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 + Serotype recognition of some DQB1*03 allelesAllele Query Form IMGT/HLA - European Bioinformatics Institute DQB1* DQ8 Sample allele % % % size (N) 66 6687 8 111 34 70 Alleles link-out to IMGT/HLA Databease at EBI + Select list of HLA DQB1*0302 frequencies freq ref. Population (%) Guatemala Mayans48.1 Mexico N.Leon Mestizos22.5 USA South Texas Hispanics20.6 Sweden18.7 Russia Siberia Negidal18.6 Russia Murmansk Saomi18.5 Jordan Amman17.8 Samoa17.2 England Caucasoid16.4 Finland15.7 France14.5 Japan Central10.8 Greece Crete9.2 Spain Basque Arratia Valley6.7 Algeria Oran6.6 China Beijing and Xian6.1 Ethiopia Amhara5.6 USA SE African American4.9 USA Alaska Yupik Natives3.8 India North Hindus3.0 Zimbabwe Harare Shona2.2 Russia Siberia Eskimos0.9 Rwanda Kigali Hutu and Tutsi0.5 PNG Eastern Highlands Goroka0.0 Tunisia Jerba Berber0.0 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 haplotypes in Caucasian Americans Freq Serotype cis-isoform % rank DQ8 α3-β8 9. 626th ♠ 0. 93 ♠DQA1*0302 & *0303 not resolved
DQ8 is determined by the antibody recognition of β8 and is complicated by the fact that DQ8 recognizes some HLA-DQB1 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 and DQB1, respectively.
DQB1*0302 + HLA DQB1*0305 frequencies freq ref. Population (%) Lebanon Kafar Zubian5.9 Lebanon Niha el Shouff2.5 Lakota Sioux2.1 Tunisia2.0 Lebanon Yuhmur1.8 Guatemala Mayans1.5 Morocco1.0 Pakistan1.0 Saudi Arabia Guraiat and Hail0.8 China Lijiang Naxi0.7 Russia Chuvash0.6 Tunisia Matmata Berber0.6 Czech Republic0.5 India Delhi0.5 DQB1 and is found most often in the haplotype DQA1:DQB1, about 10% of the time it is found in the haplotype DQA1:DQB1. DQB1*0302 are almost always linked to DR4, DRB1, , and in caucasians. The first and third DRB1 are most strongly associated with rheumatoid arthritis.
DQB1*0305 DQB1 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 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 alleles(2) occur over the majority of the population, DQ8.1 is the overwhelming majority cis-isoform of DQ8. A rare haplotype DQA1:DQB1 is detected below 1% of all DQ8 haplotypes in Asia and Mesoamerica. Another rarer haplotype, DQA1:DQB1
DQ8.1 DQA1*03:DQB1*0302 haplotype frequencies in the Americas(given as frequency in %)ReferenceDQA1DQB1Estimated Population *03 *0302 DQ8.1 Lacandon Mayan(Mexico) 79.0 77.9 77.9 Perija-Yucpa(Venezuela) 74.0 75.0 74.9 Mayan(Guatemala) 48.1 47.6 Mazatecans(Mexico) 48.5 48.5 47.5 Lamas(Peru) 45.2 44.7 Dakota Sioux(S. Dakota) 52.1 45.0 44.5 Mixtec(Oaxaca, Mexico) 40.0 35.9 35.4 Lakota Sioux(S. Dakota) 25.7 25.5 Terena(Brazil) 17.5 17.0 Cauc., San Antonio(USA) 11.7 11.7 Caucasian(USA) 18.5 10.5 10.5 African American(SE. USA) 4.9 4.5 Tlinglet(Alaska, USA) 14.0 8.5 8.5 Eskimo(Alaska, USA) 3.8 3.8Canoncito Navajo(NM, USA) 6.3 3.5 3.5 Eskimo(E. Greenland) 0.0 0.00.0
DQA1:DQB1 (DQ8.1) is the most common DQ8 subtype representing over 98% of the DQ8 bearing population. Infrequently, DQA1:DQB1, but this substitution of the alpha chain, DQA1* versus , 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.
+ DQA1*03:DQB1*0302 levels in Asia(given as frequency in %)ReferenceDQA1DQB1Estimated Population *03 *0302 DQ8.1 Nivkhi(NNE. Sakalin I.) 0.0 0 and 2. Zorastra, Yadz(Iran) 20.8 0.8 0.8 and 2. Khoton(Mongolia) 24.4 1.2 1.2 Madang(Papua New Guinea) 1.5 1.5 1.5 and 2. Yao(China) 2.6 2.6 and 2. Naxi(Lijiang, China) 2.7 2.7 Ainu(Japan) 3.0 3.0 and 2. Shandong Han(China) 3.1 3.1 Four references:1., 2., 3., and 4. Khalkha(Mongolia) 22.3 6.1 6.1 Thais 21.5 7.4 7.4 and 2. Ket, Yenisey(Siberia) 14.7 8.4 8.4 South Korea 10.3 10.3 Japanese 10.8 10.8 and 2. Nganasan(Siberia) 39.6 11.4 11.4 and 2. Uygars, Ürümqi (China) 21.9 11.4 11.4 Kazakh 11.4 11.4 and 2. Negidal(Siberia) 50.0 18.6 18.6 Cook Isl.(Pacific) 25.0 25.0
Abundance in Asia Hiatus of DQ8 in the NE Siberian Arctic, Elevated Levels in Amur Region and Eastern Turks
The levels of DQ8 in SW to West Pacific Rim are at variable haplotype frequencies, from 2 to 30%, and level off around 10% for Ryūkyūan, Japanese, Koreans, Amur Regions and in the NW Pacific Rim drop to less than 1% in the Nivkhi. There is a modern hiatus of DQ8 in the Alaska-Eastern Siberian region and it is unclear whether this is due to replacement, selection, or the mode in which first Americans arrived (i.e. strictly maritime route). The DR types associated with DQ8 are DRB1*0403, *0404, *0406, *0407, *0408, and *0401 is split between many DQA1:B1 haplotypes. DQB1*0405 is commonly associated with DQA1*0303:DQB1*04 and so it is not included in DRB1*0401 in high resolution assessments. The Cook Island DQ8 had only one associated DR haplotype suggesting diversity limiting introduction into the region, either via the TW-(Japan/Korea/China) route or through the west, for example the Bunun have high DRB1*0403. The majority of DRB1*04 appear to have redistributed from eastern Asia from an unknown source, possibly in Central Asia or India. The distribution can be compared with Native Groups such as South Americans. Three groups with high levels, the Kogui, Sikuni, and Yucpa, have about 75% DQ8, the dominant DRB1* allele in 2 of 3 is the *0411 (N. China = 0), but *0407 (Ryūkyū, Japanese, Mansi-Eastern Ural, Naxi Chinese) and *0403 (Nganasan, Buryat, Negidal, Tunisians, Ryūkyū, Korea, Ainu) are also found. In North America DRB1*0404 and *0407 are more common than *0403 and, in the Lakota Sioux, B1*0411 is rare. The DRB1*0404-DQ8 haplotype is more common in North Western Asia, and Northern Europe.
+ DQA1*03/DQB1*0302 levels in Europe, Middle East and Africa(given as frequency in %)ReferenceDQA1DQB1Estimated Population *03 *0302 DQ8.1 and 2. Nenets (N. Russia) 40.9 20.9 20.0 and 2. Murmansk Saomi(Russia) 38.3 18.5 17.2 and 2. Arkhange Pomors(Russia) 22.6 17.1 16.4 and 2. Swedish 24.2 18.7 16.1 and 2. Caucasian(England) 23.7 16.4 15.9 and 2. Finland 15.7 15.2 France's CEPH 21.3 14.5 13.5 and 2. Dane 20.9 13.2 13.2 Dutch 11.2 11.0 Irish 10.6 and 2. NW Slavic (Russia) 16.0 11.0 10.5 German 10.5 9.9 Russian 8.9 7.2 Cantabarian(Spain) 19.3 8.4 7.0 Spanish 8.9 6.5 Sardinian 4.9 4.9 Italian 4.6 4.5 United Arab Emirates 0.83 0.8 Jordan 24.1 17.9 17.9 Africa !Kung 36.7 36.7 Khoi 14.9 13.9 Oromo 17.5 9.0 9.0 Morocco 17.2 8.9 8.6 Tunisia 10.31 10.0 8.0 Amhara 11.2 5.6 5.6 Aka pygmies 3.2 3.0 Negroid(N. Africa) 3.12.7 Cameron 11.5 1.5 1.2 Bantu Congo 0.6 0.5 Gabonese 7.5 0.5 Bubi 17.5 0.0 0.0
High levels of DQ8 in Northern Europe DQ8 is also abundant also in Northern Europe and is found at high frequencies in the German-Scandinavian-Uralic population north of Switzerland. HLA A-B haplotypes suggest that a migration from people east of the Urals is responsible for DQ8, possibly from as far east as the West Pacific Rim. The high level of DQ8 and DQ2.5 is something of great interest for DQ mediated diseases of Scandinavia and Northern Europe. DQ8 is also found in Iberia and places where east to west gene flow by other genetic markers cannot be substantiated, and the levels within the African or Middle Eastern population are possible sources, Iberia has considerable A1/B1 equilibration suggesting independent sources from Africa.
Global spread of DQ8