Confirmation of the DRB1-DQB1 loci as the major component of IDDM1 in the isolated founder population of Sardinia

There is considerable uncertainty and debate concerning the application of linkage disequilibrium (LD) mapping in common multifactorial diseases, incl uding the choice of population and the density of the marker map. Previousl y, it has been shown that, ih the large cosmopolitan population of the UK, the established type 1 diabetes IDDM1 locus in the HLA region could be mapp ed with high resolution by LD. The LD curve peaked at marker D6S2444, 85 kb from the HLA class II gene DQB1, which is known td be a major determinant of IDDM1. However, given the many unknown parameters underlying LD, a valid ation of the approach in a genetically distinct population is necessary. In the present report we have achieved this by the LD mapping of IDDM1 in the isolated founder population of Sardinia. Using a dense map of microsatelli te markers, we determined the peak of LD to be located at marker D6S2447, w hich is only 6.5 kb from DQB1. Next, we typed a large number of SNPs defini ng allelic variation at functional candidate genes within the critical regi on. The association curve, with both classes of marker, peaked at the loci DRB1-DQB1. These results, while representing conclusive evidence that the c lass II loci DRB1-DQB1 dominate the association of the HLA region to type 1 diabetes, provide empirical support for LD mapping.