Association between the IVS4G>T mutation in the TCF7L2 gene and susceptibility to diabetes in cystic fibrosis patients.
Ontology highlight
ABSTRACT:
SUBMITTER: Furgeri DT
PROVIDER: S-EPMC3519805 | biostudies-literature | 2012
REPOSITORIES: biostudies-literature
Publications
Association between the IVS4G>T mutation in the TCF7L2 gene and susceptibility to diabetes in cystic fibrosis patients.
Furgeri Daniela Tenório DT Marson Fernando Augusto de Lima FA Ribeiro Antonio Fernando AF Bertuzzo Carmen Silvia CS
BMC research notes 20121010
<h4>Background</h4>Clinical complications appear to be a decisive factor for the prognosis of patients. Diabetes is an important complication of cystic fibrosis(CF). In our study we evaluated the association between the IVS4G>T mutation in the TCF7L2 gene with the presence of diabetes in patients with CF.<h4>Findings</h4>We evaluated 145 patients with CF in relation to the genotype of the IVS4G>T mutation. For this, the PCR method associated with specific enzyme digestion was used. The genotypes ...[more]
Similar Datasets
Project description:Insulin-requiring diabetes affects 25-50% of young adults with cystic fibrosis (CF). Although the cause of diabetes in CF is unknown, recent heritability studies in CF twins and siblings indicate that genetic modifiers play a substantial role. We sought to assess whether genes conferring risk for diabetes in the general population may play a risk modifying role in CF.We tested whether a family history of type 2 diabetes affected diabetes risk in CF patients in 539 families in the CF Twin and Sibling family-based study. A type 2 diabetes susceptibility gene (transcription factor 7-like 2, or TCF7L2) was evaluated for association with diabetes in CF using 998 patients from the family-based study and 802 unrelated CF patients in an independent case-control study.Family history of type 2 diabetes increased the risk of diabetes in CF (OR 3.1; p = 0.0009). A variant in TCF7L2 associated with type 2 diabetes (the T allele at rs7903146) was associated with diabetes in CF in the family study (p = 0.004) and in the case-control study (p = 0.02; combined p = 0.0002). In the family-based study, variation in TCF7L2 increased the risk of diabetes about three-fold (HR 1.75 per allele, 95% CI 1.3-2.4; p = 0.0006), and decreased the mean age at diabetes diagnosis by 7 years. In CF patients not treated with systemic glucocorticoids, the effect of TCF7L2 was even greater (HR 2.9 per allele, 95% CI 1.7-4.9, p = 0.00011).A genetic variant conferring risk for type 2 diabetes in the general population is a modifier of risk for diabetes in CF.
| S-EPMC2877501 | biostudies-literature
Project description:Background and objectivesCystic fibrosis patients suffer from chronic lung infections that require long-term antibiotic therapy. Pseudomonas readily evolve resistance, rendering antibiotics ineffective. In vitro experiments suggest that resistant bacteria may be treated by exploiting their collateral sensitivity to other antibiotics. Here, we investigate correlations of sensitivity and resistance profiles of Pseudomonas aeruginosa that naturally adapted to antibiotics in the cystic fibrosis lung.MethodologyResistance profiles for 13 antibiotics were obtained using broth dilution, E-test and VITEK mass spectroscopy. Genetic variants were determined from whole-genome sequences and interrelationships among isolates were analyzed using 13 MLST loci.ResultOur study focused on 45 isolates from 13 patients under documented treatment with antibiotics. Forty percent of these were clinically resistant and 15% multi-drug resistant. Colistin resistance was found once, despite continuous colistin treatment and even though colistin resistance can readily evolve experimentally in the laboratory. Patients typically harbored multiple genetically and phenotypically distinct clones. However, genetically similar clones often had dissimilar resistance profiles. Isolates showed mutations in genes encoding cell wall synthesis, alginate production, efflux pumps and antibiotic modifying enzymes. Cross-resistance was commonly observed within antibiotic classes and between aminoglycosides and ?-lactam antibiotics. No evidence was found for consistent phenotypic resistance to one antibiotic and sensitivity to another within one genotype.Conclusions and implicationsEvidence supporting potential collateral sensitivity in clinical P. aeruginosa isolates remains equivocal. However, cross-resistance within antibiotic classes is common. Colistin therapy is promising since resistance to it was rare despite its intensive use in the studied patients.
| S-EPMC4906436 | biostudies-literature
Project description:AIM:To investigate if mutations in TCF7L2 are associated with "atypical diabetes" in the Uruguayan population. METHODS:Healthy, nondiabetic controls (n = 133) and patients with type 2 diabetes (n = 177) were selected from among the presenting population at level-3 referral healthcare centers in Uruguay. Patients with type 2 diabetes were subgrouped according to "atypical diabetes" (n = 92) and "classical diabetes" (n = 85). Genotyping for the rs12255372 and rs7903146 single nucleotide polymorphisms (SNPs) in the TCFTL2 gene was carried out with TaqMan® probes. Random samples were sequenced by Macrogen Ltd. (South Korea). Statistical analysis of the SNP data was carried out with the SNPStats online tool (http://bioinfo.iconcologia.net/SNPstats). The best inheritance model was chosen according to the lowest values of Akaike's information criterion and Bayesian information criterion. Differences between groups were determined by unpaired t-tests after checking the normal distribution or were converted to normalize the data. The association of SNPs was tested for matched case-control samples by using ?2 analysis and calculation of odds ratios (ORs) with 95% confidence intervals (CIs). All statistical tests were performed using SPSS v10.0 and EpiInfo7 statistical packages. Significant statistical differences were assumed in all cases showing adjusted P < 0.05. RESULTS:We genotyped two TCF7L2 SNPs (rs7903146 and rs12255372) in a population-based sample of 310 Uruguayan subjects, including 133 healthy control subjects and 177 clinical diagnosed with type 2 diabetes. For both SNPs analyzed, the best model was the dominant type: rs12255372 = G/G vs G/T+T/T, OR = 0.63, 95%CI: 0.40-0.98, P < 0.05 and rs7903146 = C/C vs C/T+T/T, OR = 0.79, 95%CI: 0.41-1.55, P = 0.3. The rs12255372 SNP showed high association with the type 2 diabetes cases (OR = 1.60, 95%CI: 1.20-2.51, P < 0.05). However, when the type 2 diabetics group was analyzed according to the atypical and classical subgroupings, the association with diabetes existed only for rs12255372 and the classical subgroup (vs controls: OR = 2.1, 95%CI: 1.21-3.75, P < 0.05); no significant differences were found for either SNP or atypical diabetes. CONCLUSION:This is the first time SNPs_TCF7L2 were genotyped in a diabetic population stratified by genotype instead of phenotype. Classical and atypical patients showed statistical differences.
| S-EPMC6153121 | biostudies-literature
Project description:BACKGROUND: Transcription factor 7-like 2 (TCF7L2) has been shown to be associated with type 2 diabetes mellitus (T2MD) in multiple ethnic groups in the past two years, but, contradictory results were reported for Chinese and Pima Indian populations. The authors then performed a large meta-analysis of 36 studies examining the association of type 2 diabetes mellitus (T2DM) with polymorphisms in the TCF7L2 gene in various ethnicities, containing rs7903146 C-to-T (IVS3C>T), rs7901695 T-to-C (IVS3T>C), a rs12255372 G-to-T (IVS4G>T), and rs11196205 G-to-C (IVS4G>C) polymorphisms and to evaluate the size of gene effect and the possible genetic mode of action. METHODS: Literature-based searching was conducted to collect data and three methods, that is, fixed-effects, random-effects and Bayesian multivariate mete-analysis, were performed to pool the odds ratio (OR). Publication bias and study-between heterogeneity were also examined. RESULTS: The studies included 35,843 cases of T2DM and 39,123 controls, using mainly primary data. For T2DM and IVS3C>T polymorphism, the Bayesian OR for TT homozygotes and TC heterozygotes versus CC homozygote was 1.968 (95% credible interval (CrI): 1.790, 2.157), 1.406 (95% CrI: 1.341, 1.476), respectively, and the population attributable risk (PAR) for the TT/TC genotypes of this variant is 16.9% for overall. For T2DM and IVS4G>T polymorphism, TT homozygotes and TG heterozygotes versus GG homozygote was 1.885 (95%CrI: 1.698, 2.088), 1.360 (95% CrI: 1.291, 1.433), respectively. Four ORs among these two polymorphisms all yielded significant between-study heterogeneity (P < 0.05) and the main source of heterogeneity was ethnic differences. Data also showed significant associations between T2DM and the other two polymorphisms, but with low heterogeneity (P > 0.10). Pooled ORs fit a codominant, multiplicative genetic model for all the four polymorphisms of TCF7L2 gene, and this model was also confirmed in different ethnic populations when stratification of IVS3C>T and IVS4G>T polymorphisms except for Africans, where a dominant, additive genetic mode is suggested for IVS3C>T polymorphism. CONCLUSION: This meta-analysis demonstrates that four variants of TCF7L2 gene are all associated with T2DM, and indicates a multiplicative genetic model for all the four polymorphisms, as well as suggests the TCF7L2 gene involved in near 1/5 of all T2MD. Potential gene-gene and gene-environmental interactions by which common variants in the TCF7L2 gene influence the risk of T2MD need further exploration.
| S-EPMC2653476 | biostudies-literature
Project description:AIM:Our aim was to investigate the relationship between transcription factor 7-like 2 (TCF7L2) polymorphisms and breast cancer susceptibility. METHODS:PubMed, Embase and CNKI databases were used to search the related studies investigating the correlation between TCF7L2 polymorphisms and breast cancer susceptibility. Pooled ORs and 95% CIs, based on five genetic models, were applied to estimate the association betweenTCF7L2 polymorphisms and breast cancer. A fixed-effect model or a random-effect model was applied according to the between-study heterogeneity. RESULTS:We analyzed six single nucleotide polymorphisms (SNPs) in TCF7L2 gene, namely rs12255372, rs7903146, rs7900150, rs3750805, rs1225404 and rs7003146. The increased risk of breast cancer was associated with TCF7L2 polymorphisms (22 vs. 11: OR=1.16, 95% CI=1.02-1.32; 22+12 vs. 11: OR=1.06, 95% CI=1.02-1.10; 22 vs. 11+12: OR=1.15, 95% CI=1.04-1.27; 2 vs. 1: OR=1.07, 95% CI=1.02-1.13; 12 vs. 11: OR=1.05, 95% CI=1.01-1.09). Among the locus, rs7903146 polymorphism was significantly associated with the risk for breast cancer under five genetic models (TT vs. CC: OR=1.29, 95% CI=1.08-1.53; TT+CT vs. CC: OR=1.09, 95% CI=1.01-1.18; TT vs. CC+CT: OR=1.24, 95% CI=1.05-1.48; T vs. C: OR=1.11, 95% CI=1.04-1.19; CT vs. CC: OR=1.08, 95% CI=1.00-1.17). Additionally, rs7900150 also showed effects on the susceptibility of breast cancer (TT vs. AA: OR=1.22, 95% CI=1.07-1.39; TT+AT vs. AA: OR=1.06, 95% CI=1.00-1.14; TT vs. AA+AT: OR=1.21, 95% CI=1.07-1.37; T vs. A: OR=1.09, 95% CI=1.02-1.15; AT vs. AA: OR=1.04, 95% CI=1.01-1.33). Meanwhile, we found that rs3750805 polymorphism could increased the risk for breast cancer (TT+AT vs. AA: OR=1.12, 95% CI=1.01-1.24). CONCLUSION:Our meta-analysis demonstrates that TCF7L2 polymorphisms may increase the risk for breast cancer.
| S-EPMC4537972 | biostudies-literature
Project description:Many reports in different populations have demonstrated linkage of the 10q24-q26 region to schizophrenia, thus encouraging further analysis of this locus for detection of specific schizophrenia genes. Our group previously reported linkage of the 10q24-q26 region to schizophrenia in a unique, homogeneous sample of Arab-Israeli families with multiple schizophrenia-affected individuals, under a dominant model of inheritance. To further explore this candidate region and identify specific susceptibility variants within it, we performed re-analysis of the 10q24-26 genotype data, taken from our previous genome-wide association study (GWAS) (Alkelai et al, 2011). We analyzed 2089 SNPs in an extended sample of 57 Arab Israeli families (189 genotyped individuals), under the dominant model of inheritance, which best fits this locus according to previously performed MOD score analysis. We found significant association with schizophrenia of the TCF7L2 gene intronic SNP, rs12573128, (p?=?7.01×10??) and of the nearby intergenic SNP, rs1033772, (p?=?6.59×10??) which is positioned between TCF7L2 and HABP2. TCF7L2 is one of the best confirmed susceptibility genes for type 2 diabetes (T2D) among different ethnic groups, has a role in pancreatic beta cell function and may contribute to the comorbidity of schizophrenia and T2D. These preliminary results independently support previous findings regarding a possible role of TCF7L2 in susceptibility to schizophrenia, and strengthen the importance of integrating linkage analysis models of inheritance while performing association analyses in regions of interest. Further validation studies in additional populations are required.
| S-EPMC3256145 | biostudies-literature
Project description:AIMS/INTRODUCTION:Studies have been carried out to evaluate the correlation between TCF7L2 genetic polymorphisms and gestational diabetes mellitus (GDM) risk. However, the conclusions from these studies are incomplete, because partial single nucleotide polymorphisms (SNPs) were analyzed. We carried out a meta-analysis aimed to systematically evaluate TCF7L2 gene polymorphisms and GDM susceptibility in all population and racial/ethnic subgroups to afford a foundation for future research. MATERIALS AND METHODS:Published studies censoring TCF7L2 variants and GDM risk were captured from the EMBASE, PubMed, CNKI and Wanfang databases. The meta-analysis was processed using software of RevMan 5.2 and Stata13. The relationship between TCF7L2 polymorphism and GDM occurrence was evaluated by pooled odds ratios. Stratified analysis based on race/ethnicity was also carried out. The allele-specific odds ratios and 95% confidence intervals were counted, and based on homogeneity evaluated using the I2 -test, fixed- or random-effects pooled measures were selected. RESULTS:A total of 22 studies were covered, capturing eight TCF7L2 SNPs and involving 5,573 cases and 13,266 controls. Six of eight SNPs showed significant relationships with GDM occurrence, of which the SNPs rs7903146, rs12255372 and rs7901695 were the most powerful. Stratified analysis by race/ethnicity showed discrepant results in these three SNPs. In Caucasians and other races, all these SNPs were found to have a significant association with GDM risk, but in Asians, only SNP rs7903146 showed a significant association. CONCLUSIONS:Six of eight SNPs were found to have significant associations between TCF7L2 variants and GDM risk in the overall population, with the most powerful in SNPs being rs7903146, rs12255372 and rs7901695, but the contribution of these SNPs to GDM risk were variable among different racial/ethnic groups.
| S-EPMC5497039 | biostudies-literature
Project description:RationaleSputum biomarkers of infection and inflammation are noninvasive measures that enable quantification of the complex pathophysiology of cystic fibrosis (CF) lung disease. Validation of these biomarkers as correlates of disease severity is a key step for their application.ObjectivesWe constructed a large database from four multicenter studies to quantify the strength of association between expectorated sputum biomarkers and FEV(1.)MethodsFEV(1) (range, 25-120% predicted) and quantitative data on expectorated sputum biomarkers including free neutrophil elastase, IL-8, neutrophils, Pseudomonas aeruginosa, and Staphylococcus aureus were obtained from 269 participants (ages, 9-54 years) from 33 centers. Cross-sectional and longitudinal statistical analyses were performed to estimate associations between the markers and FEV(1), including the use of multivariable analyses.ResultsElastase was negatively correlated with FEV(1) (correlation [r] = -0.35; 95% confidence interval [CI]: -0.46, -0.22). On average, patients with CF who differed in their elastase measurements by 0.5 log differed in their FEV(1) values by -7.3% (95% CI: -9.7, -4.6). Neutrophil counts and IL-8 were also each negatively correlated. In a multivariable regression, elastase and neutrophil counts were able to explain the majority of variation in FEV(1). Elastase was further shown to have a significant longitudinal association with FEV(1), specifically a -2.9% decline in FEV(1) (95% CI: -5.0, -0.9) per 1-log increase in elastase. Although correlated with FEV(1), bacterial densities were unable to explain clinically meaningful differences in FEV(1) within and across patients.ConclusionsThese data support the role of sputum biomarkers as correlates of disease severity in a diverse CF population.
| S-EPMC2720115 | biostudies-literature
Project description:The cystic fibrosis transmembrane conductance regulator (CFTR) holds an important role in retaining lung function, but its association with lung cancer is unclear. A case-control study was conducted to determine the possible associations of the genetic variants in the CFTR gene with lung cancer risk. Genotypes of the most common deletion DeltaF508, one functional SNP, and eight tag SNPs in the CFTR gene were determined in 574 lung cancer patients and 679 controls. A logistic regression model, adjusting for known risk factors, was used to evaluate the association of each variant with lung cancer risk, as confirmation haplotype and sub-haplotype analyses were performed. DeltaF508 deletion and genotypes with minor alleles in one tag SNP, rs10487372, and one functional SNP, rs213950, were inversely associated with lung cancer risk. The results of haplotype and sub-haplotype analyses were consistent with single variant analysis, all pointing to deletion DeltaF508 being the key variant for significant haplotypes and sub-haplotypes. Individuals with 'deletion-T' (DeltaF508/rs10487372) haplotype had a 68% reduced risk for lung cancer compared to common haplotype 'no-deletion-C' (OR=0.32; 95% CI=0.15-0.68; p=0.01). Genetic variations in the CFTR gene might modulate the risk of lung cancer. This study, for the first time, provides evidence of a protective role of the CFTR deletion carrier in the etiology of lung cancer.
| S-EPMC2895007 | biostudies-literature
Project description:Pseudomonas aeruginosa is a major cause of morbidity and mortality in cystic fibrosis patients. This study compared the antimicrobial susceptibilities of 153 P. aeruginosa isolates from the United Kingdom (UK) (n = 58), Belgium (n = 44), and Germany (n = 51) collected from 118 patients during routine visits over the period from 2006 to 2012. MICs were measured by broth microdilution. Genes encoding extended-spectrum ?-lactamases (ESBL), metallo-?-lactamases, and carbapenemases were detected by PCR. Pulsed-field gel electrophoresis and multilocus sequence typing were performed on isolates resistant to ?3 antibiotic classes among the penicillins/cephalosporins, carbapenems, fluoroquinolones, aminoglycosides, and polymyxins. Based on EUCAST/CLSI breakpoints, susceptibility rates were ?30%/?40% (penicillins, ceftazidime, amikacin, and ciprofloxacin), 44 to 48%/48 to 63% (carbapenems), 72%/72% (tobramycin), and 92%/78% (colistin) independent of patient age. Sixty percent of strains were multidrug resistant (MDR; European Centre for Disease Prevention and Control criteria). Genes encoding the most prevalent ESBL (BEL, PER, GES, VEB, CTX-M, TEM, SHV, and OXA), metallo-?-lactamases (VIM, IMP, and NDM), or carbapenemases (OXA-48 and KPC) were not detected. The Liverpool epidemic strain (LES) was prevalent in UK isolates only (75% of MDR isolates). Four MDR sequence type 958 (ST958) isolates were found to be spread over the three countries. The other MDR clones were evidenced in ?3 isolates and localized in a single country. A new sequence type (ST2254) was discovered in one MDR isolate in Germany. Clonal and nonclonal isolates with different susceptibility profiles were found in 20 patients. Thus, resistance and MDR are highly prevalent in routine isolates from 3 countries, with meropenem, tobramycin, and colistin remaining the most active drugs.
| S-EPMC5075080 | biostudies-other