HLA-DQ2 second-domain polymorphisms may explain increased trans-associated risk in celiac disease and dermatitis herpetiformis.

Sequence polymorphism in the DQ2 beta chain was investigated in 80 Caucasoid patients with CD, 23 patients with DH, and 64 healthy controls. A set of amplification primers were designed to amplify a 281-bp region between amino acids 95 and 135 encoding the second domain of the DQ beta chain gene. A polymorphism at amino acid 135 was shown to distinguish DR3 and DR7 haplotypes. Two SSO probes were designed to identify amino acid sequences (133-135) RND (DR3-DQ2) and RNG (DR7-DQ2). To establish whether polymorphism existed elsewhere in the second-domain sequence, which could explain the migratory characteristics of the CD-associated DR3-DQ2 beta-chain reported by Roep et al. DQB1 second-domain PCR products were sequenced from the genomic DNA of three CD patients. The results showed that the polymorphism at amino acid 135 distinguishing DR3 and DR7 haplotypes was present in CD, DH patients, or normal controls of the appropriate DR and DQ genotypes by oligonucleotide hybridization. Cloning and sequencing of DQB1 second domains of three CD patients (two DR3,3 and one DR3,7) gave normal sequences expected from their genotypes. No specific polymorphism of DQB1 second domains on CD-associated DR3 haplotypes distinguishes them from normal DR3 haplotypes. We conclude that individuals positive for the DR3,7 genotype have the potential to express a unique trans-encoded heterodimer with enhanced ability to predispose people to CD.