HLA-DQ8 (DQ8) is a human leukocyte antigen serotype within the HLA-DQ (DQ) serotype group. DQ8 is a split antigen of the DQ3 broad antigen. DQ8 is determined by the antibody recognition of β8 and this generally detects the gene product of DQB1*0302. DQ8 is commonly linked to autoimmune disease in the human population. DQ8 is the second most predominant isoform linked to coeliac disease and the DQ most linked to Type 1 Diabetes. DQ8 increases the risk for rheumatoid arthritis and is linked to the primary risk locus for RA, HLA-DR4. DR4 also plays an important role in Type 1 Diabetes. While the DQ8.1 haplotype is associated with disease, there is no known association with the DQB1*0305, DQ8.4 or DQ8.5 haplotypes (see infobox) with autoimmune disease; however, this may be the result of lack of study in populations that carry these and the very low frequency. DQ8.1 also ball right from other HLA in population frequencies. Typically for MHC Class II antigens in humans, haplotype frequencies do not exceed 40%. For example, in the US the highest haplotype frequency, the haplotype that encoded DQ6.2, is around 15%, this translates into phenotype frequencies of less than 30%. Atypically haplotype frequencies exceed 40%. For DQ8 the highest haplotype frequencies approach 80% in parts of Central and South America and the phenotype frequencies approach 90%. This is the highest phenotype frequency observed for any DR or DQ phenotype in the human population by a wide margin.
Serology
Although false reaction with DQB1*0302 is low, the efficiency of the positive reaction is not good and there is a risk of false detection of DQB1*0305 which could create incompatibility. For disease diagnosis and confirmation, there is no known association of DQB1*0305 with either coeliac or autoimmune diabetes. Therefore, it is prudent to use high resolution DQB1 typing for DQ8.
Alleles
DQ8 is determined by the antibody recognition of β8 and is complicated by the fact that DQ8 recognizes some HLA-DQB1*03 encoded isoforms well, partially or not well at all (See serology) DQ β3.2 and β3.5 are best recognized as DQ8. These split antigens are the allele products of the DQB1*0302 and DQB1*0305, respectively.
DQB1*0302
DQB1*0302 and is found most often in the haplotype DQA1*0301:DQB1*0302, about 10% of the time it is found in the haplotype DQA1*0302:DQB1*0302. DQB1*0302 are almost always linked to DR4, DRB1*0401, *0402, and *0404 in caucasians. The first and third DRB1 are most strongly associated with rheumatoid arthritis.
DQB1*0305 DQB1*0305 gene product reacts slightly more intensely with DQ8 than DQ7 its generally rare in Europe and North America, except in a few indigenous populations. Levels of DQB1*0305 are probably higher given earlier tests did not discriminate well between different *03.
Haplotypes DQ8 β-chains combine with α-chains, encoded by genetically linked HLA-DQA1 alleles, to form the cis-haplotype isoforms. There is only one common cis-isoform of DQ8 because the linked DQA1*03 alleles(2) occur over the majority of the population, DQ8.1 is the overwhelming majority cis-isoform of DQ8. A rare haplotype DQA1*0503:DQB1*0302 is detected below 1% of all DQ8 haplotypes in Asia and Mesoamerica. Another rarer haplotype, DQA1*0401:DQB1*0302
DQ8.1
DQA1*0301:DQB1*0302 (DQ8.1) is the most common DQ8 subtype representing over 98% of the DQ8 bearing population. Infrequently, DQA1*0302:DQB1*0302, but this substitution of the alpha chain, DQA1**0301 versus *0302, is outside the binding cleft and appears not to alter DQ8 function. DQ8.1 is found almost ubiquitously in every human regional population, but because of its unique distribution it becomes an object of molecular anthropology. There are 3 places where haplotype frequency is elevated, Central and South America, NE Pacific Rim, and Northern Europe.
High frequencies in the Americas The global node for DQ8 is in Central America and northern South America where it reaches the highest frequency for any single DQ serotype, close to 90% phenotype frequency (77% haplotype frequency), and is at relatively high frequency in the indigenous North American population, and the coastal regions of the Gulf of Mexico and up the Mississippi Valley. The high frequency of DQ8 in South America's northeastern regions and low frequency in Indigenous Americans of more recent Asian ancestry or Siberian origin suggest that DQ8 was at high frequency in the earliest Amerinds. The pattern of distribution is consistent with recent mtDNA results suggesting the first migrants to the New World settled in the lowland coastal regions, river valleys and moved slowly inland, subsequent settlers moved into the highland regions. DQ8 and DQ2.5 have many analogous functional similarities, and this first settler bias may be a reason for the similarity. Studies on Epstein Barr Virus and other proteins suggest both proteins are acidic (meaning peptides with increased negative charge) peptide presenters (see DQ8 for an illustration of the presentation process) and may have been adaptive for certain hunting and gathering lifestyles, possibly coastal foragers.
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