JDRF/Wellcome Trust Diabetes and Inflammation Laboratory at University of Cambridge


Director: Professor John Todd


Specific Aims

(1) Carry out a genome-wide association study (GWAS) with the Wellcome Trust Case Control Consortium (wtccc.org.uk) and complete a GWAS of nonsynonymous single nucleotide polymorphisms (SNPs) to identify novel type 1 diabetes (T1D) susceptibility regions using the JDRF/WT cases.

(2) Complete the analysis of the MHC HLA region in T1D using a high density SNP map and classical typing data.

(3) Continue major collaborations with the WTCCC and the Type 1 Diabetes Genetics Consortium (t1dgc.org) in the genetic analysis of T1D, including GWAS results access and bioinformatics tools in T1DBase.

(4) Ship DNA samples and cell lines to the NIDDK repository.

(5) In vivo modelling of human T1D susceptibility genes in the NOD mouse model.

(6) Correlate T1D susceptibility genotypes with phenotypes, such as gene expression, biomarkers and surface and induced phenotype in immune cells, using plasma, serum and blood samples from people with T1D and their relatives, and healthy volunteers from the Cambridge BioResource (cambridgebioresource.org.uk) in order to identify disease pathways and mechanisms, with a particular focus on the interleukin-2 and vitamin D pathways.

Accomplishments

(1) 38 manuscripts and publications since December 2006.

(2) Identification and analysis of at least four new T1D susceptibility regions (WTCCC, 2007, Nature 447, 661-678; Todd JA et al, 2007 Nat. Genet. 39, 857-864)

(http://t1dbase.org/page/MarkerOverview/display/?marker_id=rs1000112).

(3) Identification of the HLA-B and HLA-A genes in the MHC as additional determinant of T1D

susceptibility over and above the HLA class II genes (Nejentsev S et al, 2007, Nature 450, 887-892).

(4) Launched a major new GWAS of JDRF/WT cases and controls with the T1DGC.

(5) Detailed genetic mapping of the IL2RA region and correlation of IL2RA genotype with plasma

concentration of the immune activation biomarker soluble IL-2RA/CD25 (Lowe C et al, 2007, Nat. Genet. 39, 1074-1082).

(6) Cell lines shipped to NIDDK repository, with DNA samples to be sent by Q3, 2008.

(7) Evidence that NOD mouse PTPN22 gene is altered genetically and that increased expression, and presumably, activity, correlates with T1D susceptibility, as found in humans.

Publications/Presentations

The Wellcome Trust Case Control Consortium. (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661-678.

Todd, J.A., Walker, N.M., Cooper, J.D., Smyth, D.J., Downes, K., Plagnol, V., Bailey, R., Nejentsev, S., Field, S.F., Payne, F., Lowe, C.E., Szeszko, J.S., Hafler, J.P., Zeitels, L., Yang, J.H.M., Vella, A., Nutland, S., Stevens, H.E., Schuilenburg, H., Coleman, G., Maisuria, M., Meadows, W., Smink, L.J., Healy, B., Burren, O.S., Lam, A.H., Ovington, N.R., Allen, J., Adlem, E., Leung, H.-T., Wallace, C., Howson, J.M.M., Guja, C., Ionescu-Tirgoviste, C., Genetics of Type 1 Diabetes in Finland, Simmonds, M.J., Heward, J.M., Gough, S.C.G., The Wellcome Trust Case Control Consortium, Dunger, D.B., Wicker, L.S. and Clayton,

D.G. (2007) Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat. Genet. 39, 857-864. Lowe, C.E., Cooper, J.D., Brusko, T., Walker, N.M., Smyth, D.J., Bailey, R., Bourget, K., Plagnol, V., Field, S., Atkinson, M., Clayton, D.G., Wicker,

L.S. and Todd, J.A. (2007) Large-scale genetic fine mapping and genotype-phenotype associations implicate IL2RA region polymorphism in type 1 diabetes. Nat. Genet. 39, 1074-1082.

Who benefits from this research

Identification and characterization of the genetic basis of T1D reveals the major pathways and mechanisms of disease. This information can help inform in the design of clinical studies and prevention trials, and their outcomes, including in the selection of participants in clinical studies. T1D susceptibility genes can help identify disease biomarkers. The JDRF/WT DIL provides samples, expertise, genetic information, informatics and statistical tools and methods to the research community.

Future Plans

(1) With the Type 1 Diabetes Genetics Consortium (t1dgc.org) undertake a genome-wide association study (GWAS) of 2,500 controls and 4,000 cases and combine the data with the GWAS results from the Wellcome Trust Case Control Consortium (wtccc.org.uk) from 3,000 controls and 2,000 and other available T1D and control data (e.g. GAIN data for 1,800 T1D cases from the GoKinD study) in order to locate novel susceptibility regions and genes.

(2) Analyse the data from the WTCCC available in 2008 from resequencing and genotyping of known T1D regions to design a “T1D SNP chip” to genotype the JDRF/WT T1D cases (7,000) and controls (7,000) to define and localise haplotype associations and candidate variants, as a prerequisite for functional studies.

(3) Correlate T1D susceptibility genotypes with phenotypes, such as gene expression, biomarkers and surface and induced phenotype in immune cells, using plasma, serum and blood samples from people with T1D and their relatives, and healthy volunteers from the Cambridge BioResource (cambridgebioresource.org.uk), including in vivo mouse modelling, in order to identify disease pathways and mechanisms, with a particular focus on the interleukin-2 and vitamin D

Website: http://www-gene.cimr.cam.ac.uk/todd/