1,277 research outputs found
A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease
No full textThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Genetics in coeliac disease.
No full textCoeliac disease has a strong genetic component, higher than for many other common complex diseases. Possession of the HLA-DQ2 variant is required for presentation of disease causing dietary antigens to T cells, although this is also common in the healthy population. Non-HLA genetic factors account for the majority of heritable risk. Linkage studies have identified promising regions on chromosomes 5 and 19, with multiple other loci awaiting definitive confirmation in independent studies. Inherited variants in the tightly clustered chromosome 2q CD28-CTLA4-ICOS region are associated with disease, although of weak effect size. Larger sample sizes are necessary in coeliac disease genetic studies to detect small effects, alternatively meta-analysis offers promise. Newer methods including gene expression analysis and genome wide association studies will advance understanding of genetic susceptibility. Identification of coeliac disease genes may improve diagnostic/prognostic markers, basic understanding of disease aetiology, permit development of novel therapeutics and provide insight into other autoimmune disorders
Identification of TUB as a novel candidate gene influencing body weight in humans
No full textPreviously, 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
Shared genetics in coeliac disease and other immune-mediated diseases
No full textGutierrez-Achury J, Coutinho de Almeida R, Wijmenga C (University Medical Centre Groningen and University of Groningen, Groningen, the Netherlands; University of Brasilia School of Health Sciences, Brasilia, DF, Brazil). Shared genetics in coeliac disease and other immune-mediated diseases (Symposium). J Intern Med 2011; 269: 591-603. Identifying disease-associated variants can improve the predictive models of disease risk and provide mechanistic insights into disease development. Coeliac disease (CD) is the only autoimmune trait with a known environmental trigger, which makes it an excellent model for studying the complexity of genetic and environmental factors in the development of autoimmunity. In this review, we will focus on the genetic loci that have recently been associated with CD and that contain genes involved in innate and adaptive immunity. Some of these loci are shared with other immune-mediated diseases, suggesting an overlap of the genetic mechanisms involved in the development of such diseases. Some therapies, e.g. tumour necrosis factor inhibitors or a gluten-free diet, are already proving effective for more than one autoimmune disease. Follow-up of individuals with a high genetic risk of CD and other autoimmune diseases could help to elucidate the role of environmental factors (such as infectious agents or alterations in the microbiome) and prevent disease development
Differential association of two PTPN22 coding variants with Crohn's disease and ulcerative colitis.
No full textDiaz-Gallo, L.-M., Espino-Paisán, L., Fransen, K., Gõmez-García, M., Van Sommeren, S., Cardeña, C., Rodrigo, L., Mendoza, J.L., Taxonera, C., Nieto, A., Alcain, G., Cueto, I., Lõpez-Nevot, M.A., Bottini, N., Barclay, M.L., Crusius, J.B., Van Bodegraven, A.A., Wijmenga, C., Ponsioen, C.Y., Gearry, R.B., Roberts, R.L., Weersma, R.K., Urcelay, E., Merriman, T.R., Alizadeh, B.Z., Martin, J
Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease.
No full textNMR spectroscopic determination of the solution structure of a branched nucleic acid from residual dipolar couplings by using isotopically labeled nucleotides
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Meta-Analysis of Genome-Wide Linkage Studies in Celiac Disease.
No full textOBJECTIVE: A meta-analysis of genome-wide linkage studies allows us to summarize the extensive information available from family-based studies, as the field moves into genome-wide association studies.
METHODS: Here we apply the genome scan meta-analysis (GSMA) method, a rank-based, model-free approach, to combine results across eight independent genome-wide linkages performed on celiac disease (CD), including 554 families with over 1,500 affected individuals. We also investigate the agreement between signals we identified from this meta-analysis of linkage studies and those identified from genome-wide association analysis using a hypergeometric distribution.
RESULTS: Not surprisingly, the most significant result was obtained in the HLA region. Outside the HLA region, suggestive evidence for linkage was obtained at the telomeric region of chromosome 10 (10q26.12-qter; p = 0.00366), and on chromosome 8 (8q22.2-q24.21; p = 0.00491). Testing signals of association and linkage within bins showed no significant evidence for co-localization of results.
CONCLUSION: This meta-analysis allowed us to pool the results from available genome-wide linkage studies and to identify novel regions potentially harboring predisposing genetic variation contributing to CD. This study also shows that linkage and association studies may identify different types of disease-predisposing variants
Common variants of the TCF7L2 gene are associated with increased risk of type 2 diabetes mellitus in a UK-resident South Asian population
No full textBackground
Recent studies have implicated variants of the transcription factor 7-like 2 (TCF7L2) gene in genetic susceptibility to type 2 diabetes mellitus in several different populations. The aim of this study was to determine whether variants of this gene are also risk factors for type 2 diabetes development in a UK-resident South Asian cohort of Punjabi ancestry.
Methods
We genotyped four single nucleotide polymorphisms (SNPs) of TCF7L2 (rs7901695, rs7903146, rs11196205 and rs12255372) in 831 subjects with diabetes and 437 control subjects.
Results
The minor allele of each variant was significantly associated with type 2 diabetes; the greatest risk of developing the disease was conferred by rs7903146, with an allelic odds ratio (OR) of 1.31 (95% CI: 1.11 – 1.56, p = 1.96 × 10-3). For each variant, disease risk associated with homozygosity for the minor allele was greater than that for heterozygotes, with the exception of rs12255372. To determine the effect on the observed associations of including young control subjects in our data set, we reanalysed the data using subsets of the control group defined by different minimum age thresholds. Increasing the minimum age of our control subjects resulted in a corresponding increase in OR for all variants of the gene (p ≤ 1.04 × 10-7).
Conclusion
Our results support recent findings that TCF7L2 is an important genetic risk factor for the development of type 2 diabetes in multiple ethnic groups
The autoimmune puzzle - shared and specific genetics of immune-related diseases
No full textImmune-mediated disorders are common diseases affecting 5-10% of the population. They include two sets of diseases: the classical autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis and coeliac disease; and inflammatory diseases, such as inflammatory bowel disease, psoriasis, asthma and others. All these diseases have a complex genetic background, meaning that the combination of an unknown number of genes, each with a moderate or small individual effect, and one or more environmental factors are required for the disease to develop. The major genetic risk factor for all these diseases is the HLA locus on chromosome 6p21. The studies described in this thesis were aimed at unravelling the shared genetic aspects of autoimmunity and at characterising the shared and specific non-HLA risk factors in immune-related diseases that may explain the co-morbidity seen for these diseases. In part one of this thesis the overview of genetic studies in complex diseases is presented. In part two, the studies performed using the candidate gene- and candidate- pathway approaches are reported. The innate immune pathways screen led to the discovery of two variants associated to inflammatory bowel disease. Part three describes the genome-wide association strategy on the example of coeliac disease. Two steps of extended replication of the initial GWAS led to the discovery of 10 non-HLA genes in coeliac disease. Part four is focused on the shared and specific genetic aspects and the molecular pathways underlying immune-related diseases. We also zoom specifically to the shared genetics of coeliac disease and rheumatoid arthritis. In the discussion part, the studies described in the thesis are put in to prospective, and the past, present and future of genetic research in to complex immune-related diseases is discusse
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