DQ2 represents the second highest risk factor for coeliac disease, the highest risk is a close family member with disease. Due to its link to coeliac disease, DQ2 has the highest association of any HLA serotype with autoimmune disease, close to 95% of all coeliacs have DQ2, of that 30% have 2 copies of DQ2. Of the DQ2 homozygotes who eat wheat, lifelong risk is between 20 and 40% for coeliac disease. The relationship of DQ2 and coeliac disease, however, is complex because there are multiple DQ2 isoforms. The DQ α5β2 (DQ2.5) isoform is strongly associated with CD. This isoform is partially encoded by the DQB1*02 genes in HLA-DQ2 positive individuals.
DQB1*0201 is genetically linked to
DQA1*0501 forming the
DQ2.5 haplotype that encodes both α5 and β2 subunits. The DQ2.5 haplotype confers the single highest genetic risk for disease, however comparable risk can also come from very similar alleles on different haplotypes. The immunodominant site for DQ2.5 is on α2-gliadin. The site is a protease resistant 33mer that has 6 overlapping DQ2.5 restricted epitopes. This creates very strong binding of T-cells for DQ2.5-33mer complexes. DQ2.5 binds gliadin, but the binding is sensitive to deamidation caused by
tissue transglutaminase. In almost all case the highest affinity sites of gluten are derived by deamidation. The HLA DQB1*0202 and its linked DQA1* alleles (the DQ2.2 haplotype) do not produce the α5 subunit. While the DQ2.2 heterodimer cannot effectively present α-2 gliadin, it can present other gliadins. In at least 1% of coeliacs DQ2.2 confers adaptive immunity to gliadin permitting coeliac disease.
DQ2.5 and gluten As mentioned the DQA1:DQB1 haplotype produces DQ2.5cis which by frequency and efficiency in alpha-gliadin presentation is the major factor in adaptive immunity. The isoform, referred to frequently as
the DQ2 heterodimer or DQ2 (DQA1:DQB1) and more recently DQ2.5 can be differentiated from responses from other DQ isoforms, including other DQ2. Specifically, that this DQ2 heterodimer is responsible for presenting the α2-gliadin that most effectively stimulates pathogenic T-cells. The highest risk for coeliac disease is in Western Ireland and overlaps one of three global nodes of the DQ2.5 haplotype in Western Europe. The DQ2.5 haplotype is linked to DR3 and DR3 is not linked to DQ2.2. Therefore, using either serotyping or genotyping, DQ2.5 can be distinguished from DQ2.2 or DQ2.3. The refined studies of risk and immunology suggest that all DQ2 can mediate coeliac disease, but that DQ2.5 is the primary genetic risk factor. A genome wide survey of markers linked to CD, reveals that highest linkage is for a marker within the DQA1 allele of the DQ2.5 haplotype. The association of DQB1 is almost as high. Greatly elevating risk is the ability of the DQ2.5 haplotype encoded isoforms to increase abundance on the cell surface in DQ2.5 double homozygotes. While most people can form two or four different isoforms of DQ. Double homozygotes (of DQA1 and DQB1) can only form DQ2.5cis. This occurs when a person inherits a DQ2.5cis bearing chromosome from each parent. While the frequency of DQ2.5 haplotype is only 4 times higher than the general population, the number of DQ2.5 homozygotes is 10 to 20 times higher than the general population. Multiple copies of the DQ2.5 haplotype do not cause
apparent increases of severity, DQ2.5/DQ2 increases risk of life-threatening complications and more severe histological findings. Of the approximately 90% of coeliacs that bear the DQ2.5 isoform only 4% produce DQ2.5 by pair alleles from different haplotypes, this isoform is called DQ2.5trans and differs slightly, one amino acid, from DQ2.5cis.
DQ2.2 and gluten DQ2.2 does not produce all the necessary subunits to efficiently present the most pathogenic gluten proteins to the immune system. With the DQ2.2 isoform (DQ α2-β2), polar substitutions (
amino acids such as
asparagine,
glutamine,
glycine,
serine, and
threonine) are not bound well to DQ2.2. The gliadin peptides that bind DQ2.5 are enriched in the amino acid glutamine. Since the β2 provides half the structural information for gluten presentation, other haplotypes might provide the rest. Such haplotypes are known to exist and these haplotypes confer different risk on DQ2.2. DQ2.2 however can present less pathogenic epitopes such as proteolytic peptides of gamma-gliadin. This appears to be the mediator of disease in 1% of coeliacs that are homozygotes for DQ2.2. The
DQ2.2/DQ7.5 phenotype. Also called DQ2.5trans in some publications.
DQ7.5 haplotype is the DQA1:DQB1 haplotype. The DQA1*0505 allele is similar to the DQA1*0501 allele of the DQ2.5 haplotype. When DQA1*0505 or DQA1*0501 gene products are processed to the cell surface they become α5. The gene products of DQB1*0202 and DQB1*0201 are almost identical and function similarly. As a result, one isoform produced by the phenotype of two haplotypes, DQ2.2/DQ7.5, is HLA DQ α5β2. A small percentage of coeliac disease patients have this haplotype. The other 3 isoforms are α2β2(DQ2.2), α2β7 (DQ7.2), and α5β7 (DQ7.5).
DQ2.2/DQ2.5. Random pairing of heterologous DQ alpha and beta isoforms produces 4 different isoforms at 1:1:1:1 ratios. The fraction of DQ2.5 can be 25%. In the case of this
phenotype, HLA DQB1*02 alleles are encoded by both
chromosome 6 (maternal and paternal derived). Since DQB1*0201 and *0202 function similarly, only two types of isoforms can be produced and the ratio becomes 1:1. This increases the random number of isoforms from 25% to 50% that can cause disease, and as a result increases risk of celiac disease and probably increases risk of severe complications such as refractory celiac disease and lymphoma. This fraction of coeliacs is important because they can only produce α2β2 and are useful for determining the role of DQ2.2 in coeliac disease. ==Juvenile diabetes association==