Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the past decade, the genetics of type 1 (insulin-dependent) diabetes mellitus (IDDM) has been studied extensively and the disorder has become a paradigm for genetically complex diseases. Previous genome screens and studies focused on candidate genes have provided evidence for genetic linkage between polymorphic DNA markers and 15 putative IDDM susceptibility loci, designated IDDM1-IDDM15. We have carried out a second-generation screen of the genome for linkage and analysed the data by multipoint linkage methods. An initial panel of 212 affected sibpairs (ASPs) was genotyped for 438 markers spanning all autosomes, and an additional 467 ASPs were used for follow-up genotyping. Other than the well-established linkage with the HLA region at chromosome 6p21.3, there was only one region, located on chromosome 1q and not previously reported, where the log likelihood ratio (lod) was greater than 3. Lods between 1.0 and 1.8 were found in six other regions, three of which have been reported in other studies. Another reported region, on chromosome 6q and loosely linked to HLA, also had an elevated lod. Little or no support was found for most reported IDDM loci (lods were less than 1), despite larger sample sizes in the present study.
 ...
PMID:A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus. 966 86

Over the last few years several studies of linkage between non-HLA loci and type 1 diabetes mellitus have mapped several putative susceptibility genes on chromosome 6q; in fact, positive evidence of linkage and/or association of IDDM5 (6q25), IDDM8 (6q27) and IDDM15 (6q21) with type 1 diabetes has been reported. We have studied these loci in diabetic families of Basque origin, a genetically homogeneous population, to avoid artifactual association results due to admixture within the sample analysed. Statistical analyses of linkage were performed using a transmission disequilibrium test (TDT). We could not confirm linkage for IDDM5, IDDM8 and IDDM15 in our population, possibly due to population-specific differences in genetic susceptibility and/or environmental triggering factors to type 1 diabetes.
 ...
PMID:Analysis of chromosome 6q in Basque families with type 1 diabetes. GEPV-N. Basque-Navarre Endocrinology and Paediatric Group. 1120 51

Type 1 diabetes (T1D) is a genetically complex disorder of glucose homeostasis that results from the autoimmune destruction of the insulin-secreting cells of the pancreas. Two previous whole-genome scans for linkage to T1D in 187 and 356 families containing affected sib pairs (ASPs) yielded apparently conflicting results, despite partial overlap in the families analyzed. However, each of these studies individually lacked power to detect loci with locus-specific disease prevalence/sib-risk ratios (lambda(s)) <1.4. In the present study, a third genome scan was performed using a new collection of 225 multiplex families with T1D, and the data from all three of these genome scans were merged and analyzed jointly. The combined sample of 831 ASPs, all with both parents genotyped, provided 90% power to detect linkage for loci with lambda(s) = 1.3 at P=7.4x10(-4). Three chromosome regions were identified that showed significant evidence of linkage (P<2.2x10(-5); LOD scores >4), 6p21 (IDDM1), 11p15 (IDDM2), 16q22-q24, and four more that showed suggestive evidence (P<7.4x10(-4), LOD scores > or =2.2), 10p11 (IDDM10), 2q31 (IDDM7, IDDM12, and IDDM13), 6q21 (IDDM15), and 1q42. Exploratory analyses, taking into account the presence of specific high-risk HLA genotypes or affected sibs' ages at disease onset, provided evidence of linkage at several additional sites, including the putative IDDM8 locus on chromosome 6q27. Our results indicate that much of the difficulty in mapping T1D susceptibility genes results from inadequate sample sizes, and the results point to the value of future international collaborations to assemble and analyze much larger data sets for linkage in complex diseases.
 ...
PMID:Seven regions of the genome show evidence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex families. 1150 94

Type 1 diabetes mellitus (TIDM) has a multifactorial etiology, with major genetic-susceptibility determinants located in the HLA and insulin-gene (INS) regions. Linkage data implicating other disease-susceptibility loci are conflicting. This is likely due to (1) the limited power for detection of contributions of additional susceptibility loci, given the limited number of informative families available for study, (2) factors such as genetic heterogeneity between populations, and (3) potential gene-gene and gene-environment interactions. To circumvent some of these problems, we have conducted a genomewide linkage analysis for T1DM-susceptibility loci in 408 multiplex families from Scandinavia, a population expected to be homogeneous for genetic and environmental factors. In addition to verifying the HLA and INS susceptibility loci, the study provides confirmation of IDDM15 on chromosome 6q21. Suggestive evidence of additional susceptibility loci was found on chromosomes 2p, 5q, and 16p. For some loci, the support for linkage increased substantially when families were stratified on the basis of HLA or INS genotypes, with statistically significant heterogeneity between the stratified subgroups. Our data support both the existence of non-HLA genes of significance for T1DM and interaction between HLA and non-HLA loci in the determination of the T1DM phenotype.
 ...
PMID:A genomewide scan for type 1-diabetes susceptibility in Scandinavian families: identification of new loci with evidence of interactions. 1159 29

There is substantial interest in the identification of genes underlying susceptibility to complex human diseases because of the potential utility of such genes in disease prediction or therapy. Type 1 diabetes is an example of one such disorder and is presumed to arise from the effect of multiple genes and environmental factors. One identified locus has a major effect on type 1 diabetes susceptibility (IDDM1), whereas other loci have significant, yet small, individual effects (IDDM2, IDDM15). It is unclear whether susceptibility for type 1 diabetes arises because of the effects of loci acting independently or whether there are important interactions between loci. Although genetic tools are continuing to be developed to enable examination of candidate regions, the means to identify and narrow "true" susceptibility regions continues to be limited by the lack of statistical power resulting from inadequately sized collections of families. This report provides an evaluation of the approaches for identification of regions harboring type 1 diabetes genes, methods to identify the gene regions that interact to define the risk for type 1 diabetes, and efforts to fine-map the variants responsible.
 ...
PMID:Challenges and strategies for investigating the genetic complexity of common human diseases. 1247 65

We address the analytical problem of evaluating the evidence for linkage at a test locus while taking into account the effect of a known linked disease locus. The method we propose is a multimarker regression approach that models the identity-by-descent states for affected sib-pairs at a series of linked markers in terms of the identity-by-descent state at the known disease locus. Our method allows analysis to be performed at a test location (or a series of locations) without the requirement that identity-by-descent be directly observed at either the test or the known conditioning locus. An advantage of our method is that identity-by-descent states from multiple markers are included simultaneously in the test of linkage, without recourse to multipoint imputation. The properties and power of the method are examined under various null and alternative hypotheses. The method is applied to data from a study of 1,056 type 1 diabetes families to examine the evidence for an additional putative locus (IDDM15) on chromosome 6q, linked to IDDM1 in the HLA region on chromosome 6p. After accounting for the strong effect of IDDM1 and the differing rates of male and female recombination in the region, we find only marginal evidence for IDDM15 (P = 0.03 to 0.002, using different methods) approximately 15 cM centromeric of the original localisation.
 ...
PMID:A multimarker regression-based test of linkage for affected sib-pairs at two linked loci. 1638 70