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Genetic Determinants (genetic + determinant)
Kinds of Genetic Determinants Selected AbstractsGenetic Determinants of Alcohol Addiction and Metabolism: A Survey in ItalyALCOHOLISM, Issue 2 2001Roberta Pastorelli Background: Although multiple genes are involved in alcoholism and can contribute differently to the risk of dependence and liver damage, no studies have investigated susceptibility to addiction in combination with susceptibility to liver damage due to differences in ethanol metabolism. Methods: We evaluated the role of three polymorphic genes related to alcohol metabolism (CYP2E1) and, possibly, dependence (DRD2 and SLC6A4 promoter) in a series of 60 alcoholics admitted to a specialized referral center in Florence, Italy. Eighteen had a diagnosis of liver cirrhosis. A control series of 64 blood donors were identified at the same hospital. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism methods. Results: No difference was found in the frequency of the CYP2E 1 Rsa I c2 allele (2.5% among alcoholics and 4.7% among controls) and the Dra I C allele (6.7% and 10.1%). Similarly, no difference was found in the frequency of the DRD2 A1 allele (15.8% and 13.3%) and the B1 allele (10.8% and 8.6%). The proportion of controls with a combined B1 genotype (B1/B1 or B1/B2) was significantly associated with smoking (p= 0.03). The distribution of the S and L allele of the SLC6A4 gene was similar in the two groups, with 15% and 14%, respectively, homozygous S/S carriers. A significant association, however, emerged in the group of alcoholics, with a five times higher risk for S/S carriers of developing cirrhosis (p < 0.05). This association with liver persisted even after exclusion of the subgrouped of 10 hepatitis C virus positive alcoholics. Conclusions: Overall, our results provided no evidence of an increased susceptibility to develop alcoholism that was associated with the three genotypes investigated, either alone or in combination. An increased risk of developing liver cirrhosis for S/S homozygous carriers among alcohol-dependent patients was observed for the first time. [source] Genetic determinants for activated fluoropyrimidine chemotherapyDRUG DEVELOPMENT RESEARCH, Issue 2 2006William H. GmeinerArticle first published online: 5 JUN 200 Abstract Fluoropyrimidines (FPs) remain widely used for the treatment of diverse malignancies more than four decades following the initial report of 5-fluorouracil (5FU), the archetypal FP, as a novel compound with potential anti-neoplastic activity. Subsequent decades of research have enriched our understanding of the biochemical mechanisms that are important for FP activation as well as the genetic determinants that are predictive of the likely success, or failure, of FP chemotherapy for a particular individual. The concept that chemotherapy should be customized to complement the genetic profiles of cancer patients has become increasingly important as genotyping of tumor samples has become possible and as the number of available anticancer drugs has increased. Significant progress has been made in identifying the gene expression profiles for cancer patients who are likely to benefit from treatment with FPs. In this review, we will summarize the results of retrospective clinical studies correlating response to FP chemotherapy with the expression of specific genes, such as TS and DPD. We will also present a summary of FPs in current clinical use, including orally bioavailable FPs such as capecitabine, as well as FPs that are in pre-clinical development, such as FdUMP[10]. Refinement of a target population through pharmacogenetic analysis and development of novel FPs that evoke very high response rates in this target population will likely result in the use of FP regimens in the coming era when cancer becomes a largely manageable disease. Drug Dev. Res. 67:119,129, 2006. © 2006 Wiley-Liss, Inc. [source] Genetic determinants of adult hippocampal neurogenesis correlate with acquisition, but not probe trial performance, in the water maze taskEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2002G. Kempermann Abstract A number of reports have indicated that adult neurogenesis might be involved in hippocampal function. While increases in adult neurogenesis are paralleled by improvements on learning tasks and learning itself can promote the survival of newly generated neurons in the hippocampus, a causal link between learning processes and adult hippocampal neurogenesis is difficult to prove. Here, we addressed the related question of whether the baseline level of adult neurogenesis is predictive of performance on the water maze task as a test of hippocampal function. We used ten strains of recombinant inbred mice, based on C57BL/6, which are good learners and show high baseline levels of neurogenesis, and DBA/2, which are known to be poor learners and which exhibit low levels of adult neurogenesis. Two of these strains, BXD-2 and BXD-8, showed a 26-fold difference in the number of newly generated neurons per hippocampus. Over all strains, including the parental strains, there was a significant correlation between the number of new neurons generated in the dentate gyrus and parameters describing the acquisition of the water maze task (slope of the learning curves). Similar results were seen when the parental strains were not included in the analysis. There was no correlation between adult hippocampal neurogenesis and probe trial performance, performance on the rotarod, overall locomotor activity, and baseline serum corticosterone levels. This result supports the hypothesis that adult neurogenesis is involved in specific aspects of hippocampal function, particularly the acquisition of new information. [source] Genetic determinants of hair color and parkinson's disease risk,ANNALS OF NEUROLOGY, Issue 1 2009Xiang Gao MD Objective A history of melanoma is associated with increased risks for Parkinson's disease (PD). We examined whether hair color, one of the most important phenotypes of pigmentation and a risk factor for melanoma, was associated with PD risk in the Health Professionals Follow-up Study (HPFS; 1986,2002) and the Nurses' Health Study (NHS; 1980,2002). Methods We included 38,641 men and 93,661 women who were free of PD at baseline. Information on natural hair color in early adulthood (age 18,21 years) was assessed via a questionnaire. We also conducted a case,control study (298 PD cases) nested in these two cohorts to examine the association between the melanocortin1-receptor Arg151Cys polymorphism and PD risk. Relative risks (RRs) were estimated using Cox proportional hazards models in the cohort analyses and conditional logistic regression in the nested case,control study. Results PD risk increased with decreasing darkness of hair color. Pooled RRs for PD were 1 (reference), 1.40, 1.61, and 1.93 (95% confidence interval, 1.1,3.4) for black, brown, blond, and red hair, respectively, after adjusting for age, smoking, ethnicity, and other covariates. The associations between hair color and PD were particularly strong for relative younger onset of PD (<70 yr) (adjusted RR for red vs black hair = 3.83; 95% confidence interval, 1.7,8.7). In the case,control study, participants with Cys/Cys genotype, which was associated with red hair, had a greater PD risk, relative to the Arg/Arg genotype (adjusted RR, 3.15; 95% confidence interval, 1.1,9.4). Interpretation These findings suggest a potential role of pigmentation in PD. Ann Neurol 2009;65:76,82 [source] Genetic variation in D7S1875 repeat polymorphism of leptin gene is associated with increased risk for depression: a case-control study from IndiaDEPRESSION AND ANXIETY, Issue 9 2009Manav Kapoor M.Sc. Abstract Background: Epidemiologic data suggest an association between obesity and depression, however findings vary considerably across different studies. Both depression and obesity are disabling disorders associated with loss over appetite control, influenced by genetic and environmental factors and are risk factors for diseases like hypertension, cardiovascular disorders, etc. This study attempts to establish a link between the symptoms of depression, metabolic disorders, and obesity, to unravel the underlying association/s. Methods: This exploratory case,control study comprises 133 clinically diagnosed depressed individuals and 136 age matched controls. DNA from all 269 subjects was genotyped for D7S1875 repeat polymorphism in the promoter region of Leptin (LEP) gene using polymerase chain reaction. Results: Frequency of the shorter allele of D7S1875 (<208,bp) was 0.73 in the depressive group versus 0.67 in the control group (P=.01). Cases homozygous for D7S1875,208,bp alleles had significantly higher value of systolic (130 versus 122; P<.009) and diastolic (85.4 versus 81; P=.01) blood pressure (SBP and DBP) than the individuals homozygous for<208,bp allele. A similar trend was observed for SBP (127.8 versus 123.6; P=.03) among controls homozygous for the longer or the shorter allele. Thus, the LEP gene appears to be an important genetic determinant for susceptibility to depression in the Indian population (OR=1.4913, 95% CI=1.0334,2.1522; P=.04). Conclusions: Our findings suggest that LEP gene variants could be related to depression and associated co-morbidities such as hypertension. Depression and Anxiety, 2009. © 2009 Wiley-Liss, Inc. [source] Genetic variations associated with psoriasis and psoriatic arthritis found by genome-wide associationDERMATOLOGIC THERAPY, Issue 2 2010Kristina Callis Duffin ABSTRACT Psoriasis and psoriatic arthritis are immune disorders with a complex polygenic basis. HLA-Cw6, which lies in the major histocompatibility region on chromosome 6, is considered the major genetic determinant of psoriasis. Recent genome-wide association studies have identified new variants outside of the MHC with relevance to the immunology of psoriasis. Variants in or near genes that encode subunits of cytokines (IL12B, IL23A) or cytokine receptors (IL23R) are interesting given that the gene product of IL12B, p40, is the target of a recently approved monoclonal antibody therapy for psoriasis (ustekinumab). Association with psoriasis and psoriatic arthritis has been found in TNFAIP3 and TNFIP1, ubiquitin ligases in the NF-,B pathway, and IL13, a Th2 cytokine. Copy number variation of human beta-defensin and late cornified envelope genes also associate with psoriasis. Many of these genetic variations also associate with immune disorders considered psoriatic co-morbidities, including Crohn's disease and diabetes. [source] Altered conditioned fear behavior in glutamate decarboxylase 65 null mutant miceGENES, BRAIN AND BEHAVIOR, Issue 2 2003O. Stork We investigated the involvement of the 65 kDa isoform of glutamic acid decarboxylase (GAD65) and GAD65-mediated ,-aminobutyric acid (GABA) synthesis in the formation and expression of Pavlovian fear memory. To this end, behavioral, endocrine and autonomic parameters were examined during conditioned fear retrieval of mice with targeted ablation of the GAD65 gene (GAD65,/, mice). These mutant mice were found to display specific fear behavior (freezing, escape), as well as autonomic (increased defecation) and endocrine activation (increased plasma corticosterone) during fear memory retrieval. However, freezing was reduced and flight and escape behavior were increased in GAD65,/, mice compared to their wild type and heterozygous littermates, while corticosterone levels and defecation rates did not differ between genotypes. Active defensive behavior of GAD65,/, mice was observed during both auditory cued and contextual retrieval of fear memory, as well as immediately after conditioning. These data indicate a selectively altered behavioral fear response in GAD65,/, mice, most likely due to deficits in threat estimation or the elicitation of appropriate conditioned fear behavior, and suggest that GAD65 is a genetic determinant of conditioned fear behavior. GAD65,/, mice provide a valuable tool to further dissect the GABAergic mechanisms involved in fear and anxiety and to model GABA-related neurological and psychiatric disorders. [source] Role of functional polymorphisms of NRAMP1 gene for the development of Crohn's diseaseINFLAMMATORY BOWEL DISEASES, Issue 10 2008Maria Gazouli PhD Abstract Background: Crohn's disease (CD) is characterized by chronic activation of macrophages. Natural resistance-associated macrophage protein 1 (NRAMP1) gene exerts many pleiotropic effects on macrophage functions. Hence, NRAMP1 may be also involved in the resistance to intracellular pathogens, and this effector of the innate immunity might be involved in CD pathogenesis. Polymorphic alleles at the NRAMP1 locus have been previously associated with susceptibility both to the putative infectious agents and to autoimmune disorders. Based on these indications, in the present study we investigate its candidacy as a genetic determinant for CD in a Greek population in an association-based study, comparing frequencies of 274 CD patients to these of 200 healthy control subjects. Methods: The 5,(GT)n promoter polymorphism and 9 either single nucleotide (SNPs) or insertion/deletion type polymorphisms were genotyped across the NRAMP1 gene. Reverse-transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry were performed in order to investigate the NRAMP1 mRNA levels in RNA isolated from biopsies of CD patients as well as protein expression in tissues. Results: Three NRAMP1 polymorphisms [5,(GT)n, D543N, and INT4G/C] were significantly associated with CD. Consistent with previous autoimmune disease studies, allele 3 at the functional 5,(GT)n promoter region repeat polymorphism, was significantly associated with CD when compared to healthy controls (odds ratio 1.50; 95% confidence interval [CI]: 1.16,1.95; P = 0.002). Interestingly, we observed that CD patients homozygous for allele 3 expressed higher NRAMP1 mRNA levels compared to carriers of allele 2. Furthermore, the protein levels of allele 3 carriers in tissues were also elevated compared to those of allele 2 carriers. Based on these data we can speculate that overrepresentation of allele 3 in CD patients could lead to hyperactivation of bowel-wall macrophages that are chronically exposed to lipopolysaccharide and this could subsequently cause the autoimmune-like phenotype characteristic of CD. Conclusions: Collectively, our data indicate that genetic polymorphisms of NRAMP1 might be associated with susceptibility to CD. (Inflamm Bowel Dis 2008) [source] A recombined haplotype in the major histocompatibility region contains a cluster of genes conferring high susceptibility to ulcerative colitis in the Spanish populationINFLAMMATORY BOWEL DISEASES, Issue 9 2005Laura Fernández PhD Abstract Background: The most consistently described associations in ulcerative colitis (UC) have been with human leukocyte antigen (HLA) class II alleles. Our aim was to look for associations among distinct genetic polymorphisms in the major histocompatibility complex (MHC) that might play a role in determining the susceptibility to UC and especially to the extensive form of the disease. Methods: A case-control study was performed with a total of 253 patients with UC and 315 healthy controls recruited from a single Spanish center. All the samples and 4 cell lines carrying DRB1*0103 or DRB1*1501 alleles were typed for the HLA-DRB1 class II gene and for a panel of HLA class III markers (D6S273, BAT_2, TNFa, b, c, d, e, IKBL+738, MICA). Results: The frequency of the alleles DRB1*0103, IKBL+738(C) (extending our previous results) and BAT_2-8 (newly typed) was increased in patients compared with controls (P = 0.00001, odds ratio [OR] = 5.90; P = 0.002, OR = 2.42; and P = 0.0001, OR = 3.04, respectively), and these associations were greatest in patients with extensive disease compared with patients with distal disease (P = 0.02, OR = 2.53; P = 0.002, OR = 3.06; and P = 0.03, OR = 2.08, respectively). The allelic combination DRB1*0103/D6S273-5/BAT_2-8/TNFa11b4c1d3e3/IKBL+738(C)/MICA5.1 that includes the telomeric class III markers of the 7.1 ancestral haplotype is highly increased in patients with UC (P = 0.0001, OR = 10.57), especially in those with the extensive form of the disease (P = 0.02, OR = 3.41 extensive versus distal). Conclusions: The above-mentioned pattern, most likely formed by recombination of the telomeric fragment of the MHC 7.1 ancestral haplotype, seems to be the most important genetic determinant of susceptibility to the extensive form of UC in our population. [source] The IBD international genetics consortium provides further evidence for linkage to IBD4 and shows gene-environment interactionINFLAMMATORY BOWEL DISEASES, Issue 1 2005Marie Pierik MD Abstract Background and Aims: The inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis are complex disorders with an important genetic determinant. One gene associated with CD has been identified: NOD2/CARD15. Two independent genome-wide scans found significant evidence (logarithm of odds [LOD] 3.6) and suggestive evidence (LOD 2.8) for linkage on locus 14q11-12, also known as the IBD4 locus. To further characterize this locus, we assessed gene-environment interaction (IBD4 × smoking) and phenotypic heterogeneity in a large cohort of IBD-affected sibling pairs as part of an ongoing international collaborative effort. Patients and Methods: A total of 733 IBD families, comprising 892 affected sibling pairs, were genotyped for microsatellites D14S261, D14S283, D14S972, and D14S275, spanning the IBD4 locus. Information on gender, ethnicity, age at onset, smoking at diagnosis, extraintestinal manifestations, and disease location was available. Results: A significant distortion in the mean allele sharing (MAS) between affected siblings was observed for CD patients only at each of the four markers (54.6%, 52.8%, 50.4%, and 53.3%, respectively). Maximum linkage for CD was observed at marker D14S261 (multipoint nonparametric linkage score 2.36; P , 0.01; MAS 54.6%). MAS was higher in CD families in which all siblings or at least one sibling smoked compared with nonsmoking CD families (MAS, 58.90%, 57.50%, and 52.80%, respectively). Conclusions: The IBD International Genetics Consortium replicated the IBD4 locus on chromosome 14q for CD and also showed evidence for a gene-environment interaction at this locus. Further studies are needed to explore the mechanism by which smoking influences IBD4. [source] LRRK2 mutations and risk variants in Japanese patients with Parkinson's disease,MOVEMENT DISORDERS, Issue 7 2009Cyrus P. Zabetian MD Abstract Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic determinant of Parkinson's disease (PD) in European-derived populations, but far less is known about LRRK2 mutations and susceptibility alleles in Asians. To address this issue, we sequenced the LRRK2 coding region in 36 patients with familial PD, then genotyped variants of interest in an additional 595 PD cases and 1,641 controls who were all of Japanese ancestry. We also performed a meta-analysis of studies on G2385R, a polymorphism previously reported to associate with PD. One pathogenic (G2019S) and one putative pathogenic (R1067Q) mutation were each observed in two patients with sporadic PD. The overall mutation frequency among patients was 0.6%. G2385R was highly associated with PD under a dominant model in our dataset (adjusted OR, 1.83; 95% CI, 1.31,2.54; P = 3.3 × 10,4) and similar results were seen in the meta-analysis (summary OR assuming fixed effects, 2.55; 95% CI, 2.10,3.10). G2385R represents the first consistently replicated common PD susceptibility variant in a non-European population and its effect size is substantially greater than that reported for other well-validated genetic risk factors for the disease. However, LRRK2 mutations appear to be rare among Japanese patients with PD. © 2009 Movement Disorder Society [source] There is no evidence of an association in children and teenagers between the apolipoprotein E ,4 allele and post-traumatic brain swellingNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 6 2004T. J. Quinn Traumatic brain injury (TBI) is an important cause of mortality and disability in children and teenagers. A particular feature of the neuropathology at post-mortem is brain swelling. The cause of the swelling in some cases is not known, while in others it is associated with traumatic axonal injury or hypoxia. Apolipoprotein E (APOE) ,4 allele is known to be an important genetic determinant of outcome in children after TBI. We hypothesized a relationship between possession of APOE,4 and diffuse traumatic brain swelling. A total of 165 cases aged between 2 and 19 years were identified from the department's tissue archive. APOE genotype was determined by polymerase chain reaction (PCR) in 106 cases. Bilateral swelling was present in 44 cases (11 with APOE,4), unilateral swelling in 25 cases (7 with APOE,4) and in 36 cases (9 with APOE,4) there was no evidence of brain swelling. There was no significant relationship between possession of APOE,4 and the presence of cerebral swelling (,2 = 0.09, df = 2, P = 0.96). The 95% confidence interval for difference in proportions with swelling, in, those, with, and, without, the,APOE,,4, is,,19%, to 22%. Thus, a significant relationship was not found between diffuse brain swelling and possession of APOE,4, and in this cohort of patients there was an identifying cause of the brain swelling in all cases. [source] Plasminogen activator inhibitor-1 and asthma: role in the pathogenesis and molecular regulationCLINICAL & EXPERIMENTAL ALLERGY, Issue 8 2009Z. Ma Summary Plasminogen activator inhibitor (PAI)-1 is a major inhibitor of the fibrinolytic system. PAI-1 levels are markedly increased in asthmatic airways, and mast cells (MCs), a pivotal cell type in the pathogenesis of asthma, are one of the main sources of PAI-1 production. Recent studies suggest that PAI-1 may promote the development of asthma by regulating airway remodelling, airway hyperresponsiveness (AHR), and allergic inflammation. The single guanosine nucleotide deletion/insertion polymorphism (4G/5G) at ,675 bp of the PAI-1 gene is the major genetic determinant of PAI-1 expression. Plasma PAI-1 level is higher in people with the 4G/4G genotype than in those with the 5G/5G genotype. A strong association between the 4G/5G polymorphism and the risk and the severity of asthma has been suggested. Levels of plasma IgE and PAI-1 and severity of AHR are greater in asthmatic patients with the 4G/4G genotype than in those with the 5G/5G genotype. The PAI-1 promoter with the 4G allele renders higher transcription activity than the PAI-1 promoter with the 5G allele in stimulated MCs. The molecular mechanism for the 4G allele-mediated higher PAI-1 expression is associated with greater binding of upstream stimulatory factor-1 to the E-box adjacent to the 4G site (E-4G) than to the E-5G. In summary, PAI-1 may play an important role in the pathogenesis of asthma. Further studies evaluating the mechanisms of PAI-1 action and regulation may lead to the development of a novel prognostic factor and therapeutic target for the treatment and prevention of asthma and other PAI-1-associated diseases. [source] The common G-allele of interleukin-18 single-nucleotide polymorphism is a genetic risk factor for atopic asthma.CLINICAL & EXPERIMENTAL ALLERGY, Issue 2 2006The SAPALDIA Cohort Study Summary Background IL-18 is a pleiotrophic cytokine involved in both, T-helper type 1 (Th1) and Th2 differentiation. Recently genetic variants in the IL-18 gene have been associated with increased risk of atopy and asthma. Objective To examine the relationship of a genetic, haplotype-tagging promotor variant ,137G/C in the IL-18 gene with atopic asthma in a large, well-characterized and population-based study of adults. Methods Prospective cohort study design was used to collect interview and biological measurement data at two examination time-points 11 years apart. Multivariate logistic regression analysis was used to assess the association of genotype with asthma and atopy. Results The G-allele of the IL-18 promotor variant (,137G/C) was associated with a markedly increased risk for the prevalence of physician-diagnosed asthma with concomitant skin reactivity to common allergens. Stratification of the asthma cases by skin reactivity to common allergens revealed an exclusive association of IL-18 ,137 G-allele with an increased prevalence of atopic asthma (adjusted odds ratio (OR): 3.63; 95% confidence interval: (1.64,8.02) for GC or GG carriers vs. CC carriers), and no according association with asthma and concomitant negative skin reactivity (adjusted OR: 1.13; 0.66,1.94). The interaction between IL-18 ,137G/C genotype and positive skin prick test was statistically significant (P=0.029). None of 74 incident asthma cases with atopy at baseline exhibited the CC genotype. Conclusion Our results strongly suggest that this variant of the IL-18 gene is an important genetic determinant involved in the development of atopic asthma. [source] Genetic determinants for activated fluoropyrimidine chemotherapyDRUG DEVELOPMENT RESEARCH, Issue 2 2006William H. GmeinerArticle first published online: 5 JUN 200 Abstract Fluoropyrimidines (FPs) remain widely used for the treatment of diverse malignancies more than four decades following the initial report of 5-fluorouracil (5FU), the archetypal FP, as a novel compound with potential anti-neoplastic activity. Subsequent decades of research have enriched our understanding of the biochemical mechanisms that are important for FP activation as well as the genetic determinants that are predictive of the likely success, or failure, of FP chemotherapy for a particular individual. The concept that chemotherapy should be customized to complement the genetic profiles of cancer patients has become increasingly important as genotyping of tumor samples has become possible and as the number of available anticancer drugs has increased. Significant progress has been made in identifying the gene expression profiles for cancer patients who are likely to benefit from treatment with FPs. In this review, we will summarize the results of retrospective clinical studies correlating response to FP chemotherapy with the expression of specific genes, such as TS and DPD. We will also present a summary of FPs in current clinical use, including orally bioavailable FPs such as capecitabine, as well as FPs that are in pre-clinical development, such as FdUMP[10]. Refinement of a target population through pharmacogenetic analysis and development of novel FPs that evoke very high response rates in this target population will likely result in the use of FP regimens in the coming era when cancer becomes a largely manageable disease. Drug Dev. Res. 67:119,129, 2006. © 2006 Wiley-Liss, Inc. [source] From soil to gut: Bacillus cereus and its food poisoning toxinsFEMS MICROBIOLOGY REVIEWS, Issue 4 2008Lotte P. Stenfors Arnesen Abstract Bacillus cereus is widespread in nature and frequently isolated from soil and growing plants, but it is also well adapted for growth in the intestinal tract of insects and mammals. From these habitats it is easily spread to foods, where it may cause an emetic or a diarrhoeal type of food-associated illness that is becoming increasingly important in the industrialized world. The emetic disease is a food intoxication caused by cereulide, a small ring-formed dodecadepsipeptide. Similar to the virulence determinants that distinguish Bacillus thuringiensis and Bacillus anthracis from B. cereus, the genetic determinants of cereulide are plasmid-borne. The diarrhoeal syndrome of B. cereus is an infection caused by vegetative cells, ingested as viable cells or spores, thought to produce protein enterotoxins in the small intestine. Three pore-forming cytotoxins have been associated with diarrhoeal disease: haemolysin BL (Hbl), nonhaemolytic enterotoxin (Nhe) and cytotoxin K. Hbl and Nhe are homologous three-component toxins, which appear to be related to the monooligomeric toxin cytolysin A found in Escherichia coli. This review will focus on the toxins associated with foodborne diseases frequently caused by B. cereus. The disease characteristics are described, and recent findings regarding the associated toxins are discussed, as well as the present knowledge on virulence regulation. [source] Genetic features of circular bacteriocins produced by Gram-positive bacteriaFEMS MICROBIOLOGY REVIEWS, Issue 1 2008Mercedes Maqueda Abstract This review highlights the main genetic features of circular bacteriocins, which require the co-ordinated expression of several genetic determinants. In general terms, it has been demonstrated that the expression of such structural genes must be combined with the activity of proteins involved in maturation (cleavage/circularization) and secretion outside the cell via different transporter systems, as well as multifaceted immunity mechanisms essential to ensuring the bacteria's self-protection against such strong inhibitors. Several circular antibacterial peptides produced by Gram-positive bacteria have been described to date, including enterocin AS-48, from Enterococcus faecalis S-48 (the first one characterized), gassericin A, from Lactobacillus gasseri LA39, and a similar one, reutericin 6, from Lactobacillus reuteri LA6, butyrivibriocin AR10, from the ruminal anaerobe Butyrivibrio fibrisolvens AR10, uberolysin, from Streptococcus uberis, circularin A, from Clostridium beijerinckii ATCC 25752, and subtilosin A, from Bacillus subtilis. We summarize here the progress made in the understanding of their principal genetic features over the last few years, during which the functional roles of circular proteins with wide biological activity have become clearer. [source] Heritability of plasma amyloid , in typical late-onset Alzheimer's disease pedigreesGENETIC EPIDEMIOLOGY, Issue 1 2001Nilufer Ertekin-Taner Abstract Plasma amyloid ,42 peptide (A,42) levels are significantly elevated in all genetic forms of early-onset Alzheimer's disease caused by familial Alzheimer's disease mutations or Down's syndrome. Moreover, recent studies have determined that both plasma A,42 and A,40 levels are significantly elevated in late-onset Alzheimer's disease (LOAD) patients, their cognitively normal first-degree relatives, and members of typical LOAD families when compared to appropriate controls. To determine the magnitude of the genetic component affecting plasma A, levels, we estimated the heritability of plasma A,42 and A,40 in 15 extended, multigenerational LOAD pedigrees, using a variance components method. Heritability estimates as high as 73 and 54% were found for plasma A,42 and A,40 levels, respectively. Inclusion of the ApoE ,4 dosage as a covariate was not found to have a significant effect on the heritability of these traits. These results suggest that genetic determinants other than ApoE account for a very substantial percentage of the phenotypic variance in plasma A, levels. The high heritability and the significant elevation of these traits in LOAD pedigrees suggest that at least some of the genetic determinants of plasma A, levels may lead to elevated A, and LOAD in these families. Thus, we suggest that plasma A, levels are quantitative traits that may be excellent surrogate markers for use in linkage analysis to identify loci that are important in typical LOAD. Genet. Epidemiol. 21:19,30, 2001. © 2001 Wiley-Liss, Inc. [source] Mouse chromosome 11 harbors genetic determinants of hippocampal strain-specific nicotinic receptor expressionHIPPOCAMPUS, Issue 8 2008Scott W. Rogers Abstract Differences between isogenic mouse strains in cellular expression of the neuronal nicotinic acetylcholine (ACh) receptor subunit alpha4 (nAChR,4) by the dorsal hippocampus are well known. To investigate further the genetic basis of these variations, expression of the nAChR,4 subunit was measured in congenic mouse lines derived from two strains exhibiting notable divergence in the expression of this subunit: C3H and C57BL/6. Congenic lines carrying reciprocally introgressed regions (quantitative trait loci; QTL) from chromosomes 4, 5, and 12 each retained the phenotype most closely associated with the parental strain. However, in congenic lines harboring the reciprocal transfer of a chromosome 11 QTL, a characteristic difference in the ratio of interneurons versus astrocytes expressing nAChR,4 in the CA1 region is reversed relative to the parental strain. These finding suggest that this chromosomal segment harbors genes that regulate strain distinct hippocampal morphology that is revealed by nAChR,4 expression. © 2008 Wiley-Liss, Inc. [source] Closely linked cis -acting modifier of expansion of the CGG repeat in high risk FMR1 haplotypes,HUMAN MUTATION, Issue 12 2007S. Ennis Abstract In its expanded form, the fragile X triplet repeat at Xq27.3 gives rise to the most common form of inherited mental retardation, fragile X syndrome. This high population frequency persists despite strong selective pressure against mutation-bearing chromosomes. Males carrying the full mutation rarely reproduce and females heterozygous for the premutation allele are at risk of premature ovarian failure. Our diagnostic facility and previous research have provided a large databank of X chromosomes that have been tested for the FRAXA allele. Using this resource, we have conducted a detailed genetic association study of the FRAXA region to determine any cis -acting factors that predispose to expansion of the CGG triplet repeat. We have genotyped SNP variants across a 650-kb tract centered on FRAXA in a sample of 877 expanded and normal X chromosomes. These chromosomes were selected to be representative of the haplotypic diversity encountered in our population. We found expansion status to be strongly associated with a ,50-kb region proximal to the fragile site. Subsequent detailed analyses of this region revealed no specific genetic determinants for the whole population. However, stratification of chromosomes by risk subgroups enabled us to identify a common SNP variant which cosegregates with the subset of D group haplotypes at highest risk of expansion (,=17.84, p=0.00002). We have verified that this SNP acts as a marker of repeat expansion in three independent samples. Hum Mutat 28(12), 1216,1224, 2007. © 2007 Wiley-Liss, Inc. [source] Personality dimensions measured using the Temperament and Character Inventory (TCI) and NEO-FFI on a Polish sampleINTERNATIONAL JOURNAL OF METHODS IN PSYCHIATRIC RESEARCH, Issue 4 2008ajczyk, bieta Miko Abstract The results of two self-administered, paper-and-pencil tests based on biosocial theory of personality have been compared simultanously: the Temperament and Character Inventory (TCI) and NEO Five Factor Inventory (NEO-FFI). The stability of the personality dimensions was assessed across age, sex and education level samples in a group of 406 Polish adults with major mental diseases excluded by use of PRIME-MD questionnaire. Significant effects of age, sex, and education have been found while comparing personality dimensions in both temperamental (novelty seeking, NS; harm avoidance, HA; reward dependence, RD; persistence, P) and character scales (cooperativeness, C; self-transcendence, ST) in TCI. Among subscales of temperament only NS1, RD4 were stable according to concerning factors. All converted to their age and sex norms NEO-FFI dimensions were stable according to sex. Extraversion scale was changeable depending on age (p = 0.04). Neuroticism dimension was a little higher in lower educated group (p = 0.035). To sum up, it was concluded that sex- and age-specific norms for the dimensions of the Polish version of TCI are necessary considering the established significant differences. Particular personality genetic studies should account for age, sex and also educational differences in their methods of associative studies. Conclusions: In the exploration of personality dimensions on healthy volunteers the Polish version of NEO-FFI corresponds better than TCI to theory of stability and genetic determinants of human personality. As the study included persons with excluded major mental diseases, the sample is appropriate to provide a control group in the reaserch of psychiatric patients using both TCI and NEO-FFI. Significant Outcomes: TCI scores for persons with excluded mental disease are highly changeable depending on age, sex and education. Adjusted to sex and age scores NEO-FFI corresponded better than TCI to stability and genetic determinants of human personality. Copyright © 2008 John Wiley & Sons, Ltd. [source] Identification of an operon and inducing peptide involved in the production of lactacin B by Lactobacillus acidophilusJOURNAL OF APPLIED MICROBIOLOGY, Issue 5 2007A.E. Dobson Abstract Aim: To determine if a 9·5-kb region on the Lactobacillus acidophilus NCFM genome, encoded the genetic determinants for regulation and production of lactacin B, a class II bacteriocin. Methods: Transcriptional analysis was used to identify a 9·5-kb polycistronic region suspected of encoding the lab operon. The 12 putative open reading frames (LBA1803,LBA1791) were organized into three clusters: a production and regulation cluster encoding a putative two-component signal transduction system; an export cluster encoding a putative ABC transporter and a final cluster composed of three unknown proteins. Seven genes were typical of bacteriocins, encoding small, cationic peptides, each with an N-terminal double-glycine leader motif. Inactivation of a predicted ABC transporter completely abolished bacteriocin activity. When cloned and expressed together, LBA1803,LBA1800 resulted in markedly higher levels of lactacin B activity. The four peptides were chemically synthesized but exhibited no bacteriocin activity, alone or in combination. Only LBA1800 induced lactacin B production in broth cultures. Conclusions: Lactacin B production is encoded within the 9·5-kb lab operon of 12 genes that are transcribed in a single transcript. LBA1800 is an inducing peptide of bacteriocin production. Significance and Impact of the Study: A three-component regulatory system common to class II bacteriocins regulates the production of this bacteriocin by Lact. acidophilus. [source] Large-Scale Genome-Wide Linkage Analysis for Loci Linked to BMD at Different Skeletal Sites in Extreme Selected Sibships,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2007Yi-Hsiang Hsu Abstract Few genome-wide linkage studies of osteoporosis have been conducted in the Asian population. We performed a genome-wide scan involving 3093 adult siblings with at least one sib-pair extremely concordant or discordant for hip BMD. Our results indicated four genome-wide significant QTLs for BMD. In comparison with 12 previous reported linkage studies, we reveal novel linkage regions that have reaching global significance. Introduction: The genetic basis for osteoporosis has been firmly established, but efforts to identify genes associated with this complex trait have been incomplete, especially in Asian populations. The purpose of this study was to identify quantitative trait loci (QTLs) for BMD in a Chinese population. Materials and Methods: We performed a genome-wide scan involving 3093 siblings 25,64 years of age from 941 families, with at least one sib-pair extreme concordant or discordant for total hip BMD from a large community-based cohort (n = 23,327) in Anhui, China. Linkage analysis was performed on BMD residuals adjusted for age, height, weight, occupation, cigarette smoking, physical activity, and alcohol consumption using the revised Haseman-Elston regression-based linkage model. Results: Our results revealed significant QTLs on chromosome 7p21.2 for femoral neck BMD (LOD = 3.68) and on chromosome 2q24.3 for total hip BMD (LOD = 3.65). Suggestive linkage regions were found to overlap among different skeletal sites on chromosomes 2q, 7p, and 16q. Sex-specific linkage analysis further revealed a significant QTL for lumbar spine BMD on chromosome 13q21.1 (LOD = 3.62) in women only. When performing multivariate linkage analysis by combining BMDs at four skeletal sites (i.e., whole body, total hip, femoral neck, and lumbar spine BMD), an additional significant QTL was found at chromosome 5q21.2 (LOD = 4.56). None of these significant QTLs found in our study overlapped with major QTLs reported by other studies. Conclusions: This study reveals four novel QTLs in a Chinese population and suggests that BMD at different skeletal sites may also share common genetic determinants. [source] Mapping Quantitative Trait Loci for Vertebral Trabecular Bone Volume Fraction and Microarchitecture in Mice,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2004Mary L Bouxsein Abstract BMD, which reflects both cortical and cancellous bone, has been shown to be highly heritable; however, little is known about the specific genetic factors regulating trabecular bone. Genome-wide linkage analysis of vertebral trabecular bone traits in 914 adult female mice from the F2 intercross of C57BL/6J and C3H/HeJ inbred strains revealed a pattern of genetic regulation derived from 13 autosomes, with 5,13 QTLs associated with each of the traits. Ultimately, identification of genes that regulate trabecular bone traits may yield important information regarding mechanisms that regulate mechanical integrity of the skeleton. Introduction: Both cortical and cancellous bone influence the mechanical integrity of the skeleton, with the relative contribution of each varying with skeletal site. Whereas areal BMD, which reflects both cortical and cancellous bone, has been shown to be highly heritable, little is known about the genetic determinants of trabecular bone density and architecture. Materials and Methods: To identify heritable determinants of vertebral trabecular bone traits, we evaluated the fifth lumbar vertebra from 914 adult female mice from the F2 intercross of C57BL/6J (B6) and C3H/HeJ (C3H) progenitor strains. High-resolution ,CT was used to assess total volume (TV), bone volume (BV), bone volume fraction (BV/TV), trabecular thickness (Tb.Th), separation (Tb.Sp), and number (Tb.N) of the trabecular bone in the vertebral body in the progenitors (n = 8/strain) and female B6C3H-F2 progeny (n = 914). Genomic DNA from F2 progeny was screened for 118 PCR-based markers discriminating B6 and C3H alleles on all 19 autosomes. Results and Conclusions: Despite having a slightly larger trabecular bone compartment, C3H progenitors had dramatically lower vertebral trabecular BV/TV (,53%) and Tb.N (,40%) and higher Tb.Sp (71%) compared with B6 progenitors (p < 0.001 for all). Genome-wide quantitative trait analysis revealed a pattern of genetic regulation derived from 13 autosomes, with 5,13 quantitative trait loci (QTLs) associated with each of the vertebral trabecular bone traits, exhibiting adjusted LOD scores ranging from 3.1 to 14.4. The variance explained in the F2 population by each of the individual QTL after adjusting for contributions from other QTLs ranged from 0.8% to 5.9%. Taken together, the QTLs explained 22,33% of the variance of the vertebral traits in the F2 population. In conclusion, we observed a complex pattern of genetic regulation for vertebral trabecular bone volume fraction and microarchitecture using the F2 intercross of the C57BL/6J and C3H/HeJ inbred mouse strains and identified a number of QTLs, some of which are distinct from those that were previously identified for total femoral and vertebral BMD. Identification of genes that regulate trabecular bone traits may ultimately yield important information regarding the mechanisms that regulate the acquisition and maintenance of mechanical integrity of the skeleton. [source] Association of Molecular Variants, Haplotypes, and Linkage Disequilibrium Within the Human Vitamin D-Binding Protein (DBP) Gene With Postmenopausal Bone Mineral Density,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2003Yoichi Ezura Abstract Possible contribution of vitamin D-binding protein (DBP) gene for determination of BMD was tested by characterizing 13 SNPs in 384 adult Japanese women. When the effect of a specific single SNP was tested, five SNPs (,39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, and IVS11+1097G>C) correlated with BMD significantly at various levels. The chromosomal dosage of one haplotype (T-C-C-G-T-C in ,39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, D432E, and IVS11+1097G>C) displayed significant correlation with adjusted radial BMD (r = 0.15, p = 0.008; n = 331). Multiple regression analyses revealed a most significant correlation with the combination of IVS1+827C>T and D432E (r2 = 0.029, p = 0.005). These results indicate a complex combined effect of several SNPs within the DBP gene that might underlie susceptibility to low radial BMD and osteoporosis. Introduction: Osteoporosis results from the interplay of multiple environmental and genetic determinants. The gene encoding vitamin D-binding protein (DBP), a key factor for regulating calcium homeostasis through the vitamin D endocrine system, is a probable candidate for conferring susceptibility to osteoporosis. Methods: To test a possible contribution of the DBP gene for determination of bone mineral density (BMD) of adult women, we have characterized 13 single nucleotide polymorphisms (SNPs) within the DBP gene in DNA from 384 adult Japanese women and attempted to correlate specific SNPs with BMD. Results and Conclusions: Sixteen major haplotypes accounted for 80% of the variations, indicating allelic complexity in this genomic region. Pairwise linkage disequilibrium (LD), measured by the D, and r2 statistics, demonstrated a general pattern of decline with increasing distance, but individual LD values within small genomic segments were diverse. Regression analysis for adjusted BMD revealed significant correlation with respect to five of them (,39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, and IVS11+1097G>C) at various levels. An intronic SNP (IVS11+1097G>C) with the highest significance of association (p = 0.006) showed significant LD with four SNPs located around the first exon (r2 values >0.18, D, > 0.5). A non-synonymous coding SNP, D432E, showed a comparable level of correlation, but it was in a moderate LD only with IVS11+1097G>C. The chromosomal dosage of one haplotype (T-C-C-G-T-C in ,39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, D432E and IVS11+1097G>C) estimated in each subject displayed significant correlation with adjusted radial BMD (r = 0.15, p = 0.008; n = 331). Furthermore, multiple regression analyses revealed that the most significant correlation was achieved for the combination of IVS1+827C>T and D432E (r2 = 0.029, p = 0.005). These results indicate a complex combined effect of several SNPs within the DBP gene that might underlie susceptibility to low radial BMD and osteoporosis. [source] Identification of genetic determinants of IGF-1 levels and longevity among mouse inbred strainsAGING CELL, Issue 5 2010Magalie S. Leduc Summary The IGF-1 signaling pathway plays an important role in regulating longevity. To identify the genetic loci and genes that regulate plasma IGF-1 levels, we intercrossed MRL/MpJ and SM/J, inbred mouse strains that differ in IGF-1 levels. Quantitative trait loci (QTL) analysis of IGF-1 levels of these F2 mice detected four QTL on chromosomes (Chrs) 9 (48 Mb), 10 (86 Mb), 15 (18 Mb), and 17 (85 Mb). Haplotype association mapping of IGF-1 levels in 28 domesticated inbred strains identified three suggestive loci in females on Chrs 2 (13 Mb), 10 (88 Mb), and 17 (28 Mb) and in four males on Chrs 1 (159 Mb), 3 (52 and 58 Mb), and 16 (74 Mb). Except for the QTL on Chr 9 and 16, all loci co-localized with IGF-1 QTL previously identified in other mouse crosses. The most significant locus was the QTL on Chr 10, which contains the Igf1 gene and which had a LOD score of 31.8. Haplotype analysis among 28 domesticated inbred strains revealed a major QTL on Chr 10 overlapping with the QTL identified in the F2 mice. This locus showed three major haplotypes; strains with haplotype 1 had significantly lower plasma IGF-1 and extended longevity (P < 0.05) than strains with haplotype 2 or 3. Bioinformatic analysis, combined with sequencing and expression studies, showed that Igf1 is the most likely QTL gene, but that other genes may also play a role in this strong QTL. [source] Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shorteningAGING CELL, Issue 1 2010Chen-Yu Liao Summary Chronic dietary restriction (DR) is considered among the most robust life-extending interventions, but several reports indicate that DR does not always extend and may even shorten lifespan in some genotypes. An unbiased genetic screen of the lifespan response to DR has been lacking. Here, we measured the effect of one commonly used level of DR (40% reduction in food intake) on mean lifespan of virgin males and females in 41 recombinant inbred strains of mice. Mean strain-specific lifespan varied two to threefold under ad libitum (AL) feeding and 6- to 10-fold under DR, in males and females respectively. Notably, DR shortened lifespan in more strains than those in which it lengthened life. Food intake and female fertility varied markedly among strains under AL feeding, but neither predicted DR survival: therefore, strains in which DR shortened lifespan did not have low food intake or poor reproductive potential. Finally, strain-specific lifespans under DR and AL feeding were not correlated, indicating that the genetic determinants of lifespan under these two conditions differ. These results demonstrate that the lifespan response to a single level of DR exhibits wide variation amenable to genetic analysis. They also show that DR can shorten lifespan in inbred mice. Although strains with shortened lifespan under 40% DR may not respond negatively under less stringent DR, the results raise the possibility that life extension by DR may not be universal. [source] Association of candidate susceptible loci with chronic infection with hepatitis B virus in a Chinese populationJOURNAL OF MEDICAL VIROLOGY, Issue 3 2010Ding-Qiang Chen Abstract A number of genetic loci have been proposed to be associated with persistent hepatitis B virus (HBV) infection. This study aimed to evaluate the association and interaction of susceptible genes with HBV persistence in a Chinese population. A total of 17 polymorphisms in 9 candidate genes were studied in 361 Chinese chronic hepatitis B patients and 304 patients who recovered spontaneously. Distributions of susceptible polymorphisms were examined in healthy Chinese and Caucasian populations. Gene,gene interactions were tested by the multifactor dimensionality reduction (MDR) method. The TNF ,308 G/G genotype and G allele, IL-10RB codon 47 A allele, and MCP-1 ,2518 G/G genotype and G allele were more frequent in patients than controls (P,<,0.01, after multiple corrections Pc,<,0.05), while the frequencies of TNF ,308 A/G genotype and IL-10 ,592 A/A genotype were significantly higher in controls than in the patient group (Pc,<,0.05). The frequencies of the risk allele MCP-1 ,2518 G and CTLA4 6230 G were much higher in Chinese than in the Caucasian groups (P,<,0.001). An interaction between CCR5 ,2459, TNFA ,863, IL-10RB codon 47, and MCP-1 ,2518 was detected by MDR (P,=,0.001). The results indicate that genetic determinants may affect the outcome of HBV infection in both independent and synergic manners. J. Med. Virol. 82:371,378, 2010. © 2010 Wiley-Liss, Inc. [source] Linkage analysis of factor VIII and von Willebrand factor loci as quantitative trait lociJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 8 2003M. C. H. De Visser Summary., Elevated factor (F)VIII levels contribute to venous thrombotic risk. FVIII levels are determined to a large extent by levels of von Willebrand factor (VWF), its carrier protein which protects FVIII against proteolysis. VWF levels are largely dependent on ABO blood group. Subjects with blood group non-O have higher VWF and FVIII levels than individuals with blood group O. Apart from ABO blood group no genetic determinants of high FVIII levels have been identified, whereas clustering of FVIII levels has been reported within families even after adjustment for ABO blood group and VWF levels. We investigated the FVIII and VWF loci as possible quantitative trait loci (QTL) influencing FVIII and VWF levels. Two sequence repeats in the FVIII gene and three repeats in the VWF gene were typed in 52 FV Leiden families. Multipoint sib-pair linkage analysis was performed with the MAPMAKER/SIBS program. FVIII levels adjusted for VWF levels and age, and VWF levels adjusted for ABO blood group and age, were used for this linkage analysis. No linkage of FVIII levels to the FVIII locus was found, whereas we found evidence that the VWF locus contains a QTL for VWF levels [maximum likelihood no dominance variance lod score = 0.70 (P = 0.04) and non-parametric Z-score = 1.92 (P = 0.03)]. About 20% of the total variation in VWF levels may be attributed to this VWF locus. [source] Interpreting Urine Drug Tests: Prevalence of Morphine Metabolism to Hydromorphone in Chronic Pain Patients Treated with MorphinePAIN MEDICINE, Issue 7 2008Ajay D. Wasan MD ABSTRACT Objective., Pain medicine practitioners frequently use urine drug testing (UDT) to monitor adherence to opioid therapy. It can be difficult to interpret a result as normal or abnormal in relation to which opioid compounds are expected to be found in the urine. We investigated whether hydromorphone may be a metabolite of morphine normally appearing in UDT of patients prescribed morphine. Design., This is a retrospective case-control study of urine toxicology results in pain patients taking only morphine. Inclusion criteria included urine results positive for morphine only (controls) or morphine and hydromorphone (cases). Demographic and medical history variables, and any history of aberrant drug behavior were recorded and related to the presence or absence of hydromorphone in the urine. Results., Hydromorphone was present in 21 of 32 cases (66%), none of whom had a history of aberrant drug behavior. Positive cases occurred more frequently in women, in those taking higher daily doses of morphine, and in those with higher urine morphine concentrations (P < 0.05). Only morphine urine concentration was a significant predictor of the hydromorphone metabolite in a logistic regression model (P < 0.05). Conclusions., Hydromorphone is likely a minor metabolite of morphine, normally appearing in the UDT of patients taking morphine. This finding assists in determining whether a UDT result is normal or abnormal, and subsequently whether a patient is compliant with opioid therapy. This observation should be confirmed by a prospective study in a controlled environment. Variables such as gender, morphine dose, morphine urine concentration, and genetic determinants of morphine metabolism should be investigated further. [source] | ||||||||||||||||||||||||||||