Identification of TUB as a novel candidate gene influencing body weight in humans

Previously, we identified a locus on 11p influencing obesity in families with type 2 diabetes. Based on mouse studies, we selected TUB as a functional candidate gene and performed association studies to determine whether this controls obesity. We analyzed the genotypes of 13 single nucleotide polymorphisms (SNPs) around TUB in 492 unrelated type 2 diabetic patients with known BMI values. One SNP (rs1528133) was found to have a significant effect on BMI (1.54 kg/m(2), P = 0.006). This association was confirmed in a population enriched for type 2 diabetes, using 750 individuals who were not selected for type 2 diabetes. Two SNPs in linkage disequilibrium with rs1528133 and mapping to the 3' end of TUB, rs2272382, and rs2272383 also affected BMI by 1.3 kg/m2 (P = 0.016 and P = 0.010, respectively). Combined analysis confirmed this association (P = 0.005 and P = 0.002, respectively). Moreover, comparing 349 obese subjects (BMI >30 kg/m(2)) from the combined cohort with 289 normal subjects (BMI <25 kg/m(2)) revealed that the protective alleles have a lower frequency in obese subjects (odds ratio 1.32 [95% CI 1.04-1.67], P = 0.022). Altogether, data from the tubby mouse as well as these data suggest that TUB could be an important factor in controlling the central regulation of body weight in humans

Genetic variants associated with protein C levels

Clinical epidemiolog

Association between age, IL-10, IFNγ, stimulated C-peptide and disease progression in children with newly diagnosed Type 1 diabetes

AIMS: The relation of disease progression and age, serum interleukin 10 (IL-10) and interferon gamma (IFNγ) and their genetic correlates were studied in paediatric patients with newly diagnosed Type 1 diabetes. METHODS: Two hundred and twenty-seven patients from the Hvidoere Study Group were classified in four different progression groups as assessed by change in stimulated C-peptide from 1 to 6 months. CA repeat variants of the IL-10 and IFNγ gene were genotyped and serum levels of IL-10 and IFNγ were measured at 1, 6 and 12 months. RESULTS: IL-10 decreased (P < 0.001) by 7.7% (1 month), 10.4% (6 months) and 8.6% (12 months) per year increase in age of child, while a twofold higher C-peptide concentration at 1 month (p = 0.06), 6 months (P = 0.0003) and 12 months (P = 0.02) was associated with 9.7%, 18.6% and 9.7% lower IL-10 levels, independent of each other. IL-10 concentrations did not associate with the disease progression groups. By contrast, IFNγ concentrations differed between the four progression groups at 6 and 12 months (P = 0.02 and P = 0.01, respectively); patients with rapid progressing disease had the highest levels at both time points. Distribution of IL-10 and IFNγ genotypes was equal among patients from the progression groups. CONCLUSION: IL-10 serum levels associate inversely with age and C-peptide. As age and C-peptide also associate, a triangular association is proposed. Genetic influence on IL-10 production seems to be masked by distinct disease mechanisms. Increased serum IFNγ concentrations associate with rapid disease progression. Functional genetic variants do not associate with a single progression pattern group, implying that disease processes override genetically predisposed cytokine production

Association analysis of functional variants of the FcgRIIa and FcgRIIIa genes with type 1 diabetes, celiac disease and rheumatoid arthritis.

Contains fulltext : 52450.pdf (publisher's version ) (Closed access)FcgRIIa and FcgRIIIa are potent modulators of the immune system which bind (auto)antibodies and activate immune cells. The FcgRIIa*A519G and FcgRIIIa*A559C functional variants have been associated with several immune-related diseases. We studied FcgRIIa*A519G and FcgRIIIa*A559C SNPs in type 1 diabetes (T1D), celiac disease (CD) and rheumatoid arthritis (RA) patients and controls and included a meta-analysis of all recent studies of FcgRIIIa*A559C and RA. Our cohorts comprised 350 T1D, 519 CD, 639 RA patients and 1359 controls, who were genotyped for FcgRIIa*A519G and FcgRIIIa*A559C variants. Regression and expectation maximization (EM) algorithm-based haplotype analyses were used for the data analysis. We found significant differences in genotype frequencies of FcgRIIa between controls and patients with T1D (P = 0.04), CD (P = 0.000005) and RA (P = 0.04). The FcgRIIa*519GG genotype showed an increased risk for both T1D [odds ratio (OR) = 1.51; 95% confidence interval (95% CI) 1.08-2.12; P = 0.015] and CD (OR = 1.81; 95% CI 1.35-2.37; P = 0.000004), but not for RA. There was no difference in the frequency of FcgRIIIa*A559C genotypes or allelotypes between controls with T1D, CD and RA. We found that FcgRIIa and FcgRIIIa haplotype frequencies differed significantly between controls and patients with T1D (P = 0.05) and with CD (P = 0.00038) but not with RA. Our meta-analysis showed a significant 1.37(95% CI 1.14-1.66)-fold increased risk of RA for the FcgRIIIa*559CC (158VV) genotype (P = 0.001). This is the first report that the FcgRIIa*519GG genotype predisposes to T1D and CD. We confirmed that the FcgRIIIa*559CC genotype is associated with RA. If replicated, our findings would suggest FcgRIIa*519G as a common risk factor for auto-immune diseases. This may have clinical implications with regard to efficacy or safety of antibody-based immuno-modulator therapies

Evidence of association of macrophage migration inhibitory factor gene polymorphisms with systemic lupus erythematosus

The aim of this study was to evaluate the potential association of functional polymorphisms of macrophage migration inhibitory factor with systemic lupus erythematosus. Our study includes 711 systemic lupus erythematosus (SLE) patients and 755 healthy controls. We genotyped the migration inhibitory factor (MIF) -173G/C using a polymerase chain reaction (PCR) system with predeveloped TaqMan allelic discrimination assay and the MIF -794 CATTn microsatellite polymorphism using a PCR-fluorescent method. A statistically significant difference in the distribution of the MIF -173*C allele between SLE patients and controls (P=0.004, OR=1.34, 95% CI=1.05-1.27) was observed. In addition, the frequency of the MIF -173* C/C genotype was higher in SLE patient (P=0.002, OR 2.58, 95% CI 1.32-5.10). No differences in the distribution of CATTn were found. However, the haplotypes analyses showed that only the CATT7-MIF -173* C haplotype was associated with a higher susceptibility to SLE (P=0.001, OR 1.84, 95% CI 1.35-2.79). No association with clinical features was detected in any case. These results suggest that both, MIF -173*C allele and CATT7-MIF -173*C haplotype, confer susceptibility to SLE in our population. © 2006 Nature Publishing Group. All rights reserved

Evidence of association of macrophage migration inhibitory factor gene polymorphisms with systemic lupus erythematosus

The aim of this study was to evaluate the potential association of functional polymorphisms of macrophage migration inhibitory factor with systemic lupus erythematosus. Our study includes 711 systemic lupus erythematosus (SLE) patients and 755 healthy controls. We genotyped the migration inhibitory factor (MIF) -173G/C using a polymerase chain reaction (PCR) system with predeveloped TaqMan allelic discrimination assay and the MIF -794 CATTn microsatellite polymorphism using a PCR-fluorescent method. A statistically significant difference in the distribution of the MIF -173*C allele between SLE patients and controls (P=0.004, OR=1.34, 95% CI=1.05-1.27) was observed. In addition, the frequency of the MIF -173* C/C genotype was higher in SLE patient (P=0.002, OR 2.58, 95% CI 1.32-5.10). No differences in the distribution of CATTn were found. However, the haplotypes analyses showed that only the CATT7-MIF -173* C haplotype was associated with a higher susceptibility to SLE (P=0.001, OR 1.84, 95% CI 1.35-2.79). No association with clinical features was detected in any case. These results suggest that both, MIF -173*C allele and CATT7-MIF -173*C haplotype, confer susceptibility to SLE in our population. © 2006 Nature Publishing Group. All rights reserved

Analysis of the association between CD40 and CD40 ligand polymorphisms and systemic sclerosis

Contains fulltext : 109347.pdf (publisher's version ) (Open Access)INTRODUCTION: The aim of the present study was to investigate the possible role of CD40 and CD40 ligand (CD40LG) genes in the susceptibility and phenotype expression of systemic sclerosis (SSc). METHODS: In total, 2,670 SSc patients and 3,245 healthy individuals from four European populations (Spain, Germany, The Netherlands, and Italy) were included in the study. Five single-nucleotide polymorphisms (SNPs) of CD40 (rs1883832, rs4810485, rs1535045) and CD40LG (rs3092952, rs3092920) were genotyped by using a predesigned TaqMan allele-discrimination assay technology. Meta-analysis was assessed to determine whether an association exists between the genetic variants and SSc or its main clinical subtypes. RESULTS: No evidence of association between CD40 and CD40LG genes variants and susceptibility to SSc was observed. Similarly, no significant statistical differences were observed when SSc patients were stratified by the clinical subtypes, the serologic features, and pulmonary fibrosis. CONCLUSIONS: Our results do not suggest an important role of CD40 and CD40LG gene polymorphisms in the susceptibility to or clinical expression of SSc

A multicenter study confirms CD226 gene association with systemic sclerosis-related pulmonary fibrosis

Contains fulltext : 110852.pdf (publisher's version ) (Open Access)INTRODUCTION: CD226 genetic variants have been associated with a number of autoimmune diseases and recently with systemic sclerosis (SSc). The aim of this study was to test the influence of CD226 loci in SSc susceptibility, clinical phenotypes and autoantibody status in a large multicenter European population. METHODS: A total of seven European populations of Caucasian ancestry were included, comprising 2,131 patients with SSc and 3,966 healthy controls. Three CD226 single nucleotide polymorphisms (SNPs), rs763361, rs3479968 and rs727088, were genotyped using Taqman 5'allelic discrimination assays. RESULTS: Pooled analyses showed no evidence of association of the three SNPs, neither with the global disease nor with the analyzed subphenotypes. However, haplotype block analysis revealed a significant association for the TCG haplotype (SNP order: rs763361, rs34794968, rs727088) with lung fibrosis positive patients (PBonf = 3.18E-02 OR 1.27 (1.05 to 1.54)). CONCLUSION: Our data suggest that the tested genetic variants do not individually influence SSc susceptibility but a CD226 three-variant haplotype is related with genetic predisposition to SSc-related pulmonary fibrosis