Effect of linkage status of affected sib-pairs on the search for novel type 1 diabetes susceptibility genes in the HLA complex

Type 1 diabetes susceptibility is influenced by a number of genes, of which those with the strongest effects map to the human leucocyte antigen (HLA) complex. Evidence for linkage of non-HLA genes in several affected sib-pair analyses was increased if the HLA or gender status of the sibs was considered independently. We investigated whether linkage status at the HLA complex differentially affected transmission of alleles to sibs depending on their HLA or gender linkage status. Genotypes of 2437 markers typed on 11 279 individuals from 2363 families, stratified according to HLA and gender, were examined using the transmission disequilibrium test. Several significant single nucleotide polymorphisms (SNPs) loci were found near the class II genes; no significant SNPs were found by these analyses near the class I or class II genes. Other significant effects were found when the gender of the sibs or the parents was considered. There was not a significant difference in HLA-DRB genotypes between the stratified sets. These results suggest the presence of novel recessive susceptibility gene(s) within the HLA complex.