The inter-regional distribution of HLA class II haplotypes indicates the suitability of the Sardinian population for case-control association studiesin complex diseases

We have analysed HLA class II gene-based substructure of the Sardinian popu lation in order to evaluate the possible influence of this parameter in the mapping of common disease loci using association methods. We first examine d the distribution of the HLA-DRB1-DQA1-DQB1 haplotypes in 631 newborns fro m seven different regions of the island, and found that the most frequent h aplotypes were uniformly distributed in all regions, but at frequencies uni que to Sardinia. Other haplotypes, common in other white European populatio ns, are consistently rare or absent across the whole island. Analysis of mo lecular variance (AMOVA) showed a very low degree of genetic differentiatio n between the coastal regions, which have suffered repeated invasions over many years, and the most internal and isolated part of the island. This sug gests that there has been little genetic flow from the various populations that have invaded the island during the last 3000 years and that Sardinia i s a relatively homogeneous population. The validity of these unrelated cont rol HLA haplotype frequencies and our claim of homogeneity were established by demonstrating the near identity of the affected family-based control (A FBAC) HLA haplotype frequencies in 243 type 1 diabetes and 495 multiple scl erosis families from Sardinia and those of the unrelated controls. These re sults indicate that robust case-control studies can be carried out in Sardi nia offering cost efficiency over certain family-based designs.