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At least 1,171 records · Page 65Linked to original sources
PubMed2002

Contribution of known and unknown susceptibility genes to early-onset diabetes in scandinavia: evidence for heterogeneity.

In an attempt to identify novel susceptibility genes predisposing to early-onset diabetes (EOD), we performed a genome-wide scan using 433 markers in 222 individuals (119 with diabetes) from 29 Scandinavian families with > or =2 members with onset of diabetes < or =45 years. The highest nonparametric linkage (NPL) score, 2.7 (P < 0.01), was observed on chromosome 1p (D1S473/D1S438). Six other regions on chromosomes 3p, 7q, 11q, 18q, 20q, and 21q showed a nominal P value <0.05. Of the EOD subjects in these 29 families, 20% were GAD antibody positive and 68% displayed type 1 diabetes HLA risk alleles (DQB*02 or 0302). Mutations in maturity-onset diabetes of the young (MODY) 1-5 genes and the A3243G mitochondrial DNA mutation were detected by single-strand conformation polymorphism and direct sequencing. To increase homogeneity, we analyzed a subsample of five families with autosomal dominant inheritance of EOD (greater than or equal to two members with age at diagnosis < or =35 years). The highest NPL scores were found on chromosome 1p (D1S438-D1S1665; NPL 3.0; P < 0.01) and 16q (D16S419; NPL 2.9; P < 0.01). After exclusion of three families with MODY1, MODY3, and mitochondrial mutations, the highest NPL scores were observed on chromosomes 1p (D1S438; NPL 2.6; P < 0.01), 3p (D3S1620; NPL 2.2; P < 0.03), 5q (D5S1465; NPL 2.1; P < 0.03), 7q (D7S820; NPL 2.0; P < 0.03), 18q (D18S535; NPL 1.9; P < 0.04), 20q (D20S195; NPL 2.5; P < 0.02), and 21q (D21S1446; NPL 2.2; P < 0.03). We conclude that considerable heterogeneity exists in Scandinavian subjects with EOD; 24% had MODY or maternally inherited diabetes and deafness, and approximately 60% were GAD antibody positive or had type 1 diabetes-associated HLA genotypes. Our data also point at putative chromosomal regions, which could harbor novel genes that contribute to EOD.

Adult↗
PubMed2004

Microbulbifer maritimus sp. nov., isolated from an intertidal sediment from the Yellow Sea, Korea.

A Gram-negative, rod-shaped, non-spore-forming, slightly halophilic bacterium (strain TF-17T) was isolated from an intertidal sediment from the Yellow Sea, Korea. Pigment of strain TF-17T was similar to that of Microbulbifer elongatus, but different from those of Microbulbifer hydrolyticus and Microbulbifer salipaludis. Strain TF-17T was distinguishable from M. elongatus by some phenotypic properties, including motility, optimal growth temperature and others. Phylogenetic analysis based on 16S rDNA sequences showed that strain TF-17TT clustered with the type strains of the three Microbulbifer species with validly published names. Strain TF-17T exhibited 16S rDNA sequence similarity levels of 95.1-95.7% to the type strains of the three Microbulbifer species. The predominant respiratory lipoquinone found in strain TF-17T was ubiquinone-8. The major fatty acid was iso-C(15 : 0) and significant amounts of iso-C(11 : 0) 3-OH and iso-C(17 : 1)omega9c were also present. The DNA G+C content of strain TF-17T was 59.9 mol%. Levels of DNA-DNA relatedness between strain TF-17T and the type strains of the three Microbulbifer species were in the range 10.0-13.0%. On the basis of phenotypic and phylogenetic data and genotypic distinctiveness, strain TF-17T (=KCCM 41774T=JCM 12187T) is proposed as the type strain of a novel species of the genus Microbulbifer, Microbulbifer maritimus sp. nov.

Alteromonadaceae↗
PubMed2002

The genotype distribution of the XRCC1 gene indicates a role for base excision repair in the development of therapy-related acute myeloblastic leukemia.

Polymorphisms in several DNA repair genes have been described. These polymorphisms may affect DNA repair capacity and modulate cancer susceptibility by means of gene-environment interactions. We investigated DNA repair capacity and its association with acute myeloblastic leukemia (AML). We studied polymorphisms in 3 DNA repair genes: XRCC1, XRCC3, and XPD. We also assessed the incidence of a functional polymorphism in the NQO1 gene, which is involved in protection of cells from oxidative damage. We genotyped the polymorphisms by using polymerase chain reaction-restriction fragment-length polymorphism analysis in 134 patients with de novo AML, 34 with therapy-related AML (t-AML), and 178 controls. The distributions of the XRCC3 Thr241Met and NQO1 Pro187Ser genotypes were not significantly different in patients and controls. However, the distribution of the XRCC1 Arg399Gln genotypes was significantly different when comparing the t-AML and control groups (chi(2), P =.03). The presence of at least one XRCC1 399Gln allele indicated a protective effect for the allele in controls compared with patients with t-AML (odds ratio 0.44; 95% confidence interval, 0.20-0.93). We found no interactions between the XRCC1 or XRCC3 and NQO1 genotypes. We also found no differences in the distribution of the XPD Lys751Gln or XRCC1 Arg194Trp genotypes. Our data provide evidence of a protective effect against AML in individuals with at least one copy of the variant XRCC1 399Gln allele compared with those homozygous for the common allele.

Adolescent↗
PubMed2003

Functional polymorphisms in matrix metalloproteinase-1 and monocyte chemoattractant protein-1 and rheumatoid arthritis.

The aim of this study is to investigate whether the functional polymorphisms in the promoter of matrix metalloproteinase-1 (MMP-1) and in the regulatory region of the monocyte chemoattractant protein-1 (MCP-1) gene are associated with susceptibility to rheumatoid arthritis (RA) and its clinical features. The MMP-1 1G/2G polymorphism and the MCP-1 promoter A/G polymorphism were determined by polymerase chain reaction-restriction fragment length polymorphism in 117 RA patients and 97 healthy controls. The genotype distribution of the MMP-1 promoter did not differ between RA patients and control subjects. However, in the 2G/2G genotype, ESR and Plat were higher than the 1G/1G genotype. The genotype distribution of the MCP-1 promoter did not differ between the RA and control groups. Clinically there was no significant difference among RA patients according to the MCP-1 promoter genotypes. Our data show that the functional promoter polymorphism in the MMP-1 promoter may not play an important role in the susceptibility of RA, but the polymorphism may be related to clinical phenotypes.

Adolescent↗
PubMed2005

Association of CTLA4 polymorphism with regulatory T cell frequency.

A common single nucleotide polymorphism in CTLA4 has been linked with susceptibility and outcome in autoimmune and infectious diseases, respectively. Here, we show that this polymorphism is associated with the frequency of CD4(+)CD25(+) regulatory T cells in healthy human volunteers. We further show that, on a per cell basis, such regulatory T cells appear to be functionally indistinguishable across CTLA4 genotypes. These data implicate CTLA4 in regulatory T cell development, and provide a mechanism to account for the link between polymorphisms at this locus and the biological outcome of adaptive immune responses to self and to pathogens.

Antigens, CD↗
PubMed2007

Association of GABRG2 polymorphisms with idiopathic generalized epilepsy.

Missense mutations in the gamma2 subunit of gamma-aminobutyric acid (GABA) receptor gene have recently been described in families with idiopathic generalized epilepsies. This study aimed to evaluate whether polymorphisms of the gamma2 subunit of the GABA receptor gene are associated with idiopathic generalized epilepsies. A total of 77 children with idiopathic generalized epilepsies and 83 normal control subjects were included in the study. Polymerase chain reaction was used to identify the C/T and A/G polymorphisms of the gamma2 subunit of the GABA receptor gene on chromosome 5q33. Genotypes and allelic frequencies in both groups were compared. The gamma2 subunit of the GABA receptor (nucleotide position 3145 in intron G-> A) gene in both groups was not significantly different. In contrast, the gamma2 subunit of GABA receptor (SNP211037)-C allele frequency in patients with idiopathic generalized epilepsies was significantly higher than that in healthy control subjects (P = 0.002). The odds ratio for developing idiopathic generalized epilepsies in individuals with the gamma2 subunit of the GABA receptor (SNP211037)-C/C genotype was 3.61 compared with individuals with the gamma2 subunit of the GABA receptor (SNP211037)-T/T genotype. These data suggest that the gamma2 subunit of the GABA receptor gene might be one of the susceptibility factors for idiopathic generalized epilepsies.

Adolescent↗
PubMed1990

Ontogeny and expression of chicken A blood group antigens.

Expression of chicken red blood cell (RBC) surface antigens was studied by using a monoclonal antibody (ISU-cA) specific for chicken A blood group antigens. Erythrocytes were examined from embryos of 3-18 days of incubation and from chicks at hatch up to 21 weeks of age. Specific antigens were detected on embryonic RBC surfaces by immunofluorescence as early as 3 days of incubation. Antigenic expression was examined by both haemagglutination and immunofluorescence and found to increase with age from embryos to mature birds. The antigen concentration on the cell surface was found to be affected by genotype; heterozygotes had an intermediate level of antigen between that of the two parental genotypes. These data confirm the co-dominance that is observed with most blood group antigens. Flow cytometric analysis allowed confirmation that the entire erythrocyte population gradually increased in antigenic expression over time, rather than having an antigen-negative subpopulation being replaced by a positive subpopulation.

Animals↗
PubMed2001

Modelling the phenylalanine blood level response during treatment of phenylketonuria.

A vast body of phenylketonuria (PKU) patient monitoring data is deposited in clinical files and, after having served the actual needs, has remained there largely unused. We propose a kinetic model that will allow continued analysis of such data for further elucidation of the patient's metabolic phenotype and phenylalanine (Phe) disposal characteristics. Our PKU model of a single compartment with the input of alimentary Phe and two outputs--(1) first-order Phe conversion to tyrosine and acidic metabolites, and (2) zero-order Phe usage for net protein synthesis--has been developed with the graphics-oriented ModelMaker (then Cherwell Scientific Ltd, Oxford, UK) software package. The corresponding differential and integrated rate equations are presented to enable transfer of the model to equation-oriented simulation packages. The model offers a possible explanation for discrepancies in some genotype-phenotype data.

Child↗
PubMed2005

Association of G-protein beta-3 subunit gene (GNB3) T825 allele with Type II diabetes.

To date, the human G-protein beta 3 subunit (GNB3) gene and some of its variants represent some of the best examples of genetic influences that are involved in the determination of hypertension and obesity, which make it a sensible candidate gene for type 2 diabetes. To assess the influence of GNB3 in type II diabetes mellitus (NIDDM), we carried out a retrospective, case-control study of variant GNB3 825C>T for putative correlations with NIDDM amongst nationals from the United Arab Emirates (Emirati) - an ethnic group characterized by no alcohol intake and no cigarette smoking. We investigated a sample population of 510 Emirati (257 men, 253 women) comprising two groups - 254 controls and 256 patients with clinical diagnoses of type 2 diabetes (cases). The GNB3 C825T dimorphism showed an association with NIDDM Chi2 =22.5, 2 df, P<0.001). Further analysis revealed that the GNB3 T/T 825 genotype was positively associated with NIDDM (Yates corrected Chi2=20.6, 2 df, P<0.001; odds ratio of 2.44 with a 95% confidence interval of 1.64 - 3.63) compared to pooled CC/CT genotypes. Our data shows that GNB3 T825 allele may be involved in the pathogenesis of DM through a pathway that is different from the one implicated in obesity.

Adult↗
PubMed2003

Fas A670G polymorphism, apoptotic capacity in lymphocyte cultures, and risk of lung cancer.

Tobacco carcinogens can damage DNA, leading to apoptosis. There may be individual variation in apoptotic capacity (AC), and this variation may explain difference in AC associated with risk of lung cancer, if genome integrity is not restored by efficient DNA repair. To test the hypothesis that genetically determined AC is associated with risk of lung cancer, we conducted a pilot case-control study of 68 patients with newly diagnosed, untreated lung cancer and 74 cancer-free controls. We measured the AC of their cultured peripheral blood lymphocytes in response to in vitro exposure to an ultimate tobacco carcinogen, benzo[a]pyrene diol epoxide (BPDE), by using terminal dUTP nucleotide end labeling and flow cytometry. We also investigated the frequency of the -A670G polymorphism in Fas, a gene involved in controlling the apoptotic pathway, by using polymerase chain reaction-restriction fragment length polymorphism analysis. After exposing the cells to 4 microM BPDE for 5 h, we observed a significantly lower AC in lung cancer patients (155.2+/-143.9%) than in the controls (216.6+/-184.6%) (P<0.05). Low AC was an independent risk factor (adjusted odds ratio (OR)=2.69, 95% confidence interval (CI)=1.18-6.15) for lung cancer after adjustment for age, sex, ethnicity, smoking status and apoptotic baseline in a logistic regression model. Although the Fas -A670G polymorphism was not an independent risk factor for lung cancer, it appeared to modulate the risk. The adjusted ORs for lung cancer risk associated with lower AC were 4.00 (95% CI=1.48-10.80) among those with the Fas -670 AG and GG genotypes and 0.97 (95% CI=0.18-5.30) among those with the Fas -670AA genotype. These data suggest that alteration in the apoptotic pathway may be a risk factor for lung cancer and this risk may be modulated by the Fas -A670G polymorphism. Larger prospective studies are needed to verify these findings.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1995

Chemotaxonomic analyses of Bacteroides gracilis and Bacteroides ureolyticus and reclassification of B. gracilis as Campylobacter gracilis comb. nov.

The cellular fatty acids, respiratory quinones, and proteins of the generically misnamed taxa Bacteroides gracilis and Bacteroides ureolyticus were analyzed and compared with the corresponding chemotaxonomic features of their closest relatives, the campylobacters. Our results and previously published data for genotypic and phenotypic characteristics were used in a polyphasic approach to reconsider the classification of these organisms. We transfer B. gracilis to the genus Campylobacter as Campylobacter gracilis comb. nov. B. ureolyticus can be considered a campylobacter on genotypic grounds; in contrast, the proteolytic metabolism and fatty acid components of this taxon exclude it from the genus Campylobacter. We prefer to consider this taxon a species incertae sedis pending the isolation and characterization of additional B. ureolyticus-like bacteria.

Bacterial Proteins↗
PubMed1998

Association of cytochrome P450 1B1 (CYP1B1) polymorphism with steroid receptor status in breast cancer.

A key enzyme involved in the production of potentially carcinogenic estrogen metabolites and the activation of environmental carcinogens is cytochrome P450 1B1 (CYP1B1), the predominant member of the CYP1 family expressed in normal breast tissue and breast cancer. Because of the preeminent role of CYP1B1 in mammary estrogen/carcinogen metabolism, we examined the CYP1B1 gene to determine whether genetic differences could account for interindividual differences in breast cancer risk. We focused on exon 3, because it encodes the catalytically important heme binding domain of the enzyme, and discovered three polymorphisms of which two are associated with amino acid substitutions in codons 432 (Val-->Leu) and 453 (Asn-->Ser), designated as m1 and m2, respectively. Approximately 40% of Caucasian women have the m1 Val allele compared with nearly 70% of African-American women (P < 0.0001). The allele frequency also differs significantly in m2, with the rare Ser allele being present in 17.4% of Caucasians but only in 3.4% of African Americans (P < 0.0003). To determine whether the polymorphic CYP1B1 alleles hold implications as potential breast cancer risk factors, we compared the CYP1B1 genotypes in 164 Caucasian and 59 African-American breast cancer cases with those in age-, race-, and frequency-matched controls. Odds ratio calculations failed to show a significant association between any of the genotypes and breast cancer. Because CYP1B1 is known to be involved in mammary estrogen metabolism, we investigated whether the estrogen receptor status is influenced by the CYP1B1 genotypes. Caucasian patients with the m1 Val/Val genotype have a significantly higher percentage of estrogen receptor-positive (P = 0.02) and progesterone receptor-positive breast cancers (P = 0.003). There was no correlation with the m2 genotypes. These data suggest that the CYP1B1 polymorphisms in exon 3 are not associated with increased breast cancer risk but that the m1 polymorphism may be functionally important for steroid receptor expression in breast cancer of Caucasian patients.

Aryl Hydrocarbon Hydroxylases↗
PubMed2005

Beta 2 adrenergic receptor polymorphisms in cystic fibrosis.

There has been a recent emphasis on identifying modifier genes that influence the severity of cystic fibrosis (CF) lung disease. The beta-2-adrenergic receptor is expressed on airway smooth muscle, is the target for inhaled beta agonists, and has several common polymorphisms in its gene, ADRB2. Polymorphisms changing glycine to arginine or glutamate to glutamine in codons 16 and 27, respectively, were associated with differences in clinical response to inhaled beta agonists in individuals with asthma. We compared acute airway responsiveness and 5-year decline in pulmonary function in CF patients with different ADRB2 genotypes. One hundred and six subjects performed spirometry before and after the administration of an inhaled bronchodilator, and had ADRB2 genotype determined for codons 16 and 27. Comparing the percent change in FEV(1) and FEF(25-75) continuously revealed differences in the degree of airway responsiveness to bronchodilator between ADRB2-genotyped groups. However, there was no significant relationship between the ADRB2 genotype at positions 16 and 27 and bronchodilator response when defined as 12% improvement in FEV(1). Five-year decline in percent predicted FEV(1) showed no association with ADRB2 genotype. These data are consistent with variants of the ADRB2 gene having different responses to bronchodilator, but the long-term effects, if any, are not apparent over a 5-year period.

Administration, Inhalation↗
PubMed2006

FokI polymorphism of the vitamin D receptor gene correlates with parameters of bone mass and turnover in a female population of the Italian island of Lampedusa.

One of the most promising genetic approaches to dissecting a multifactorial disease is represented by genetically isolated population studies. We studied a genetic marker in a cohort of women living on the Mediterranean island of Lampedusa, a geographically isolated population. Lampedusa, located between the African coast and Sicily, consists of a young genetic isolate (<20 generations) with an exponential growth in the last generations. We analyzed the association between the FokI vitamin D receptor (VDR) gene polymorphism, previously proposed as a predictor of bone mass, with parameters of bone mass and turnover in a cohort of pre- and postmenopausal women living on Lampedusa. In 424 women (277 postmenopausal and 147 premenopausal), allelic frequencies were 49% for the F allele and 51% for the f allele. Using analysis of covariance, we found that subjects with ff genotype exhibited a significantly (P < 0.001) lower lumbar spine bone mass, by dual-energy X-ray absorptiometry, and lower values of bone ultrasonographic parameters (speed of sound and broadband ultrasound attenuation) relative to those with Ff and FF genotypes. Conversely, osteocalcin and serum cross-laps were significantly higher in ff and Ff compared to FF genotype. Our data suggest that FokI VDR polymorphism may contribute to the determination of bone mass and turnover in both pre- and postmenopausal women in this geographically isolated population.

Bone Density↗
PubMed2003

Neuropsychological deficits associated with Alzheimer's disease in the very-old: discrepancies in raw vs. standardized scores.

The profiles of neuropsychological deficits associated with Alzheimer's disease (AD) in Young-Old (M age and 70) and Very-Old (M age > 80) patients were compared, along with possible modifying effects of apolipoprotein E (APOE) genotype on these profiles. A comprehensive battery of neuropsychological tests was administered to the two AD patient groups (Young-Old: n = 33; Very-Old: n = 48) and their respective age-matched normal control (NC) groups who remained free of dementia on follow-up examinations over a 1 to 10 year period (Young-Old: n = 43; Very-Old: n = 36). AD and NC groups did not differ in education levels or gender distributions. Young-Old AD and Very-Old AD groups were comparable in education, gender, dementia severity, and disease duration. Results showed that both AD groups achieved comparable raw scores on all the neuropsychological measures. However, when scores were standardized on the basis of performance of their respective NC groups (i.e., age-corrected z scores), Very-Old AD patients significantly outperformed Young-Old AD patients on tests of executive functions, visuospatial skills, and delayed memory. Furthermore, the relationship between age and memory and executive function deficits in AD was modified by APOE genotype. These data suggest that the profile of neuropsychological deficits associated with AD in the Very-Old lacks the disproportionate saliency of episodic memory and executive function deficits typical of the Young-Old.

Aged↗
PubMed2004

Hepatitis B virus genotype A and D and clinical outcomes of liver transplantation for HBV-related disease.

Hepatitis B virus (HBV) genotypes have been associated with specific patterns of disease and response to antiviral therapy. We investigated the effect of HBV genotype on HBV recurrence and mortality after liver transplantation (LT). Pretransplant sera of 45 hepatitis B surface antigen (HBsAg) positive adults were submitted for HBV genotyping by a reverse-phase hybridization line probe assay with genotype-specific probes. Data were correlated with clinical outcomes after transplantation. Genotype A (n =15), D (n = 13) and A/D (n = 12) accounted for 89% of all genotypes. Coinfection with two HBV genotypes was encountered in 14 (31.1%) patients. Eighteen patients (40 %) developed HBV recurrence at a median of 10 months posttransplant (range, 1-53) and 10 patients (22 %) died at a median of 24 months (range, 3-63). Genotype D patients were more likely to develop HBV recurrence or die compared with genotype A patients, although this did not reach statistical significance. Dual infection with genotype A/D resulted in mortality similar to that of genotype A but recurrence similar to that of genotype D. Active viral replication at time of transplantation was the only independent factor (P = 0.03) that predicted HBV recurrence. In conclusion, HBV genotype A and D did not have a significant impact on clinical outcomes of LT for HBV-related liver disease in patients of European origin. These data do not support routine HBV genotyping in liver transplantation.

Adolescent↗
PubMed2006

Mutations in mutT genes of Mycobacterium tuberculosis isolates of Beijing genotype.

Missense alterations in genes mutT4 and mutT2, which encode DNA repair enzymes, were sequenced from 30 clinical isolates of Mycobacterium tuberculosis of Beijing genotype, mostly from patients with primary tuberculosis, to evaluate their contribution to anti-mycobacterial drug resistance. The mutation Arg to Gly at codon position 48 (CGG to GGG) of mutT4 was found in 21 isolates; of these, 16 isolates also harboured the mutation Gly to Arg at position 58 (GGA to CGA) of mutT2. No statistically significant association was found between mutT4 and mutT2 mutations, and drug resistance. Furthermore, no mutations in mutT4 or mutT2 were found in any of 24 isolates resistant to multiple drugs, nor in 28 anti-mycobacterial drug-susceptible isolates of different genotypes. These data confirm that the polymorphism of mutT genes is characteristic and unique to the Beijing phylogenetic lineage. The mutator phenotype does not appear to increase prevalence of drug resistance, but further studies are required to investigate the mutation rates of Beijing isolates in response to drug exposure.

Amino Acid Substitution↗
PubMed1999

Prognostic significance of cyclin D1 gene (CCND1) polymorphism in epithelial ovarian cancer.

We have investigated the influence of CCND1 genotype on clinical outcome in 138 women with epithelial ovarian cancer. CCND1 genotypes were identified from peripheral blood DNA by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. Patient CCND1 genotypes were compared with clinical details including FIGO tumor stage, residual tumor volume, tumor histology and differentiation, response to chemotherapy, progression free interval, and survival. We observed no association between patient CCND1 genotypes and tumor characteristics or response to chemotherapy. There was no significant difference in overall survival and progression free interval (PFI) among women with different CCND1 genotypes. However, analysis of data from patients who responded to postoperative chemotherapy revealed that women with CCND1 AA genotype were associated with early disease progression (P = 0.020, HR 4.58, 95% CI 1.27-16.48) and reduced survival (P = 0.026, HR 4.48, 95% CI 1.19-16.79) compared with those with CCND1 AG and GG genotypes. These data show that CCND1 genotype does not influence overall prognosis in a cohort of epithelial ovarian cancer patients, however, it is associated with disease progression in a subgroup of patients following initial response to chemotherapy.

Journal Article↗