The primary aim of the HLA and Disease Component of the 13^th IHWC as well of the IDDM Component is to identify additional genes within the HLA complex (other than those already known) with effects on disease susceptibility and resistance. This should be an excellent opportunity to foster collaboration and gain new insight into HLA-encoded predisposition to IDDM.

It is well established that alleles in HLA class II region are associated with various degrees of predisposition to and protection from Type 1, insulin-dependent diabetes mellitus, or IDDM. Both the HLA-DR and -DQ loci appear to greatly influence IDDM risk. However, there is growing evidence that the HLA class II region cannot explain all of the linkage and association between chromosome 6p and IDDM. In particular, there is evidence that HLA class I alleles (HLA-A and HLA-B) modulate disease susceptibility and clinical features. Recent data suggest the presence of an additional IDDM susceptibility gene telomeric to HLA-F. Other reports have provided evidence for another susceptibility locus, independent of HLA class II genes, located near the TNF locus in the class III region. Further characterization of this area is necessary to precisely map this additional susceptibility locus and evaluate how allelic variation at this locus influences IDDM risk.

AIMS
The IDDM Component of the 13^th IHWC aims at confirming and extending the above observations to better characterize the influence of non-class II HLA genes on IDDM susceptibility. We propose to study the regions of interest typing for HLA class I alleles and for microsatellites and single nucleotide polymorphisms (SNPs) in the class III and class I regions. Moreover, given the strong protection associated with the DRB1*1501, DQB1*0602 haplotype but the existence of rare patients with such haplotype, the workshop offers a unique opportunity to make an effort to collect such rare patients and study them with the above methodology.

The study will comprise two main data sets consisting of (1) IDDM families and (2) patients and HLA-class II matched controls:

1. TDT analysis will be performed in families (simplex or multiplex) with at least one parent homozygous for HLA DR/DQ IDDM-associated class II alleles

2. Case-control association studies will be performed in HLA class II matched patients and controls.

As in previous editions of the IHWC, families and case-control pairs will be studied through the collaborative participation of several laboratories throughout the world. The participation of those laboratories previously involved in the IHWC is strongly encouraged, as well as the participation of new laboratories. Those interested in participating should carefully fill out the IDDM-IHWC questionnaire (see below) and send it to the IDDM Component organizers (see below). As of September 1999, 35 laboratories worldwide have accepted to participate in the study. Please see the table for details. A total of 5,778 patients and 3,353 controls, HLA-typed with typing reagents developed during previous HLA Workshops (11^th and 12^th) are already available for the study. According to the information provided by the participating laboratories, more than 2,000 patients and 2,000 controls may become available in the next future as HLA typing is completed on additional patients. Moreover, more patients and controls may be recruited during the course of the study. We have also identified 512 families with at least one parent homozygous for class II DR/DQ alleles for studies involving TDT analysis as described in methods. We are very pleased that many investigators worldwide have accepted to participate in the study, showing to share our enthusiasm for collaborating in our common quest to solve the diabetes problem. Additional groups are welcome to join the study during the next few months. It is planned to close recruitment by February 2,000.

Because a number of participants may not have adequate facilities for microsatellite typing, we have identified a government-subsidized, non-profit typing facility serving as the 13th IHWC Central Laboratory for microsatellite typing. This facility is the National Center for Genotyping (CNG) in Paris, France, directed by Dr. Mark Lathrop. Microsatellite typing will be free to participants since its cost will be covered by a grant we have recently applied for. Of course DNA samples will have to be shipped to the CNG, and precise instructions for shipping and coding samples will be distributed shortly to all participants. Please note that DNA samples will only be used for studies described in the aims of the 13^th IHWC.

IMPORTANT REQUIREMENTS

• Class II (DR/DQ) genotypes, including DRB1*04 subtypes for subject inclusion.
• At least 10 µg of high quality genomic DNA available on each subject, aliquots of which should be stored and available for future use.
• For families, DNA samples on at least the parents and the proband (the first affected child) must be available.
• Availability of data on race, ethnicity, age, age of diabetes onset for all patients.