Several studies have indicated that additional genes in the major histocompatibility complex
(MHC) region, other than the class II genes HLA-DQB1 and -DRB1 (the IDDM1 locus), may
contribute to susceptibility and resistance to type 1 diabetes. The relative magnitude of these non-
DR/DQ effects is uncertain and their map location is unknown owing to the extraordinary linkage
disequilibrium that extends over the 3.5 Mb of the MHC. The homozygous parent test has been
proposed as a method for detection of additional risk factors conditional on HLA-DQB1 and -DRB1.
However, this method is inefficient since it uses only parents homozygous for the primary disease
locus, the DQB1-DRB1 haplotype. To overcome this limitation, Conditional ETDT was used in the
present report to test for association conditional on the DQB1-DRB1 haplotype, thereby allowing all
parents to be included in the analysis. First, we confirm in UK and Sardinian type 1 diabetic families
that allelic variation at HLA-DRB1 has a very significant effect on the association of DQB1 and vice
versa. The Conditional ETDT was then applied to the HLA TNF (tumour necrosis factor) region and
microsatellite marker D6S273 region, both of which have been reported to contribute to IDDM1
independent of the HLA-DQB1-DRB1 genes. We found no evidence for a major role for either of these
two regions in IDDM1.