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Antibodies against insulin measured by electrochemiluminescence predicts insulitis severity and disease onset in non-obese diabetic mice and can distinguish human type 1 diabetes status

Mon, 28 Nov 2011 00:00:00 GMT

Title: Antibodies against insulin measured by electrochemiluminescence predicts insulitis severity and disease onset in non-obese diabetic mice and can distinguish human type 1 diabetes status Authors: Lo, Bernice; Swafford, Austin D-E; Shafer-Weaver, Kimberly A; Jerome, Lawrence F; Rakhlin, Luba; Mathern, Douglas R; Callahan, Conor A; Jiang, Ping; Davison, Lucy J; Stevens, Helen E; Lucas, Carrie L; White, Jill; von Borstel, Reid; Todd, John A; Lenardo, Michael J Abstract: Abstract Background The detection of insulin autoantibodies (IAA) aids in the prediction of autoimmune diabetes development. However, the long-standing, gold standard 125I-insulin radiobinding assay (RBA) has low reproducibility between laboratories, long sample processing times and requires the use of newly synthesized radiolabeled insulin for each set of assays. Therefore, a rapid, non-radioactive, and reproducible assay is highly desirable. Methods We have developed electrochemiluminescence (ECL)-based assays that fulfill these criteria in the measurement of IAA and anti-insulin antibodies (IA) in non-obese diabetic (NOD) mice and in type 1 diabetic individuals, respectively. Using the murine IAA ECL assay, we examined the correlation between IAA, histopathological insulitis, and blood glucose in a cohort of female NOD mice from 4 up to 36 weeks of age. We developed a human IA ECL assay that we compared to conventional RBA and validated using samples from 34 diabetic and 59 non-diabetic individuals in three independent laboratories. Results Our ECL assays were rapid and sensitive with a broad dynamic range and low background. In the NOD mouse model, IAA levels measured by ECL were positively correlated with insulitis severity, and the values measured at 8-10 weeks of age were predictive of diabetes onset. Using human serum and plasma samples, our IA ECL assay yielded reproducible and accurate results with an average sensitivity of 84% at 95% specificity with no statistically significant difference between laboratories. Conclusions These novel, non-radioactive ECL-based assays should facilitate reliable and fast detection of antibodies to insulin and its precursors sera and plasma in a standardized manner between laboratories in both research and clinical settings. Our next step is to evaluate the human IA assay in the detection of IAA in prediabetic subjects or those at risk of type 1 diabetes and to develop similar assays for other autoantibodies that together are predictive for the diagnosis of this common disorder, in order to improve prediction and facilitate future therapeutic trials. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Genetic Analysis Workshop 14: microsatellite and single-nucleotide polymorphism marker loci for genome-wide scans

Fri, 30 Dec 2005 00:00:00 GMT

Title: Genetic Analysis Workshop 14: microsatellite and single-nucleotide polymorphism marker loci for genome-wide scans Abstract: Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Polymorphism discovery and association analyses of the interferon genes in type 1 diabetes

Wed, 22 Feb 2006 00:00:00 GMT

Title: Polymorphism discovery and association analyses of the interferon genes in type 1 diabetes Authors: Morris, Gerard A J; Lowe, Christopher E; Cooper, Jason D; Payne, Felicity; Vella, Adrian; Godfrey, Lisa M; Hulme, John S; Walker, Neil M; Healy, Barry C; Lam, Alex C; Lyons, Paul A; Todd, John A Abstract: Abstract Background The aetiology of the autoimmune disease type 1 diabetes (T1D) involves many genetic and environmental factors. Evidence suggests that innate immune responses, including the action of interferons, may also play a role in the initiation and/or pathogenic process of autoimmunity. In the present report, we have adopted a linkage disequilibrium (LD) mapping approach to test for an association between T1D and three regions encompassing 13 interferon alpha (IFNA) genes, interferon omega-1 (IFNW1), interferon beta-1 (IFNB1), interferon gamma (IFNG) and the interferon consensus-sequence binding protein 1 (ICSBP1). Results We identified 238 variants, most, single nucleotide polymorphisms (SNPs), by sequencing IFNA, IFNB1, IFNW1 and ICSBP1, 98 of which where novel when compared to dbSNP build 124. We used polymorphisms identified in the SeattleSNP database for INFG. A set of tag SNPs was selected for each of the interferon and interferon-related genes to test for an association between T1D and this complex gene family. A total of 45 tag SNPs were selected and genotyped in a collection of 472 multiplex families. Conclusion We have developed informative sets of SNPs for the interferon and interferon related genes. No statistical evidence of a major association between T1D and any of the interferon and interferon related genes tested was found. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Discovery, linkage disequilibrium and association analyses of polymorphisms of the immune complement inhibitor, decay-accelerating factor gene (DAF/CD55) in type 1 diabetes

Wed, 19 Apr 2006 23:00:00 GMT

Title: Discovery, linkage disequilibrium and association analyses of polymorphisms of the immune complement inhibitor, decay-accelerating factor gene (DAF/CD55) in type 1 diabetes Authors: Taniguchi, Hidenori; Lowe, Christopher E; Cooper, Jason D; Smyth, Deborah J; Bailey, Rebecca; Nutland, Sarah; Healy, Barry C; Lam, Alex C; Burren, Oliver; Walker, Neil M; Smink, Luc J; Wicker, Linda S; Todd, John A Abstract: Abstract Background Type 1 diabetes (T1D) is a common autoimmune disease resulting from T-cell mediated destruction of pancreatic beta cells. Decay accelerating factor (DAF, CD55), a glycosylphosphatidylinositol-anchored membrane protein, is a candidate for autoimmune disease susceptibility based on its role in restricting complement activation and evidence that DAF expression modulates the phenotype of mice models for autoimmune disease. In this study, we adopt a linkage disequilibrium (LD) mapping approach to test for an association between the DAF gene and T1D. Results Initially, we used HapMap II genotype data to examine LD across the DAF region. Additional resequencing was required, identifying 16 novel polymorphisms. Combining both datasets, a LD mapping approach was adopted to test for association with T1D. Seven tag SNPs were selected and genotyped in case-control (3,523 cases and 3,817 controls) and family (725 families) collections. Conclusion We obtained no evidence of association between T1D and the DAF region in two independent collections. In addition, we assessed the impact of using only HapMap II genotypes for the selection of tag SNPs and, based on this study, found that HapMap II genotypes may require additional SNP discovery for comprehensive LD mapping of some genes in common disease. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Sequencing and association analysis of the type 1 diabetes - linked region on chromosome 10p12-q11.

Wed, 16 May 2007 23:00:00 GMT

Title: Sequencing and association analysis of the type 1 diabetes - linked region on chromosome 10p12-q11. Authors: Nejentsev, Sergey; Smink, Luc J; Smyth, Deborah J; Bailey, Rebecca; Lowe, Christopher E; Payne, Felicity; Masters, Jennifer; Godfrey, Lisa M; Lam, Alex C; Burren, Oliver; Stevens, Helen; Nutland, Sarah; Walker, Neil M; Smith, Anne; Twells, Rebecca C J; Barratt, Bryan J; Wright, Charmain L; French, Lisa; Chen, Yuan; Deloukas, Panagiotis; Rogers, Jane; Dunham, Ian; Todd, John A Abstract: Abstract Background In an effort to locate susceptibility genes for type 1 diabetes (T1D) several genome-wide linkage scans have been undertaken. A chromosomal region designated IDDM10 retained genome-wide significance in a combined analysis of the main linkage scans. Here, we studied sequence polymorphisms in 23 Mb on chromosome 10p12-q11, including the putative IDDM10 region, to identify genes associated with T1D. Results Initially, we resequenced the functional candidate genes, CREM and SDF1, located in this region, genotyped 13 tag single nucleotide polymorphisms (SNPs) and found no association with T1D. We then undertook analysis of the whole 23 Mb region. We constructed and sequenced a contig tile path from two bacterial artificial clone libraries. By comparison with a clone library from an unrelated person used in the Human Genome Project, we identified 12,058 SNPs. We genotyped 303 SNPs and 25 polymorphic microsatellite markers in 765 multiplex T1D families and followed up 22 associated polymorphisms in up to 2,857 families. We found nominal evidence of association in six loci (P = 0.05 – 0.0026), located near the PAPD1 gene. Therefore, we resequenced 38.8 kb in this region, found 147 SNPs and genotyped 84 of them in the T1D families. We also tested 13 polymorphisms in the PAPD1 gene and in five other loci in 1,612 T1D patients and 1,828 controls from the UK. Overall, only the D10S193 microsatellite marker located 28 kb downstream of PAPD1 showed nominal evidence of association in both T1D families and in the case-control sample (P = 0.037 and 0.03, respectively). Conclusion We conclude that polymorphisms in the CREM and SDF1 genes have no major effect on T1D. The weak T1D association that we detected in the association scan near the PAPD1 gene may be either false or due to a small genuine effect, and cannot explain linkage at the IDDM10 region.

The candidate genes TAF5L, TCF7, PDCD1, IL6 and ICAM1 cannot be excluded from having effects in type 1 diabetes

Wed, 28 Nov 2007 00:00:00 GMT

Title: The candidate genes TAF5L, TCF7, PDCD1, IL6 and ICAM1 cannot be excluded from having effects in type 1 diabetes Authors: Cooper, Jason D; Smyth, Deborah J; Bailey, Rebecca; Payne, Felicity; Downes, Kate; Godfrey, Lisa M; Masters, Jennifer; Zeitels, Lauren R; Vella, Adrian; Walker, Neil M; Todd, John A Abstract: Abstract Background As genes associated with immune-mediated diseases have an increased prior probability of being associated with other immune-mediated diseases, we tested three such genes, IL23R, IRF5 and CD40, for an association with type 1 diabetes. In addition, we tested seven genes, TAF5L, PDCD1, TCF7, IL12B, IL6, ICAM1 and TBX21, with published marginal or inconsistent evidence of an association with type 1 diabetes. Methods We genotyped reported polymorphisms of the ten genes, nonsynonymous SNPs (nsSNPs) and, for the IL12B and IL6 regions, tag SNPs in up to 7,888 case, 8,858 control and 3,142 parent-child trio samples. In addition, we analysed data from the Wellcome Trust Case Control Consortium genome-wide association study to determine whether there was any further evidence of an association in each gene region. Results We found some evidence of associations between type 1 diabetes and TAF5L, PDCD1, TCF7 and IL6 (ORs = 1.05 – 1.13; P = 0.0291 – 4.16 × 10-4). No evidence of an association was obtained for IL12B, IRF5, IL23R, ICAM1, TBX21 and CD40, although there was some evidence of an association (OR = 1.10; P = 0.0257) from the genome-wide association study for the ICAM1 region. Conclusion We failed to exclude the possibility of some effect in type 1 diabetes for TAF5L, PDCD1, TCF7, IL6 and ICAM1. Additional studies, of these and other candidate genes, employing much larger sample sizes and analysis of additional polymorphisms in each gene and its flanking region will be required to ascertain their contributions to type 1 diabetes susceptibility. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Linkage and association analysis of GAW15 simulated data: fine-mapping of chromosome 6 region

Tue, 18 Dec 2007 00:00:00 GMT

Title: Linkage and association analysis of GAW15 simulated data: fine-mapping of chromosome 6 region Abstract: Abstract We performed linkage and family-based association analysis across chromosomes 1–22 in Replicates 1–5 of the Genetic Analysis Workshop 15 simulated data. Linkage analysis was performed using the Kong and Cox allele-sharing test as implemented in the program Merlin. Association analysis was performed using the transmission/disequilibrium test (TDT). A region on chromosome 6 was consistently highlighted as showing significant linkage to and association with the disease trait. We focused in on this region and performed fine-mapping using stepwise regression approaches using the case/control and family-based data. In this region, we also applied several new methods, implemented in the computer programs LAMP and Graphminer, respectively, that have recently been proposed for association analysis with family and/or case/control data. All methods confirmed the highly significant associations previously observed. Differentiating between potentially causal single nucleotide polymorphisms (SNPs) and other non-causal loci (associated with disease merely due to linkage disequilibrium) proved to be problematic. However, in most replicates we did identify two SNPs (either SNPs 3437 and 3439 from the dense SNP set, or SNPs 153 and 3437 from the combined non-dense/dense SNP set) that together explain most of the observed disease association in the DR/C locus region, and an additional SNP (3931 or 3933) that accounts for the association 5 cM away at locus D. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Developmentally regulated expression, alternative splicing and distinct sub-groupings in members of the Schistosoma mansoni venom allergen-like (SmVAL) gene family

Sat, 23 Feb 2008 00:00:00 GMT

Title: Developmentally regulated expression, alternative splicing and distinct sub-groupings in members of the Schistosoma mansoni venom allergen-like (SmVAL) gene family Authors: Chalmers, Iain W; McArdle, Andrew J; Coulson, Richard M R; Wagner, Marissa A; Schmid, Ralf; Hirai, Hirohisa; Hoffmann, Karl F Abstract: Abstract Background The Sperm-coating protein/Tpx-1/Ag5/PR-1/Sc7 (SCP/TAPS) domain is found across phyla and is a major structural feature of insect allergens, mammalian sperm proteins and parasitic nematode secreted molecules. Proteins containing this domain are implicated in diverse biological activities and may be important for chronic host/parasite interactions. Results We report the first description of an SCP/TAPS gene family (Schistosoma mansoni venom allergen-like (SmVALs)) in the medically important Platyhelminthes (class Trematoda) and describe individual members' phylogenetic relationships, genomic organization and life cycle expression profiles. Twenty-eight SmVALs with complete SCP/TAPS domains were identified and comparison of their predicted protein features and gene structures indicated the presence of two distinct sub-families (group 1 & group 2). Phylogenetic analysis demonstrated that this group 1/group 2 split is zoologically widespread as it exists across the metazoan sub-kingdom. Chromosomal localisation and PCR analysis, coupled to inspection of the current S. mansoni genomic assembly, revealed that many of the SmVAL genes are spatially linked throughout the genome. Quantitative lifecycle expression profiling demonstrated distinct SmVAL expression patterns, including transcripts specifically associated with lifestages involved in definitive host invasion, transcripts restricted to lifestages involved in the invasion of the intermediate host and transcripts ubiquitously expressed. Analysis of SmVAL6 transcript diversity demonstrated statistically significant, developmentally regulated, alternative splicing. Conclusion Our results highlight the existence of two distinct SCP/TAPS protein types within the Platyhelminthes and across taxa. The extensive lifecycle expression analysis indicates several SmVAL transcripts are upregulated in infective stages of the parasite, suggesting that these particular protein products may be linked to the establishment of chronic host/parasite interactions. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Observational study on variability between biobanks in the estimation of DNA concentration

Mon, 12 Oct 2009 23:00:00 GMT

Title: Observational study on variability between biobanks in the estimation of DNA concentration Authors: Brown, Jay; Donev, Alexander N; Aslanidis, Charalampos; Bracegirdle, Pippa; Dixon, Katherine P; Foedinger, Manuela; Gwilliam, Rhian; Hardy, Matthew; Illig, Thomas; Ke, Xiayi; Krinka, Dagni; Lagerberg, Camilla; Laiho, Paivi; Lewis, David H; McArdle, Wendy; Jones, Richard W; Patton, Simon; Ring, Susan M; Schmitz, Gerd; Stevens, Helen; Tybring, Gunnel; Wichmann, H Erich; Ollier, William E R; Yuille, Martin A Abstract: Abstract Background There is little confidence in the consistency of estimation of DNA concentrations when samples move between laboratories. Evidence on this consistency is largely anecdotal. Therefore there is a need first to measure this consistency among different laboratories and then identify and implement remedies. A pilot experiment to test logistics and provide initial data on consistency was therefore conceived. Methods DNA aliquots at nominal concentrations between 10 and 300 ng/μl were dispensed into the wells of 96-well plates by one participant - the coordinating centre. Participants estimated the concentration in each well and returned estimates to the coordinating centre. Results Considerable overall variability was observed among estimates. There were statistically significant differences between participants' measurements and between fluorescence emission and absorption spectroscopy. Conclusion Anecdotal evidence of variability in DNA concentration estimation has been substantiated. Reduction in variability between participants will require the identification of major sources of variation, specification of effective remedies and their implementation.

Analysis of polymorphisms in 16 genes in type 1 diabetes that have been associated with other immune-mediated diseases

Mon, 06 Mar 2006 00:00:00 GMT

Title: Analysis of polymorphisms in 16 genes in type 1 diabetes that have been associated with other immune-mediated diseases Authors: Smyth, Deborah J; Howson, Joanna M M; Payne, Felicity; Maier, Lisa M; Bailey, Rebecca; Holland, Kieran; Lowe, Christopher E; Cooper, Jason D; Hulme, John S; Vella, Adrian; Dalhman, Ingrid; Lam, Alex C; Nutland, Sarah; Walker, Neil M; Twells, Rebecca C J; Todd, John A Abstract: Abstract Background The identification of the HLA class II, insulin (INS), CTLA-4 and PTPN22 genes as determinants of type 1 diabetes (T1D) susceptibility indicates that fine tuning of the immune system is centrally involved in disease development. Some genes have been shown to affect several immune-mediated diseases. Therefore, we tested the hypothesis that alleles of susceptibility genes previously associated with other immune-mediated diseases might perturb immune homeostasis, and hence also associate with predisposition to T1D. Methods We resequenced and genotyped tag single nucleotide polymorphisms (SNPs) from two genes, CRP and FCER1B, and genotyped 27 disease-associated polymorphisms from thirteen gene regions, namely FCRL3, CFH, SLC9A3R1, PADI4, RUNX1, SPINK5, IL1RN, IL1RA, CARD15, IBD5-locus (including SLC22A4), LAG3, ADAM33 and NFKB1. These genes have been associated previously with susceptibility to a range of immune-mediated diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Graves' disease (GD), psoriasis, psoriatic arthritis (PA), atopy, asthma, Crohn disease and multiple sclerosis (MS). Our T1D collections are divided into three sample subsets, consisting of set 1 families (up to 754 families), set 2 families (up to 743 families), and a case-control collection (ranging from 1,500 to 4,400 cases and 1,500 to 4,600 controls). Each SNP was genotyped in one or more of these subsets. Our study typically had approximately 80% statistical power for a minor allele frequency (MAF) >5% and odds ratios (OR) of 1.5 with the type 1 error rate, α = 0.05. Results We found no evidence of association with T1D at most of the loci studied 0.02

Evading the annotation bottleneck: using sequence similarity to search non-sequence gene data.

Thu, 16 Oct 2008 23:00:00 GMT

Title: Evading the annotation bottleneck: using sequence similarity to search non-sequence gene data. Authors: Gilchrist, Michael J; Christensen, Mikkel B; Harland, Richard; Pollet, Nicolas; Smith, James C; Ueno, Naoto; Papalopulu, Nancy Abstract: Abstract Background Non-sequence gene data (images, literature, etc.) can be found in many different public databases. Access to these data is mostly by text based methods using gene names; however, gene annotation is neither complete, nor fully systematic between organisms, and is also not generally stable over time. This provides some challenges for text based access, especially for cross-species searches. We propose a method for non-sequence data retrieval based on sequence similarity, which removes dependence on annotation and text searches. This work was motivated by the need to provide better access to large numbers of in situ images, and the observation that such image data were usually associated with a specific gene sequence. Sequence similarity searches are found in existing gene oriented databases, but mostly give indirect access to non-sequence data via navigational links. Results Three applications were built to explore the proposed method: accessing image data, literature and gene names. Searches are initiated with the sequence of the user's gene of interest, which is searched against a database of sequences associated with the target data. The matching (non-sequence) target data are returned directly to the user's browser, organised by sequence similarity. The method worked well for the intended application in image data management. Comparison with text based searches of the image data set showed the accuracy of the method. Applied to literature searches it facilitated retrieval of mostly high relevance references. Applied to gene name data it provided a useful analysis of name variation of related genes within and between species. Conclusion This method makes a powerful and useful addition to existing methods for searching gene data based on text retrieval or curated gene lists. In particular the method facilitates cross-species comparisons, and enables the handling of novel or otherwise un-annotated genes. Applications using the method are quick and easy to build, and the data require little maintenance. This approach largely circumvents the need for annotation, which can be a major obstacle to the development of genomic scale data resources. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Investigating the utility of combining Phi29 whole genome amplification and highly multiplexed single nucleotide polymorphism BeadArrayTM genotyping

Mon, 26 Jul 2004 23:00:00 GMT

Title: Investigating the utility of combining Phi29 whole genome amplification and highly multiplexed single nucleotide polymorphism BeadArrayTM genotyping Authors: Pask, Rebecca; Rance, Helen E; Barratt, Bryan J; Nutland, Sarah; Smyth, Deborah J; Sebastian, Meera; Twells, Rebecca C J; Smith, Anne; Lam, Alex C; Smink, Luc J; Walker, Neil M; Todd, John A Abstract: Abstract Background Sustainable DNA resources and reliable high-throughput genotyping methods are required for large-scale, long-term genetic association studies. In the genetic dissection of common disease it is now recognised that thousands of samples and hundreds of thousands of markers, mostly single nucleotide polymorphisms (SNPs), will have to be analysed. In order to achieve these aims, both an ability to boost quantities of archived DNA and to genotype at low costs are highly desirable. We have investigated Φ29 polymerase Multiple Displacement Amplification (MDA)-generated DNA product (MDA product), in combination with highly multiplexed BeadArray™ genotyping technology. As part of a large-scale BeadArray genotyping experiment we made a direct comparison of genotyping data generated from MDA product with that from genomic DNA (gDNA) templates. Results Eighty-six MDA product and the corresponding 86 gDNA samples were genotyped at 345 SNPs and a concordance rate of 98.8% was achieved. The BeadArray sample exclusion rate, blind to sample type, was 10.5% for MDA product compared to 5.8% for gDNA. Conclusions We conclude that the BeadArray technology successfully produces high quality genotyping data from MDA product. The combination of these technologies improves the feasibility and efficiency of mapping common disease susceptibility genes despite limited stocks of gDNA samples. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Construction and analysis of tag single nucleotide polymorphism maps for six human-mouse orthologous candidate genes in type 1 diabetes

Fri, 18 Feb 2005 00:00:00 GMT

Title: Construction and analysis of tag single nucleotide polymorphism maps for six human-mouse orthologous candidate genes in type 1 diabetes Authors: Maier, Lisa M; Smyth, Deborah J; Vella, Adrian; Payne, Felicity; Cooper, Jason D; Pask, Rebecca; Lowe, Christopher E; Hulme, John S; Smink, Luc J; Fraser, Heather; Moule, Carolyn; Hunter, Kara M; Chamberlain, Giselle; Walker, Neil M; Nutland, Sarah; Undlien, Dag E; Ronningen, Kjersti S; Guja, Cristian; Ionescu-Tirgoviste, Constantin; Savage, David A; Strachan, David P; Peterson, Laurence B; Todd, John A; Wicker, Linda S; Twells, Rebecca C J Abstract: Abstract Background One strategy to help identify susceptibility genes for complex, multifactorial diseases is to map disease loci in a representative animal model of the disorder. The nonobese diabetic (NOD) mouse is a model for human type 1 diabetes. Linkage and congenic strain analyses have identified several NOD mouse Idd (insulin dependent diabetes) loci, which have been mapped to small chromosome intervals, for which the orthologous regions in the human genome can be identified. Here, we have conducted re-sequencing and association analysis of six orthologous genes identified in NOD Idd loci: NRAMP1/SLC11A1 (orthologous to Nramp1/Slc11a1 in Idd5.2), FRAP1 (orthologous to Frap1 in Idd9.2), 4-1BB/CD137/TNFRSF9 (orthologous to 4-1bb/Cd137/Tnrfrsf9 in Idd9.3), CD101/IGSF2 (orthologous to Cd101/Igsf2 in Idd10), B2M (orthologous to B2m in Idd13) and VAV3 (orthologous to Vav3 in Idd18). Results Re-sequencing of a total of 110 kb of DNA from 32 or 96 type 1 diabetes cases yielded 220 single nucleotide polymorphisms (SNPs). Sixty-five SNPs, including 54 informative tag SNPs, and a microsatellite were selected and genotyped in up to 1,632 type 1 diabetes families and 1,709 cases and 1,829 controls. Conclusion None of the candidate regions showed evidence of association with type 1 diabetes (P values > 0.2), indicating that common variation in these key candidate genes does not play a major role in type 1 diabetes susceptibility in the European ancestry populations studied. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Sex chromosomes and genetic association studies

Tue, 24 Nov 2009 00:00:00 GMT

Title: Sex chromosomes and genetic association studies Authors: Clayton, David G Abstract: Abstract Although the literature concerning statistical testing for genotype-phenotype association in family-based and population-based studies is very extensive, until recently the sex chromosomes have received little attention. Here it is shown that the X chromosome in particular presents special problems with respect to efficient analysis of mixed-sex population studies, and as a result of X inactivation. This paper reviews recent developments in approaching these problems. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Evidence of association with type 1 diabetes in the SLC11A1 gene region

Tue, 26 Apr 2011 23:00:00 GMT

Title: Evidence of association with type 1 diabetes in the SLC11A1 gene region Authors: Yang, Jennie H M; Downes, Kate; Howson, Joanna M M; Nutland, Sarah; Stevens, Helen; Walker, Neil M; Todd, John A Abstract: Abstract Background Linkage and congenic strain analyses using the nonobese diabetic (NOD) mouse as a model for human type 1 autoimmune diabetes (T1D) have identified several NOD mouse Idd (insulin dependent diabetes) loci, including Slc11a1 (formerly known as Nramp1). Genetic variants in the orthologous region encompassing SLC11A1 in human chromosome 2q35 have been reported to be associated with various immune-related diseases including T1D. Here, we have conducted association analysis of this candidate gene region, and then investigated potential correlations between the most T1D-associated variant and RNA expression of the SLC11A1 gene and its splice isoform. Methods Nine SNPs (rs2276631, rs2279015, rs1809231, rs1059823, rs17235409 (D543N), rs17235416 (3'UTR), rs3731865 (INT4), rs7573065 (-237 C→T) and rs4674297) were genotyped using TaqMan genotyping assays and the polymorphic promoter microsatellite (GT)n was genotyped using PCR and fragment length analysis. A maximum of 8,863 T1D British cases and 10,841 British controls, all of white European descent, were used to test association using logistic regression. A maximum of 5,696 T1D families were also tested for association using the transmission/disequilibrium test (TDT). We considered P ≤ 0.005 as evidence of association given that we tested nine variants in total. Upon identification of the most T1D-associated variant, we investigated the correlation between its genotype and SLC11A1 expression overall or with splice isoform ratio using 42 PAXgene whole blood samples from healthy donors by quantitative PCR (qPCR). Results Using the case-control collection, rs3731865 (INT4) was identified to be the variant most associated with T1D (P = 1.55 × 10-6). There was also some evidence of association at rs4674297 (P = 1.57 × 10-4). No evidence of disease association was obtained at any of the loci using the family collections (P TDT ≥ 0.13). We also did not observe a correlation between rs3731865 genotypes and SLC11A1 expression overall or with splice isoform expression. Conclusion We conclude that rs3731685 (INT4) in the SLC11A1 gene may be associated with T1D susceptibility in the European ancestry population studied. We did not observe a difference in SLC11A1 expression at the RNA level based on the genotypes of rs3731865 in whole blood samples. However, a potential correlation cannot be ruled out in purified cell subsets especially monocytes or macrophages.