Projects

Type 1 Diabetes (T1D) Component

April, 2005, Update

The 13th IHWG includes a component dedicated to the study of the HLA region in type 1 diabetes (T1D). Building on the achievements of the T1D Component of the 12th IHWG, the 13th IHWG has expanded the populations studied and for the first time combined microsatellite typing with HLA typing to identify regions containing susceptibility loci.

The main goals of the T1D component of the 13th IHWG are:
1) To capture existing data from investigators worldwide and data generated by the 13th IWHG studies with the purpose of creating a resource consisting of available HLA haplotypes and demographic/phenotypic data from patients with T1D, family members, and population-matched controls. This resource, included in dbMHC (http://www.ncbi.nlm.nih.gov/mhc/), is being created in collaboration with NCBI and will be accessible in the near future.
2) Using HLA typing (investigator-based) and microsatellite typing (performed through central core labs) we set to regions within the human HLA complex that contribute to T1D risk. Our experimental plan has been focused on testing the hypothesis that loci other than the class II HLA-DR and –DQ genes modify susceptibility or resistance to disease using case-control and family-based data sets.

The material collected consists of DNA samples and data for which the participating investigators have generated phenotypic and HLA data. The IHWG offers a unique opportunity to capture these data and create a shared resource that can be accessible to the scientific community.

The project was initiated by Sophie Caillat-Zucman together with Alberto Pugliese as co-leaders, in the context of the 13th IHWG Disease Component lead by Erik Thorsby and Lee Nelson. The following individuals have been playing an essential role: Glenys Thomson, Jan Dorman, Ann Steenkiste, Ana Maria Valdes and Hongzhe Li (data analysis), Gary Schoch and Lue Ping Zhao (Database), Anajane Smith and John Hansen (IHWG Genomic Core lab), Mark Lathrop (Centre National Genotypage), Pat Concannon (co-investigator for HBDI data), Wolfgang Helmberg (dbMHC and SCORE software), Mike Feolo and Douglas Hoffman (dbMHC).

Also critical were the contributions and willingness to share of the participating investigators, who were: Zuheir Awdeh, Sunanda Babu, Monica Berrino, Bernhard Boehm, Chaim Brautbar, Begona Calvo, Luis Castano, Frank Christiansen, Lee Ming Chuang, Pat Concannon, George Eisenbarth, Farrah El Chenawi, Pam Fain, Isabelle Fajardy, Maria Edvige Fasano, Kathleen Gillespie, Clara Gorodezky, Leonard Harrison, Margo Honeyman, Hiroshi Ikegami, Jorma Ilonen, Shoshana Israel, Uma Kanga, Bob Koeleman, Ake Lernmark, Benedicte Lie, Myriam Martinetti, Narendar Mehra, Viswanathan Mohan, Agnes Moine, W. Mynarski, Elissaveta Naumova, Jorn Nerup, Flemming Pociot, Rajni Rani, Bart Roep, Carani Sanjeevi, Guher Sahuran-Direskeneli, Gilbert Semana, Helen Stevens, Brian Tait, John Todd, Eva Tuomilehto-Wolf, Dag Undlien, Pnina Vardi, Walkyria Volpini, Marjan Zarghami.
The American Diabetes Association and the National Institutes of Health provided financial support.

STUDY POPULATION ASSEMBLED
? Population-based. A total of 3,221 patients and 2,342 healthy controls from 20 data sets have been collected.
? Family-based. Approximately 1,500 families representing 26 independent data sets are available.
o 509 families with one parent homozygous for HLA-DR/DQ
o 903 families without a homozygous parent.
o 300 HBDI families
? Countries participating: Australia, Brazil, Bulgaria, Germany, Denmark, Egypt, England, Finland, France, India, Israel, Italy, Latvia, Mexico, Netherlands, Norway, Poland, Spain (Pais Basque), Sweden, Turkey, Taiwan, USA.

MICROSATELLITE AND HLA TYPING
Approximately 10,000 samples have been typed for 12 microsatellite markers. Approximately 300 HBDI families were typed for 34 microsatellites with some markers being identical to the ones initially selected by the IHWG. Investigators completed or refined HLA typing when needed. The IHWG Genomics Core Lab supported typing for HLA-DR for selected data sets.

DATA ANALYSIS
Two separate but coordinated teams of Biostatisticians are actively engaged in data analysis. The Dorman/Steenkiste team generated the preliminary analysis presented in the Joint Report, which is schedule for publication in the HLA 2004 book. The report includes data from families with DRB1-DQB1 homozygous parents and homozygous cases and controls. The data suggest that loci centromeric of class II genes and telomeric of HLA-A (as far as HFE) may be involved in T1D susceptibility. One or more loci may also exist between the complement/HSP and TNF/LT genes in the region class III region. More analysis on these data is currently been performed. The Thomson/Valdes team have analyzed the HBDI pedigrees. The analysis performed so far provide evidence that certain DR3 and DR4 haplotypes can be more predisposing than others depending on allelic variation at selected loci. Overall, the results support the hypothesis that other loci within the HLA region, in addition to DR and DQ, contribute to T1D susceptibility. The results of these analysis are scheduled to be published in the HLA 2004 book or are being included in manuscripts in preparation.

CURRENT PLANS
The T1D Component of the 13th IHWG will continue to operate until the summer of 2005 with funding support from the NIH. The main activities planned are:
1. To perform in depth analysis of the data produced so far:
a. Full analysis of the 13th IHWG data sets
b. Analysis of HBDI data
c. Analysis of the combined 13th IHWG family data and HBDI family data
d. An analytical description of extended haplotypes and linkage disequilibrium between microsatellite markers and HLA Class I and II alleles.
e. Analysis of individual data sets in collaboration with participating investigators
2. To complete/expand capturing of available genetic/phenotypic data for submission to dbMHC
3. To stimulate participation, input and suggestions from participating investigators, including suggestions for the design and utilization of dbMHC
4. To complete and expand HLA and microsatellite typing on selected data sets (most informative ones, ongoing)
There is now an opportunity to continue studying the role of HLA complex genes in T1D and include additional cohorts representing racial and ethnic diversity. Further collaborative studies could be organized and build on what has been done so far.

Contact: Alberto Pugliese

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