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

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.

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

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.

Analysis of polymorphisms of the interleukin-18 gene in type 1 diabetes and Hardy-Weinberg equilibrium testing.

Recently, the interleukin-18 cytokine gene (IL18) was reported to be associated with type 1 diabetes. In the present report, we calculated that the reported genotypes of the two 5' region/promoter single nucleotide polymorphisms (SNPs), -607 (C-->A) (rs1946518) and -137 (G-->C) (rs187238), were not in Hardy-Weinberg equilibrium (HWE). We therefore investigated the association of the -607 and -137 SNPs in a U.

No evidence for association of the TATA-box binding protein glutamine repeat sequence or the flanking chromosome 6q27 region with type 1 diabetes.

Susceptibility to the autoimmune disease type 1 diabetes has been linked to human chromosome 6q27 and, moreover, recently associated with one of the genes in the region, TATA box-binding protein (TBP). Using a much larger sample of T1D families than those studied by others, and by extensive re-sequencing of nine other genes in the proximity, in which we identified 279 polymorphisms, 83 of which were genotyped in up to 725 T1D multiplex and simplex families, we obtained no evidence for association of the TBP CAG/CAA (glutamine) microsatellite repeat sequence with disease, or for nine other genes, PDCD2, PSMB1, KIAA1838, DLL1, dJ894D12.4, FLJ25454, FLJ13162, FLJ11152, PHF10 and CCR6.

Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms.

As part of an ongoing search for genes associated with type 1 diabetes (T1D), a common autoimmune disease, we tested the biological candidate gene IL2RA (CD25), which encodes a subunit (IL-2R alpha) of the high-affinity interleukin-2 (IL-2) receptor complex. We employed a tag single-nucleotide polymorphism (tag SNP) approach in large T1D sample collections consisting of 7,457 cases and controls and 725 multiplex families. Tag SNPs were analyzed using a multilocus test to provide a regional test for association.

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

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.

No evidence of association or interaction between the IL4RA, IL4, and IL13 genes in type 1 diabetes.

Attempts to identify susceptibility loci that, on their own, have marginal main effects by use of gene-gene interaction tests have increased in popularity. The results obtained from analyses of epistasis are, however, difficult to interpret. Gene-gene interaction, albeit only marginally significant, has recently been reported for the interleukin-4 and interleukin-13 genes (IL4 and IL13) with the interleukin-4 receptor A gene (IL4RA), contributing to the susceptibility of type 1 diabetes (T1D).

Development of an integrated genome informatics, data management and workflow infrastructure: a toolbox for the study of complex disease genetics.

The genetic dissection of complex disease remains a significant challenge. Sample-tracking and the recording, processing and storage of high-throughput laboratory data with public domain data, require integration of databases, genome informatics and genetic analyses in an easily updated and scaleable format. To find genes involved in multifactorial diseases such as type 1 diabetes (T1D), chromosome regions are defined based on functional candidate gene content, linkage information from humans and animal model mapping information.

Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus.

In the genetic analysis of common, multifactorial diseases, such as type 1 diabetes, true positive irrefutable linkage and association results have been rare to date. Recently, it has been reported that a single nucleotide polymorphism (SNP), 1858C>T, in the gene PTPN22, encoding Arg620Trp in the lymphoid protein tyrosine phosphatase (LYP), which has been shown to be a negative regulator of T-cell activation, is associated with an increased risk of type 1 diabetes. Here, we have replicated these findings in 1,388 type 1 diabetic families and in a collection of 1,599 case and 1,718 control subjects, confirming the association of the PTPN22 locus with type 1 diabetes (family-based relative risk (RR) 1.

Association analysis of the lymphocyte-specific protein tyrosine kinase (LCK) gene in type 1 diabetes.

Prior data associating the expression of lymphocyte-specific protein tyrosine kinase (LCK) with type 1 diabetes, its critical function in lymphocytes, and the linkage of the region to diabetes in the nonobese diabetic (NOD) mouse model make LCK a premier candidate for a susceptibility gene. Resequencing of LCK in 32 individuals detected seven single nucleotide polymorphisms (SNPs) with allele frequencies >3%, including four common SNPs previously reported. These and six other SNPs from dbSNP were genotyped in a two-stage strategy using 2,430 families and were all shown not to be significantly associated with type 1 diabetes.

Investigating the utility of combining phi29 whole genome amplification and highly multiplexed single nucleotide polymorphism BeadArray genotyping.

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.

Lack of association of the Ala(45)Thr polymorphism and other common variants of the NeuroD gene with type 1 diabetes.

Variation in genes necessary for normal functioning and development of beta-cells, e.g., NEUROD1, which encodes a transcription factor for the insulin gene and is important in beta-cell development, causes maturity-onset diabetes of the young.

Analysis of the type 2 diabetes-associated single nucleotide polymorphisms in the genes IRS1, KCNJ11, and PPARG2 in type 1 diabetes.

It has been proposed that type 1 and 2 diabetes might share common pathophysiological pathways and, to some extent, genetic background. However, to date there has been no convincing data to establish a molecular genetic link between them. We have genotyped three single nucleotide polymorphisms associated with type 2 diabetes in a large type 1 diabetic family collection of European descent: Gly972Arg in the insulin receptor substrate 1 (IRS1) gene, Glu23Lys in the potassium inwardly-rectifying channel gene (KCNJ11), and Pro12Ala in the peroxisome proliferative-activated receptor gamma2 gene (PPARG2).

Haplotype tag single nucleotide polymorphism analysis of the human orthologues of the rat type 1 diabetes genes Ian4 (Lyp/Iddm1) and Cblb.

The diabetes-prone BioBreeding (BB) and Komeda diabetes-prone (KDP) rats are both spontaneous animal models of human autoimmune, T-cell-associated type 1 diabetes. Both resemble the human disease, and consequently, susceptibility genes for diabetes found in these two strains can be considered as potential candidate genes in humans. Recently, a frameshift deletion in Ian4, a member of the immune-associated nucleotide (Ian)-related gene family, has been shown to map to BB rat Iddm1.

Haplotype structure, LD blocks, and uneven recombination within the LRP5 gene.

Patterns of linkage disequilibrium (LD) in the human genome are beginning to be characterized, with a paucity of haplotype diversity in "LD blocks," interspersed by apparent "hot spots" of recombination. Previously, we cloned and physically characterized the low-density lipoprotein-receptor-related protein 5 (LRP5) gene. Here, we have extensively analysed both LRP5 and its flanking three genes, spanning 269 kb, for single nucleotide polymorphisms (SNPs), and we present a comprehensive SNP map comprising 95 polymorphisms.

Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease.

Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.

Linkage and association mapping of the LRP5 locus on chromosome 11q13 in type 1 diabetes.

Linkage of chromosome 11q13 to type 1 diabetes (T1D) was first reported from genome scans (Davies et al. 1994; Hashimoto et al. 1994) resulting in P <2.