Results of the MHC Fine Mapping Workshop

Abstract

Type 1 diabetes (T1D) is strongly clustered in families, with an overall sibling risk ratio (λS) of approximately 15. One region (comprised of multiple loci) that contributes greatly to the familial clustering of T1D is the Major His tocompatibility Complex (MHC) on chromosome 6p21. The locus-specific sibling risk ratio (λS) of the MHC region is approximately 3, thereby contributing as much as 40% to the observed familial clustering. Genetic, functional, structural and model studies all suggest that the human leucocyte antigen (HLA) class II genes (HLA-DRB1 and HLA-DQB1) are the major determinants of T1D risk in the MHC region. Despite the recognized effect of HLA class II genes on risk, it is not clear what contributions other genes in this region may make. The Type 1 Diabetes Genetics Consortium (T1DGC) launched an initiative to more comprehensively examine the genetic basis of T1D in the extended MHC region encompassing 4 Mb (between 29 and 34 Mb). Characterization of genes in this region used classical HLA genotyping and a framework map of 66 microsatellite markers and over 3000 single nucleotide polymorphisms (SNPs) in 2321 affected sib-pair families. The reports in this Supplement, sponsored by the T1DGC, reflect multiple analytic approaches applied to a common set of data. Analyses of individual SNPs as well as haplotypes in the region have been performed and have incorporated the effect of the classical HLA class II gene contributions.