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Results for “Genetic predisposition”

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PubMed2006

Effect of team sport participation on genetic predisposition to adolescent smoking progression.

CONTEXT: There is much to be learned about why some adolescents progress to a regular smoking habit and others do not. OBJECTIVE: To evaluate whether (1) team sport participation buffers the effect of having 2 smoking risk genotypes (the dopamine reuptake transporter [SLC6A3] and the dopamine D(2) receptor [DRD2]) or 1 of these risk genotypes vs having none on adolescent smoking progression and (2) the buffering effects of team sports were due to physical activity associated with team sport participation. DESIGN: Longitudinal cohort study. Survey data were collected annually from grade 9 to the end of grade 12. Self-report measures included smoking, team sport participation, physical activity, depression, smoking exposure, and alcohol and marijuana use. DNA was collected via buccal swabs. Data were analyzed using latent growth modeling. SETTING: Five public high schools in Virginia. PARTICIPANTS: A total of 361 students of European ancestry. Main Outcome Measure Smoking progression. RESULTS: For adolescents participating in at least 1 team sport, but not for adolescents with no team sport participation, physical activity had a significant negative effect on smoking progression (z = -3.85, P<.001; chi(2)(1,N = 361) = 6.73, P = .009). In addition, having 1 (z = 2.69; P = .007) and 2 (z = 2.22; P = .03) smoking risk genotypes had a positive effect on physical activity. These represented significant between-group effects (chi(2)(1,N = 361) = 6.29, P = .01; chi(2)(1,N = 361) = 3.81, P = .05, respectively). Thus, having 1 or more smoking risk genotypes was related to higher levels of physical activity, which, in turn, was related to lower levels of smoking progression for adolescents participating in at least 1 team sport but not for adolescents with no team sport participation. CONCLUSIONS: This study provides the first evidence of an interaction between environmental influences and specific genes on adolescent smoking and may promote an understanding of important protective relationships in the environment.

Adolescent↗

PubMed2000

[Genetic predisposition for alcoholism].

A number of socio-economic, cultural, biobehavioral factors and ethnic/gender differences are among the strongest determinants of drinking patterns in a society. Both epidemiological and clinical studies have implicated the excessive use of alcohol in the risk of developing a variety of organ, neuronal and metabolic disorders. Alcohol abuse related metabolic derangements affect almost all body organs and their functions. Race and gender differences in drinking patterns may play an important role in the development of medical conditions associated with alcohol abuse. The incidence of alcoholism in a community is influenced by per capita alcohol consumption and covariates with the relative price and availability of alcoholic drinks. The majority of the family, twin and adoption studies suggest that alcoholism is familial, a significant proportion of which can be attributed to genetic factors. The question is how much of the variance is explained by genetic factors and to what degree is this genetically mediated disorder moderated by personal characteristics. Among the most salient personal characteristics moderating, the genetic vulnerability may be factors such as age, ethnicity, and presence of psychiatric co morbidity. Cultural factors and familial environmental factors are most likely predictors as well.

Alcohol-Related Disorders↗

PubMed2004

Pas1 haplotype-dependent genetic predisposition to lung tumorigenesis in rodents: a meta-analysis.

Rodent species and strains show wide variations in susceptibility to lung tumorigenesis. In mice, hierarchical clustering of 29 inbred laboratory strains by pulmonary adenoma susceptibility 1 (Pas1) locus polymorphisms separated the strains into either an A/J- or a C57BL/6J-type Pas1 haplotype. A pooled analysis (including >8500 mice) of studies on spontaneous and chemically induced lung tumorigenesis in these strains revealed a significantly higher risk of spontaneous lung tumors [odds ratio (OR) 12.17; 95% confidence interval (CI) 9.00-16.45] as well as of chemically induced lung tumors (OR 15.14; 95% CI 12.51-18.31) in the A/J-type haplotype. Strain differences were observed with six different carcinogens, suggesting that Pas1 locus activity is carcinogen-independent. Thus, the present meta-analysis indicates a link between the genetic control of spontaneous and chemically induced lung tumor susceptibility in mice. The Pas1 susceptibility allele is frequent in the population of inbred mouse strains, whereas a counterpart appears to be absent or rare in rat and hamster strains. These findings might help in the interpretation of results of rodent carcinogenicity bioassays and assessing the risk of lung carcinogenesis from chemicals.

Animals↗

PubMed1999

Inherited genetic predisposition in breast cancer. A population-based perspective.

Two classes of inherited susceptibility genes may be considered in the etiology of breast and other common cancers. First, genes have been identified that confer a high degree of breast cancer (BC) risk, usually associated with hereditary syndromes, but disease-associated germline variants in these genes are relatively rare in the general population. These include BRCA1, BRCA2, and TP53. The proportion of BC in the general population that can be explained by these genes is relatively small. Second, variant genotypes at other loci may confer a relatively smaller degree of cancer risk, but they are carried by a larger proportion of the general population. As a result, the proportion of BC that could be explained by these genes may be relatively large. To understand the genetic basis for BCs in the general population, both of these classes of genes may need to be considered. This paper presents an overview of genes thought to be involved in BC susceptibility. Genes that confer a high degree of risk are more likely to result in hereditary patterns of cancer that are amenable to identification by genetic epidemiologic methods using pedigree data. More common (e.g., nonhereditary) forms of BC may be optimally analyzed by molecular epidemiologic studies using case-case, case-control, or cohort designs. The use of an appropriate study design is crucial to the identification of genes with relatively small effects on BC risk. To understand the inherited factors that explain BC in the general population, consideration should be given to genes with different allele frequencies and magnitudes of effect, using appropriate analytical approaches. By understanding the complex interactions of these genes with one another and with exposures, improved risk assessment and potential for targeted cancer prevention strategies may be possible.

Breast Neoplasms↗

PubMed2006

Genetic predispositions to low-grade inflammation and type 2 diabetes.

Insulin resistance and cardiovascular disease share common pathophysiological mechanisms, as the chronic activation of the innate immune system. This system constitutes the first line of body's defense and is constituted by different barriers (e.g., epithelia, adipose tissue) and different blood and tissue components (e.g., macrophages, neutrophils). This system generates the acute-phase response in which different acute-phase proteins and cytokines are produced in response to different aggressions as infections and traumatisms. The aim of this response is to eradicate these agents, to repair the harmed tissues, and, through increased insulin resistance, to optimize the energetic substrates, which will be drained to vital tissues and organs (i.e., brain and the immune system). Evolutionary pressures have led to survival of the fittest individuals, those with the genetics that allows the best defense against infection and periods of famine. Evidence is reported according to which gene polymorphisms in the molecules regulating the inflammatory cascade are associated with body composition, insulin action, and characteristics of the metabolic syndrome. The evolutive advantages of increased inflammatory responses, hypersecretion of proinflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and IL-18], or decreased anti-inflammatory molecules (adiponectin, certain TNF-alpha isoforms, soluble CD14, etc.), would lead in westernized countries to chronic inflammation conditions, such as obesity and type 2 diabetes, resulting in cardiovascular disease.

Diabetes Mellitus, Type 2↗

PubMed2001

Genetic predisposition and environmental causes in periodic and systematic catatonia.

The nosological heterogeneity of catatonic schizophrenia was the focus of a family study involving 139 catatonic patients. The clinical dichotomization of catatonia into periodic catatonia and systematic catatonia revealed good inter-rater reliability and stability of the diagnoses at follow-up. Analysis of the cumulative morbidity risk among first-degree relatives gave an excessive familial aggregation of homogenous psychoses in periodic catatonia with a risk of 26.9%. The mode of inheritance was consistent with an autosomal dominant model. In contrast, first-degree relatives of probands with systematic catatonia had a morbidity risk of 4.6%. Subsequent investigations pointed to a potential association of systematic catatonia to exposure to midgestational infections in the index cases and linked these sporadic disorders to disturbances of fetal neurodevelopment. The periodic catatonia, an unequivocally genetically transmitted illness, is at present under investigation in a genome-wide linkage analysis.

Catatonia↗

PubMed2004

Genetic predisposition of the interleukin-6 response to inflammation: implications for a variety of major diseases?

BACKGROUND: A single-nucleotide polymorphism (SNP) in the promoter region of the interleukin-6 (IL-6) gene at position -174 (G>C) has been reported to be associated with a variety of major diseases, such as Alzheimer disease, atherosclerosis, and cardiovascular disease, cancer, non-insulin-dependent diabetes mellitus, osteoporosis, sepsis, and systemic-onset juvenile chronic arthritis. However, authors of previous in vitro and in vivo studies have reported conflicting results regarding the functionality of this polymorphism. We therefore aimed to clarify the role of the -174 SNP for the induction of IL-6 in vivo. METHODS: We vaccinated 20 and 18 healthy individuals homozygous for the -174 C and G alleles, respectively, with 1 mL of Salmonella typhii vaccine. IL-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) were measured in the blood at baseline and up to 24 h after vaccination. RESULTS: Individuals with the G genotype had significantly higher plasma IL-6 values at 6, 8, and 10 h after vaccination than did individuals with the C genotype (P <0.005). There were no differences between the two genotypes regarding serum concentrations of IL-1beta and TNF-alpha before or after vaccination. CONCLUSIONS: The -174 G>C SNP in the promoter region of the IL-6 gene is functional in vivo with an increased inflammatory response associated with the G allele. Considering the central role of IL-6 in a variety of major diseases, the present finding might be of major relevance.

Female↗

PubMed2001

Functional peculiarities of MAP2 in DBA/2J inbred mice as a component of genetic predisposition to seizures.

We compared the content of high molecular microtubule-associated protein-2 and its phosphorylation by cAMP- and Ca(2+)/calmodulin-dependent protein kinases in the brain of DBA/2J and C57Bl/6 inbred mice. The revealed differences in protein content and phosphorylation can be attributed to the mechanisms mediating audiogenic seizures in DBA/2J mice and to differential sensitivity of these inbred lines to seizure-inducing factors.

Animals↗

PubMed1998

Dietary fat, genetic predisposition, and obesity: lessons from animal models.

This review focuses on animal studies that examine the role of dietary fat in obesity. It is evident from animal experiments that the percentage of energy derived from fat in the diet is positively correlated with body fat content. With few exceptions, obesity is induced by high-fat diets in monkeys, dogs, pigs, hamsters, squirrels, rats, and mice. The mechanisms responsible for this correlation between body fat and dietary fat content are not clear. It has been proposed that a high-fat diet produces hyperphagia, which is solely responsible for the increased body fat content. However, several studies in various rodent models showed that increased body fat content still results when the hyperphagia is prevented. This suggests that some metabolic effects of high-fat diets, independent of hyperphagia, may also be contributing to the obesity induced by high-fat diets. It is also clear from animal studies that genetic factors significantly modulate the body's response to diets high in fat-derived energy. In contrast with the animal studies, studies in humans that have examined the relation between dietary fat content and body fat are inconclusive. The limitations of cross-sectional studies, the lack of controlled feeding trials, and the importance of genetic variation in response explain the absence of conclusive evidence. The lessons learned from animal models point to dietary fat as one potentially important component in the etiology of human obesity. Additional comprehensive studies are warranted to determine the role of dietary fat in the etiology of human obesity.

Adipose Tissue↗

PubMed2005

[Genetic predisposition and susceptibility to mycobacterial infections: the IL-12-IFNgamma axis deficiency].

Since ten years severe pediatric infections which were idiopathic have now molecular explanation, defined new primary immunodeficiencies. These children presented a new kind of hereditary immunodeficiency with severe and/or recurrent infections caused by only one micro-organisms family. Some of these children have mycobacterial infections. Standard immunologic explorations were normal. However, they presented a vulnerability, sometimes lethal caused by Mycobacteria. The goal of this article is to describe the IL-12-IFNgamma axis deficiency (mendelian susceptibility to mycobacterial disease).

Genetic Predisposition to Disease↗

PubMed2005

Genetic predisposition to sporadic cancer: how to handle major effects of minor genes?

Predisposition to non-familial, sporadic cancer is strongly influenced by multiple tumor susceptibility genes (TSGs), each with apparently minor effects on the cancer phenotype. Sequence analysis of the human genome has yielded numerous single nucleotide polymorphisms (SNPs), raising the expectation that new low-penetrance TSGs will be identified that can be used to estimate an individuals cancer risk. However, mouse models for human cancer showed that the effects of many low-penetrance TSGs are highly variable due to their involvement in epistatic interactions. Together, these interacting TSGs form large molecular networks, which represent cancer-associated biological modules that influence the tumorigenic process. As a consequence, although allelic variation in one TSG on a permissive genetic background can have major effects on tumor development, the net effect of allelic variation in multiple interacting TSGs remains hard to predict. Therefore, the predictive value of SNP-analysis to estimate an individuals cancer risk will be restricted to those TSGs that exhibit single-gene effects. New strategies need to be developed to evaluate cancer risk associated with biological modules that are influenced by TSG-networks.

Adenomatous Polyposis Coli↗

PubMed2005

Cytogenetics of familial Waldenstrom's macroglobulinemia: in pursuit of an understanding of genetic predisposition.

Despite recent identification of a recurrent chromosome 6q21 deletion in sporadic Waldenstrom's macroglobulinemia (WM), elucidation of the molecular pathogenesis of WM remains challenging. In contrast to the growing body of cytogenetic studies in sporadic WM, there have been virtually no informative studies of familial WM. The authors therefore undertook conventional and molecular cytogenetic evaluation of 18 patients with familial WM and 3 patients with immunoglobulin (Ig) M monoclonal gammopathy (IgM-MG) from 15 families to determine the nature and extent of chromosomal abnormalities associated with familial WM. The frequency and distribution of chromosomal changes in familial WM resembled those in sporadic WM, including lack of IgH rearrangements and t(9;14); however, we detected del6q21 in only 1 patient. Occasional findings appeared to be novel; however, none were recurrent, and their significance remains unclear. Only one abnormality found in bone marrow specimens was detected in parallel peripheral blood lymphocyte studies, suggesting that most abnormalities represented somatic changes. Although they must be viewed in light of the hypoproliferative nature of WM, our results suggest that further progress in delineating the genetic determinants of WM susceptibility might be gained from alternative approaches such as candidate gene or linkage analysis.

Adult↗

PubMed2005

[Chronic beryllium disease: a model of interaction between environmental exposure and genetic predisposition. Pathogenesis and clinical features (Part 2)].

INTRODUCTION: Chronic beryllium disease (CBD) is an occupational lung disease caused by the inhalation of beryllium dust, fumes or metallic salts. CURRENT DATA: Beryllium affects the lungs via particles deposited in the pulmonary alveoli. These are ingested by alveolar macrophages which act as antigen presenting cells to CD4+ T lymphocytes. T lymphocytes proliferate in response to beryllium antigens and combined with macrophages produce numerous epithelioid granulomas with the release of inflammatory cytokines (IFNgamma, IL-2, TNFalpha and IL6) and growth factors. Beryllium induces macrophage apoptosis which reduces its clearance from the lung which in turn contributes to the host's continual re-exposure and thus a chronic granulomatous disorder. Pulmonary granulomatous inflammation is the primary manifestation of CBD, but the disease occasionally involves other organs such as the liver, spleen, lymph nodes and bone marrow. The clinical, radiological, and histopathological features of CBD can be difficult to distinguish from sarcoidosis. The Beryllium lymphocyte proliferation test (BeLPT) demonstrates a beryllium specific immune response, confirms the diagnosis of CBD, and excludes sarcoidosis. CONCLUSIONS AND PERSPECTIVES: CBD provides a human model of pulmonary granulomatous disease produced by an occupational exposure, occurring more frequently in those with a genetic pre-disposition. It can be differentiated from sarcoidosis by specific immunological testing.

Berylliosis↗

PubMed2004

Transverse craniofacial features and their genetic predisposition in families with nonsyndromic unilateral cleft lip and palate.

OBJECTIVE: The purpose of this study was to evaluate the transverse craniofacial form in families with nonsyndromic cleft lip and palate (NSCLP). It was hypothesized that affected as well as noncleft NSCLP family members are characterized by a common array of craniofacial features that differ from the general population. DESIGN: This was a prospective cross-sectional investigation that included affected children with NSCLP and their noncleft parents and siblings. PATIENTS, PARTICIPANTS: A total of 114 subjects (14 affected girls, 17 affected girls, 15 unaffected male siblings, 10 unaffected female siblings, 29 unaffected biological mothers, and 29 unaffected biological fathers) were included. Subject records comprised of posteroanterior cephalometric radiographs obtained from all 114 subjects. MAIN OUTCOME MEASURES: The width of midfacial structures, including the orbit and nose, was increased in NSCLP families, compared with published norms. Interestingly, the face was disproportionally wider in relation to total facial height. The transverse craniofacial form of children with or without clefts significantly correlated with that of their parents. Mothers displayed strong correlation with their affected and unaffected sons, whereas fathers correlated to their daughters, suggesting a possible sex-linked developmental influence. CONCLUSION: Better understanding of the genetic inheritance of craniofacial features associated with cleft lip and palate may ultimately contribute to the development of cleft risk assessment methods.

Adolescent↗

PubMed2004

Chemopreventive drug treatment in subjects with genetic predisposition to cancer: prescriber liability and healthcare disparities.

Advancements in pharmacogenomics and chemoprevention promise to reduce cancer incidence and mortality, but utilization will undoubtedly be accompanied with ethical and legal issues that largely remain unexplored or discussed. As pharmacogenomic information is assessed more comprehensively and inexpensively, it will influence decisions regarding when and to whom chemoprevention therapy will be initiated. Pharmacogenomics will change the manner in which the liability system will perceive and analyse risks. Management of the risks related to chemopreventive treatment will differ from traditional disease management. Knowledge about cancer susceptibility will need to consider environmental factors as they relate to healthcare disparities.

Anticarcinogenic Agents↗

PubMed1999

Genetic predisposition to ocular melanoma.

Uveal melanoma is the most common primary intraocular malignancy, with an annual incidence of 6 per million. The environmental factors known to increase the risk of cutaneous melanoma appear to be less important in ocular melanoma and it is conceivable that host factors have a greater impact. The coexistence of ocular and cutaneous melanoma in some patients suggests a predisposition to both types and implicates mutations in the CDKN2A gene in a proportion of these cases. An association between ocular melanoma and breast and/or ovarian cancer has also been reported and recent studies of breast cancer families strongly implicate BRCA2 as a predisposition gene. Other more common genes predisposing to ocular melanoma may be of low penetrance. An example of a gene in this class is MC1R, which affects host response to ultraviolet radiation. Identification of genes conferring an increased risk of ocular melanoma should provide insights into the pathogenesis of this tumour. Furthermore, it offers an opportunity to identify individuals at a high risk who may benefit from targeted surveillance. At present the identification of such individuals is restricted to the small number belonging to BRCA2 families and those with the atypical mole syndrome.

Genes, BRCA1↗

PubMed2006

Women's acceptance of MRI in breast cancer surveillance because of a familial or genetic predisposition.

Magnetic resonance imaging (MRI) of the breasts is a promising screening modality for early detection in women at increased breast cancer risk. We investigated the subjective experiences with MRI and the preferences for MRI, mammography or clinical breast examination in 178 high-risk women adhering to a breast cancer surveillance programme. MRI was reported to cause limited discomfort. About 44% preferred MRI as a screening test (mammography: 14%). MRI provided the most reassurance of breast cancer being absent in case of a favourable test result. MRI seems to be acceptable as a screening test for women at increased breast cancer risk and is preferred by them over mammography.

Adult↗

PubMed2000

Cystic fibrosis mutations and genetic predisposition to idiopathic chronic pancreatitis.

Idiopathic chronic pancreatitis is a leading cause of chronic pancreatitis. Work from this and other groups has shown that idiopathic chronic pancreatitis is associated with mutations of the cystic fibrosis gene (CFTR). Many idiopathic pancreatitis patients have compound heterozygote genotypes in which both copies of the CFTR gene are abnormal. In these patients, the pancreatic disease can be viewed as a mild variant of cystic fibrosis, in which there is sufficient residual CFTR function to prevent lung disease. This article summarizes the evidence associating these abnormal CFTR genotypes with idiopathic chronic pancreatitis and reviews the implications of this association for the pathogenesis, classification, and prevention of pancreatitis.

Adolescent↗