EVIDENCE FOR A PRIMARY ASSOCIATION OF CELIAC DISEASE TO A PARTICULAR HLA-DQ a/ß HETERODIMER

Celiac disease (CD) is a malabsorptive disorder precipitated in genetically susceptible individuals by ingestion ofgluten . A significant part of the disease predisposition maps to the HLA class II region, but the primary HLA association is not known (1) . DR3 seems to be a susceptibility allele together with any other DR allele while DR7 is associated to CD almost only in combination with DR3 or DR5 (2, 3) . The HLA-DR3DQw2 haplotype demonstrates the strongest association to CD (1-5) . We investigated whether DR3DQw2 negative patients might share parts of the genetic information ofthis HLA haplotype but encoded in trans position . When we compared amino acid sequences of different DQa and DQß chains we found that the DQa chain encoded by the DR3DQw2 haplotype is identical to that encoded by DR5DQw7 (6, 7), while the DQß chain of the DR3DQw2 haplotype is identical to that of DR7DQw2 except for a single amino acid difference in the second domain (8, 9 ; Lee, J . S., personal communication) . The pairing of a and ß chains seems to be determined by amino acid residues located in the first domains (10) . Thus, individuals wao are DR5DQw7/DR7DQw2 heterozygous may by transcomplementation express the same (or almost the same) DQ a/0 heterodimers as those formed by DQAl and DQBI genes in cis position on the DR3DQw2 haplotype (see Fig . 1) . As a first step to confirm this hypothesis we typed 94 CD children with synthetic DQA1 and DQB1 allele-specific oligonucleotide (ASO) probes. Here we report that all except one ofthese CD patients carry DQAI and DQB1 genes that may encode the same DQ a/ß heterodimer.