HLA-DQ - Structure, Functions, Genetics - Genetics - Effects of Heterogeneity of Isoform Pairing

Effects of Heterogeneity of Isoform Pairing

As an MHC class II antigen-presenting receptor, DQ functions as a dimer containing two protein subunits, alpha (DQA1 gene product) and beta (DQB1 gene product), a DQ heterodimer. These receptors can be made from alpha+beta sets of two different DQ haplotypes, one set from the maternal and paternal chromosome. If one carries haplotype -A-B- from one parent and -a-b- from the other, that person makes 2 alpha isoforms (A and a) and 2 beta isoforms (B and b). This can produce 4 slightly different receptor heterodimers (or more simply, DQ isoforms). Two isoforms are in the cis-haplotype pairing (AB and ab) and 2 are in the trans-haplotype pairing (Ab and aB). Such a person is a double heterozygote for these genes, for DQ the most popular situation. If a person carries haplotypes -A-B- and -A-b- then they can only make 2 DQ (AB and Ab), but if a person carries haplotypes -A-B- and -A-B- then they can only make DQ isoform AB, called a double homozygote. In coeliac disease, certain homozygotes and are at higher risk for disease and some specific complications of coeliac disease such as Gluten-sensitive enteropathy associated T-cell lymphoma

homozygotes and double homozygotes. Homozygotes at DQ loci can change risk for disease. In mice for instance, mice with 2 copies of the DQ-like Iab haplotype are more likely to progress toward fatal disease compared to mice that are heterozygotes only for the beta allele (MHC IA_αb / IA_αb, IA_βb / IA_βbm12). In humans, celiac disease DQ2.5/DQ2 homozygotes are several times more likely to have celiac disease versus DQ2.5/DQX individuals. DQ2/DQ2 homozygotes are at elevated risk for severe complications of disease. For an explanation of the risk association see:Talk:HLA-DQ#Effects of heterogeneity of isoform pairing-Expanded

Involvement of transhaplotypes in disease
There is some controversy in the literature whether trans-isoforms are relevant. Recent genetic studies into coeliac disease have revealed that the DQA1*05:05:X/Y:DQB1*02:02 gene products explain disease not linked to the haplotype that produces DQ8 and DQ2.5, strongly suggesting the trans-isoforms can be involved in disease. But, in this example, it is known that the transproduct is almost identical to a know cis-'isoform' produced by DQ2.5. There is other evidence that some haplotypes are linked to disease but show neutral linkage with other particular haplotypes are present. At present, the bias of relative isoform frequency toward cis pairing is unknown, it is known that some trans-isoforms occur. see:Talk:HLA-DQ#Effects of heterogeneity of isoform pairing-Expanded