HLA-DQ8

Certain HLA-DQ isoforms are more commonly associated with certain autoimmune diseases. DQ8 stands out because of its association with Juvenile diabetes, Coeliac Disease. It is also linked to HLA-DR alleles that are implicated in rheumatoid arthritis and may increase risk. HLA-DQ is not spread uniformly and certain populations are at increased risk; however that risk is often dependent on environment (Triticeae glutens consumption) and increasing prevelance of some diseases may be the result of shifts of individual from low-risk environments to higher risk environments.

HLA DQ8 is the serotypic representation of an DQA1 :DQB1 haplotype. DQ8 represents the haplotypes DQA1*0301:DQB1*0302, DQA1*0302:DQB1*0302, or DQA1*0303:DQB1*0302 haplotypes. These haplotypes are associated with some of the most common autoimmune disease known. It is relatively abundant in western hemisphere. DQ8 is an ambiguous designation but the isoforms encoded by DQA1 are functionally equivilent. The more frequent of the 3 haplotypes is DQA1*0301:DQB1*0302 and represents about 80% of the global DQ8. Since old typing studies of DQA1*0302 = DQA1*0302 + DQA1*0303, the relative abundances of DQA1*0302:DQB1*0302 and DQA1*0303:DQB1*0302 are unclear. These three haplotype form that useful subgroup called DQ8.1

DQ8.1 can be identified solely with DQB1*0302 with two rare exceptions, DQA1*05/DQB1*0302 and DQA1*0401:DQB1*0302, that are found in the Americas.

DQ8 serotype is primarily represented by the DQA1*0301:DQB1*0302 haplotype.

DQ8 distribution
DQ8 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 primary areas of haplotype elevation, 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 freqeuncy 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.

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 Souix, B1*0411 is rare. The DRB1*0404-DQ8 haplotype is more common in North Western Asia, and Northern Europe.

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 were 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 equilbration suggesting independent sources from Africa.

Global Spread of DQ8
DQ8 along with a few other Haplotypes appears to be split NW/SE in Eurasia and with the evidence for DQ2.5 and other haplotypes suggest an ancient Central Asian population was displaced by a more recent African migration. There are many common markers found in France, Germans, Danes, Swedes, Tibetians, Amur River, Japanese and Koreans that are potential indicators of this bilateral spread. The DQ8 haplotypes is found at high frequencies in the !kung, albiet one expects more DQ8 in austronesia it is ubiquitously spread if at some times low frequencies, other times higher frequencies (Thai). The path of DQ8 spread to the New World is enigmatic, certainly Japan and Amur River are potent sources, but other displaced populations cannot be ruled out. If the mode of travel was through the Beringia corridor as proposed by archaeologist, the very low frequency of DQ8 at present is a very unusual find with regard to evidence for complete displacement elsewhere in the World. Markers that are shared between Japanese, Tw-aboriginals tend to decline in frequency as one approaches Siberia, mtDNA markers decline in the Kuril chain. During the Jōmon period of Japan it appears there would have been displacement by Ninhvet/Ainu ancestors and depression of DQ8 through out northern Japan, but the decline throughout the region is somewhat inexplicable outside of a catastrophic climate event between the settling of the New World and the current time. An alternative model is that there were multiple sources of DQ8 in the peopling of NE asia, some sources were from central asia and some from the indochinese region, some of the DQ8 found in NW eurasia could be from an admixture of West pacific Rim and Central asian sources, and were displaced from the more central regions but not from the more Eastern regions.

DQ8 and Selection
Like DQ2.5, DQ8 might have been under selection for maritime, coastal foraging peoples and in particular for peoples adapted to the climate/habitat situation on the northern end of the habitable west pacific rim at the Last Glacial Maximum. Triticeae cultivation may apply negative selection on DQ8. While there were numerous members of Triticeae species similar to Mid Eastern wild Triticeae in the Americas, and a great number of domesticated plants in the new world, no single species of Triticeae appears to have been domesticated in the New World, and no clear examples in closely related tribes of grasses. Amoung new world grass species in post columbian times, one species of Elymus has been domesticated for human consumption and another as a pastoral cultivar. This could be interpreted in 2 ways. First, that levels of DQ8, negatively, inhibited the domestication of Triticeae strains. Second, that the absence of such cultivars more suitable than already developed cultivars allowed DQ8 to rise or remain high, while DQ2.5 levels in NW under much longer term selection have fallen, or a little of both. Most of American cultivars were domesticated south of the Rio Grande river (exceptions are Caddo rice and Texas varigated squash, etc.). Wheat, particularly Barley and Rye are preferential cultivars in cooler climate, whereas Zea is more adaptive in tropical climates and some cultivars are relatively drought tolerant, Zea however lacks certain amino acids that must be supplimented by other foods to prevent malnutrition. The proximity of neolithization to the Equator in the New World may have much to do with the unapparent negative selection of DQ8 relative to the neolithization of Western Eurasia.

DQ8 and Disease
In the United States, however there appears to be shift in autoimmune disease risk for immigrants from Mexico. Increased immunoreactivity of Hispanics in Houston appear to be associated with DQ8 and not DQ2.5. One of the issues is whether Triticeae and other dietary shifts are involved, or, to rephrase, the tissue transglutaminase reactivity of Zea is low, but high towards triticeae, milk proteins and meat collagen. Each of these has increased in the post-columbian diet. So that there is at least the potential that damaging factors to the intestines couple with Zea-diet-adapted immune system explains the rise of a percentage diabetes and other autoimmune disease in Hispanics living in the United States.

In Japan DQ3 (DQ7, DQ8, DQ9) is associated with Myasthenia gravis in the early onset female population, though it does not appear DQ8 has the greater role, there are similarities between myastenia gravis in Japan and that detected in the Houston hispanic population, with DQ8 associated with younger females relative to the associations of all other HLA DQ types. Coeliac Disease is on the rise in Japan, and it is clear that dietary shifts are the reason, but, also there is no DQ2.5 in Japan and therefore it is not a risk factor. Diabetes, which was once considered a problem of the wealthy in Japan, but is also on the rise in the general population. The similarities with the Indigeonous Americans cannot be dismissed, because both wheat consumption, beef consumption and milk consumption are on the rise in Japan, but since there is no DQ2.5 the increased risk of late onset and Type I/II is almost eliminated from consideration.

In Europe, DQ8 is associated with Coeliac Disease and Type 1 diabetes has been well established, however since DQ8 is less common than DQ2.5 and since DQ2.5 presents more alpha-gliadin peptides it is more often attributed to Coeliac Disease. Since both DQ2.5 and DQ8 are high in Scandinavia the problem is exaccerbated by enhanced susceptibility of heterozygotes which also applies to increased frequencies of late onset Type I and ambiguous Type I/II diabetes. DQ8 is also found in many indigeonous peoples of Asia, it was detected early on in the Bedoin population of Arabia where DQ2.5 is frequently absent, and in these instances DQ8 is solely associated HLA in Coeliac Disease.

The DR4 linkage
Many disease associated with DQ8 have dual linkage with DR4, and certain DR4 (*0405) have independent and dependent risk association with DQ8, for example with Juvenile diabetes.

Links
Coeliac Disease
 * Coeliac UK (charity)
 * The Celiac Disease Foundation (U.S.)
 * The Celiac Sprue Association (U.S.)
 * National Digestive Diseases Clearinghouse - page on coeliac disease
 * National Foundation for Celiac Awareness (U.S.)
 * University of Maryland Center for Celiac Research

Type 1 Diabetes
 * Children with Diabetes
 * Type 1 Diabetes at the American Diabetes Association