Differential expression of HLA-DQA1 alleles associated with promoter polymorphism

Abstract

 The promoter regions of DQA1 alleles are polymorphic, with some of the nucleotide sequence polymorphisms being located within X and Y motifs essential for the regulation of HLA class II gene transcription. In the present study, we demonstrate that polymorphisms in the promoter regions of three DQA1 alleles influence constitutive and inducible transcription of reporter gene constructs in epithelial, B-, and T-cell lines. Promoter strength in transient transfection assays generally followed a pattern of DQA1 ^* 03011>DQA1 ^* 0101>DQA1 ^* 05011, and was not affected by the endogenous HLA haplotype of the recipient cells. TNFα significantly activated the DQA1 ^* 05011 promoter, but had little effect on the DQA1 ^* 03011 promoter. Mutagenesis of the X and Y motifs of DQA1 ^* 03011 and DQA1 ^* 05011 demonstrated that nucleotide sequence polymorphisms in the Y element had the greatest effect on the promoter strength and differential TNFα inducibility. The finding that alleles of the DQA1 gene differ in promoter strength and responsiveness to TNFα suggests a mechanism for the association of certain alleles of this gene with susceptibility to autoimmune disease.