questions surround the apparent random nature of the disease in which 1 person is hit with alcoholic chronic pancreatitis while the next is spared. Why do fewer than 10% of chronic, heavy alcohol users ever develop pancreatitis, while others develop alcoholic liver disease, neuropathy, or other alcohol-associated problems? Why do laboratory animals, fed large amounts of alcohol for prolonged periods of time, fail to develop typical chronic pancreatitis? Why are heavy alcohol users from a black African background more likely to develop pancreatic diseases than Caucasians, whereas the opposite is true for the development of liver disease? The answers underlying these questions appear to reflect the differences in underlying genetic susceptibility, environmental exposure, and the interaction between these factors. Thus, even cases of "typical" alcoholic chronic pancreatitis or other forms of pancreatitis appear to be complex diseases. Recently, several genetic mutations have been identified that increase the susceptibility to pancreatitis. However, the major common gene mutations in CFTR, PRSS1, and SPINK1 only slightly increase the risk of alcoholic chronic pancreatitis. New genetic, environmental, and triggering factors must be considered to gain further insight into the mechanisms leading to alcoholic chronic pancreatitis so that strategies for treatment and prevention can be developed.

Alcohol Drinking↗
PubMed2006

Use of analgesics and nonsteroidal anti-inflammatory drugs, genetic predisposition, and bladder cancer risk in Spain.

BACKGROUND: We assessed use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAID), aspirin, paracetamol (acetaminophen), phenacetin, and metamizol (dipyrone) and risk of bladder cancer and their interaction with polymorphisms in drug-metabolizing genes. METHODS: We analyzed personal interview data from 958 incident bladder cancer cases and 1,029 hospital controls from a multicenter case-control study in Spain. A drug matrix was developed to estimate cumulative lifetime dose of active ingredients. Polymorphisms in GSTP1, SULT1A1, CYP2E1, CYP2C9, and NAT2 were examined. RESULTS: A significant reduction in bladder cancer risk [adjusted odds ratio (OR), 0.4; 95% confidence interval (95% CI), 0.2-0.9] was observed for regular users of nonaspirin NSAIDs compared with never users. Regular users of aspirin experienced no reduction in risk (OR, 1.0; 95% CI, 0.7-1.5). Regular users of paracetamol had no overall increased risk of bladder cancer (OR, 0.8; 95% CI, 0.4-1.3), but our data suggested a qualitative interaction with the GSTP1 I105V genotype. Subjects with at least one copy of the 359L or 144C variant alleles in the NSAID-metabolizing gene CYP2C9 had a slightly decreased risk of bladder cancer (OR, 0.8; 95% CI, 0.7-1.0; P = 0.037); however, having at least one copy of the 359L or 144C variant alleles did not significantly modify the protective effect of nonaspirin NSAID use. CONCLUSION: Regular use of nonaspirin NSAIDs was associated with a reduced risk of bladder cancer, which was not modified by polymorphisms in the NSAID-metabolizing gene CYP2C9. We found no evidence of an overall effect for paracetamol or aspirin use.

Adult↗