HLA A1-B8-DR3-DQ2

HLA A1-B8-DR3-DQ2

Mgh
haplotype = HLA A1-B8-DR3-DQ2


image_source = HLA region on chromosome 6
chromosome = 6
location = 6p21.3
variable =
alias = "Super-B8", "AH8.1", "ancestral MHC 8.1"
othertype = Serotype
loci1name = Class I
loci1rows = 3
gene1name = HLA-A
gene1var = HAwA|0101
type1var = A1
loci2name =
loci2rows =
gene2name = HLA-C
gene2var = HCwA|0701
type2var = Cw7
loci3name =
loci3rows =
loci3group = 3
gene3name = HLA-B
gene3var = HBA|0801
type3var = B8
loci4name = HLA-DR
loci4rows = 2
gene4name = HLA-DRB1
gene4var = HDR1A|0301
type4var = DR3
loci5name =
loci5rows =
gene5name = HLA-DRB3
gene5var = HDR3A|0101
type5var = DR52
loci6name = HLA-DQ
loci6rows = 2
gene6name = HLA-DQA1
gene6var = HQAA|0501
type6var =
Init7Query = True
loci7name =
loci7rows =
gene7name = HLA-DQB1
gene7var = HQBA|0201
type7var = DQ2
popMax = Western Ireland
freqMax = >11.0%
length = 4700
NumLoci = 311
haplotype1 = DQ2.5
disease1 = Coeliac disease
haplotype2 = DR3-DQ2
disease2 = Juvenile diabetes, Sarcoidosis
haplotype3 = B8::DQ2
disease3 = Autoimmune hepatitis, Primary biliary cirrhosis, Myasthenia gravis, Dermatitis herpetiformis

HLA A1-B8-DR3-DQ2 haplotype (Also: "AH8.1", "COX"cite journal |author=Horton R, Gibson R, Coggill P, "et al" |title=Variation analysis and gene annotation of eight MHC haplotypes: the MHC Haplotype Project |journal=Immunogenetics |volume=60 |issue=1 |pages=1–18 |year=2008 |month=January |pmid=18193213 |pmc=2206249 |doi=10.1007/s00251-007-0262-2 |url=] , "Super B8", "ancestral MHC 8.1"cite journal |author=Rocca P, Codes L, Chevallier M, Trépo C, Zoulim F |title= [Autoimmunization induced by interferon alpha therapy in chronic hepatitis C] |language=French |journal=Gastroenterol. Clin. Biol. |volume=28 |issue=11 |pages=1173–6 |year=2004 |month=November |pmid=15657545 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/MDOI-GCB-11-2004-28-11-0399-8320-101019-ART20] or "8.1 ancestral haplotype") is a multigene that covers a majority of the human major histocompatibility complex on chromosome 6 (not to be confused with the HLA-DQ DQ8.1). A multigene haplotype is set of inherited covering several genes, or gene-alleles, common multigene haplotypes are generally the result of descent by common ancestry (share a recent common ancestor for that segment of the chromosome). Chromosomal recombination fragments multigene haplotypes as the distance to that ancestor increases in number of generations.

The haplotype can be written in an extended form covering the major histocompatibility loci as follows:

HLA A*0101 : Cw*0701 : B*0801 : DRB1*0301 : DQA1*0501 : DQB1*0201 or shorthand A1::DQ2

Although there are many other gene-alleles within the haplotype. The haplotype contains more than 250 coding that produce transcripts.

At 4.7 million nucleotides in length, A1::DQ2 is the second longest haplotype identified within the human genome. A1::DQ2 creates a conundrum for the evolutionary study of . The length of the haplotype is remarkable because of the rapid rate of evolution at the HLA locus should degrade such long haplotypes. A1::DQ2's origin is difficult to trace, suggestions of a common ancestor in Iberia or Africa have been put forward. Although its place of origin is not certain there is agreement that bearers of the European AH8.1 bear a haplotype related by a common descent. A1::DQ2 is the most frequent haplotype of its length found in US Caucasians, ~15% carry this common haplotype.cite journal |author=Maiers M, Gragert L, Klitz W |title=High-resolution HLA alleles and haplotypes in the United States population |journal=Hum. Immunol. |volume=68 |issue=9 |pages=779–88 |year=2007 |month=September |pmid=17869653 |doi=10.1016/j.humimm.2007.04.005 |url=]

Studies indicate that A1::DQ2 prominence is likely due to positive selection in the pre-Neolithic period and isolation in countries were wheat was not a prominent cereal. Outside of DR3-DQ2 with known associations to autoimmune disease, other factors within A1::DQ2 are believed to also contribute to autoimmune disease.cite journal |author=Price P, Witt C, Allcock R, "et al" |title=The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases |journal=Immunol. Rev. |volume=167 |issue= |pages=257–74 |year=1999 |month=February |pmid=10319267 |doi= |url=] Also a dozen inflammatory diseases of the immune system can attribute some risk to the haplotype. Some disease like coeliac disease primarily "associate" with certain genes. While other diseases, like type 1 diabetes may have several, highly different, genes that attribute risk. Still other diseases, like myasthenia gravis have undetermined linkage to the haplotype.

Recombination dynamics

Each person has a unique chromosomes, unless they are identical twins. These unique chromosomes are produced by recombination of each unique chromosome past by each grandparent to each parent. These chromosome chimerize within the reproductive cells of each parent which are then passed to the developing person during fertilization. The recombination that creates these blended chromosomes occurs almost randomly along the length, 1 Morgan per generation. Within 100 generations in humans (about 2100 years in ancient times) one expects a few hundred of these 'blending' events to have occurred across a single chromosome, the average size is 1 centiMorgan (or 1 cM). The average length of these 'haplotypes' are about 1 million nucleotides.

Multigene haplotypes following standard dynamics only exist in robust populations for a short time, the average distance between genes of about 200,000 nts, which means that over 250 generations (~5000 years) one expects 1/2 of adjacent genes to have new gene-alleles, unless the genes are small and very close together. This dynamic can change if the population expands rapidly from a few individuals that lived in isolation as long as other haplotypes are maintained.

A1::DQ2 does not follow the expected dynamics. Other haplotypes exist in the region of Europe where this haplotype formed and expanded, some of these haplotypes also are ancestral and also are quite large. At 4.7 million nucleotides in length and ~300 genes the locus had resisted the effects of recombination, either as a consequence of recombination-obstruction within the DNA, as a consequence of repeated selection for the entire haplotype, or both.

tructure

A1::DQ2 is 4,731,878 nucleotides in length. The haplotype begins before the gene|TRIM27 locus approximately 28.8 million nucleotides from the telomer of chomosome 6's shorter arm. AH8.1 extends past the gene|SYNGAP1 about 33.5 million nucleotides from the telomer. Marked deterioration occurs however after the DQB1 gene at 32.8 million nucleotides. A1::DQ2 is not the longest haplotype, but the longest, HLA A3-Cw7-B7-DR15-DQ6 (A3::DQ6), had already undergone significant recombination and is nearly equal in frequency to HLA A2-Cw7::DQ6 bearing version. In the US Caucasians, 57% of haplotypes with a core component, Cw7-B8, extend from HLA-A1 locus to DQ2 locus. This compares with 25%of Cw7-B7 that extend to A3::DQ6 Of 25 potential genetic recombinants of A1::DQ2, none exceed 10% of the Cw*0702-B*0801 frequency. Two recombinants A24-Cw7~DQ2, A1::B8-DR1-DQ5 are notable. Thus, A1::DQ2 haplotype is both long and shows greater deficiency of recombination (called linkage disequilibrium).

Evolution

The evolution of A1::DQ2 appears to be key to its structure. The haplotype, at 4.7 million nucleotide, exists in a population with other haplotypes which, when combined, exceed A1::DQ2 in frequency. Genetics of recombination in humans suggests that common haplotypes of this length that Cw7-B8 component should be in other haplotypes, Ax-Cw7::DQ2, A1-B8-DRx-DQx, or A1-B8-DR3-DQx (where Ax is not A1, DRx is not DR3, or DQx is not DQ2). For a haplotype of this length the process is fast, 50% loss of the complete haplotype within 500 years. And yet the haplotype is found largely intact in people who settled out of Europe 100s of years ago.

Resistance to recombination

A1::DQ2 is found in Iceland, Pomors of Northern Russia, the Serbians of Northern Slavic descent, Basque, and areas of Mexico where Basque settled in larger numbers. The haplotypes great abundance in the most isolated geographic region of Western Europe, Ireland, in Scandinavians and Swiss suggests that low abundance in France and latinized Iberia are the result of displacements that took place after the Neolithic onset. This implies a founding presence in Europe that exceeds 8000 years. The SNP analysis of the haplotype suggests a potential founding affect of 20,000 years within Europe, though conflicts in interpreting this information are now apparent. The last possible point of a constriction forcing climate was the Younger Dryas before 11,500 calendar years ago, and so the haplotype has taken on various forms of the name, Ancestral European Haplotype, lately called Ancestral Haplotype A1-B8 (AH8.1). It is one of 4 that appear common to western Europeans and other Asians. Assuming that the haplotype frequency was 50% at the Younger Dryas and declined by 50% every 500 years the haplotypes should only be present below 0.1% in any European population. Therefore it exceeds the expected frequency for a founding haplotype by almost 100 fold.

Diet in Evolution

Beyond frequent interpretations of this nature, little more is known as to why the haplotype has not undergone equilibration. The haplotype appears to be recombination resistant, it appears to also have been under positive selection relative to other haplotypes in Europe, although currently disease instances suggest cereal based negative selection is acting. One possible explanation comes from the study of remains of the pre-Neolithic period. Given food selects the haplotype now, might food have also positively selected the haplotype in the past. During the early period of European settlement, what remains of coastal settlements suggests a high marine-based food calorie intake, and, in particular, shellfish. Marine carbon component of Western European diet has declined from the Mesolithic to present, however the haplotype has not undergone equilibration, therefore diet alone cannot explain its resistance to recombination.

Formation

Of the haplotypes mentions above, A24-Cw*0702::DQ2 or A1::B8-DR1-DQ5, none appear to be ancestral to A1::DQ2. An A1::DQ2 appears in India, however its major antigen genes superficially resemble European A1-B8 and it appears to be a homoplastic recombinant from a common DR3-DQ2 ancestor, about 70,000 years ago. Components of the haplotype are found in Europe (Basque have two major haplotypes of DR3-DQ2) and A1-B8 of Indian origin is of very low frequency. In Morocco B8::DQ2, in the Western Sahara A1-B8 haplotype if found and also DQ2.5 is found in high frequency, but not as a single haplotype. In kenya two slightly variant HLA-A and B alleles for an A1-B8 haplotype. One possibility is that peoples from central Asia or the Middle East migrated into Iberia as peoples from Africa crossed into Iberia from the south prior to the Neolithic, recombination occurred resulting in the haplotype, and bearers favorably expanded into Europe prior to the Holocene. Another possibility is that if formed in West Africa, but because it was less selective in African holocene relative to European holocene climate/culture, the haplotype underwent equilibration in N. Africa. One hypothesis supported by frequencies in Iberia and North africa suggest that A1::DQ2 formed from A1::B8-DR7-DQ2 with DR3 bearing source. One possible source is the HLA Cw*1701 : B*4201 : DRB1*0302 (The most common haplotype in African Americans is an extended haplotype) However possible, it would require the introduction of a modified *0505 allele. In addition, the Indian/European branch of DQ2.5 is much older, thus it appears at least 2 major recombinant steps were required to form the haplotype, and after its formation evolution markedly slowed down.

Variants

There is a variant of A1←→B8 found in India.cite journal |author=Kaur G, Kumar N, Szilagyi A, "et al" |title=Autoimmune-associated HLA-B8-DR3 haplotypes in Asian Indians are unique in C4 complement gene copy numbers and HSP-2 1267A/G |journal=Hum. Immunol. |volume= |issue= |pages= |year=2008 |month=July |pmid=18657583 |doi=10.1016/j.humimm.2008.06.007 |url=] This variant carries the different Cw*07 (Cw*0702 is a very ancient allele that differs from Cw*0701 of A1::DQ2). It bears C4A a different DRB3 allele as well as numbers of other differences. This variant likely evolved from A24 or A26-Cw*0702-B*0801-DR3-DQ2 that independently arrived and evolved in India.

Components

Large haplotypes can be thought of as steps between adjacent loci. For example A1-Cw*0701, Cw*0701-B8, B8 to DR3, and DR3-DQ2 are each steps. Each step is a haplotype in its own right, however, the closer two loci are together, the longer it takes recombination to alter the step. Both Cw-B and DR-DQ are close together, A-Cw and B-DR are far apart. As a result components of a haplotype evolve at different paces.

A1-Cw7-B8

Early studies of families across Europe recognized what most HLA associations had already shown, that there is a inherited (genetic) linkage between A1 and B1, this was extended to Cw7 locus.cite journal |author=Hiller C, Bischoff M, Schmidt A, Bender K |title=Analysis of the HLA-ABC linkage disequilibrium: decreasing strength of gametic association with increasing map distance |journal=Hum. Genet. |volume=41 |issue=3 |pages=301–12 |year=1978 |month=April |pmid=649158 |doi= |url=]

And while the level of A-B linkage in general was nowhere near Cw-B linkage, the linkage between A1-Cw7-B8 was reasonably strong.

B8-DR3

The region between and including B8 and DR3 bears a number of genes of interest in the study of human disease. Most important of which is the TNF (tumor necrosis factors) with 3 loci in the region. Starting from B8, immediately followed by the MICA and MICB which stand for MHC I-like chain A and B. These two functional class I molecules are expressed on intestinal interocytes and may have interest in autoimmune disease, they are variable, but the MICA mutants so-far found don't seem to correlate with autoimmune diseases of the GI tract.

HLA DR3-DQ2

DR3-DQ2 is either a known or highly suspect factor in most autoimmune diseases that link to the A1::DQ2 haplotype.

Importance to Medicine

In organ transplantion

A1::DQ2 was at the forefront of histocompatibility science, A1 was the first numerical antigen HL-A1 identified in the late 1960's. HL-A8 the second refined B-serotype to be uncovered became HLA-B8. Because of the frequency of the haplotype, homozygotes are common, about 0.6% if the population, make it useful for making cell lines that can be used to test serotyping antibodies. As a result HLA-A1 and B8 produce some of the best serotyping antibodies. This aided in the proper identification of transplant matches prior to the era of PCR-gene testing.


Mgh
haplotype = B8-DR3
placement = right
chromosome = 6
location = 6p21.3
variable =
alias = "B8-DR3"; "B8-DR3"
"B*0801:DRB1*0301""
othertype = Isoform
loci1name = centomeric Class I region
loci1rows = 3
gene1name = HLA-B
gene1var = B*0801
type1var = B8
loci2name =
loci2rows =
gene2name = MICA
gene2var = [http://www.ebi.ac.uk/cgi-bin/imgt/hla/get_allele.cgi?MICA*00801 *0801]
type2var = MICA5.1
loci3name =
loci3rows =
gene3name = MICB
gene3var = [http://www.ebi.ac.uk/cgi-bin/imgt/hla/get_allele.cgi?MICB*008 *0801]
type3var = MICB24
loci4name = RCCX HVR,
Class III
loci4rows = 5
gene4name = TNFA
gene4var = -
type4var = -
loci5name =
loci5rows =
gene5name = TNFB
gene5var = -
type5var = -
loci6name =
loci6rows =
gene6name = C4A
gene6var = Null
type6var = C4AQ0
loci7name =
loci7rows =
gene7name = C4B
gene7var =
type7var = C4BS
loci8name =
loci8rows =
gene8name = CYP21
gene8var =
type8var =
loci9name = DR Loci
loci9rows = 2
gene9name = HLA-DRB3
gene9var = *0101
type9var = DR52
loci10name =
loci10rows =
gene10name = HLA-DR
gene10var = *0301
type10var = DR3
popMax = Western Ireland
freqMax = >15.0%
length = 1400
NumLoci = -
haplotype1 = B8::DQ2
disease1 = Autoimmune hepatitis, Primary biliary cirrhosis,Juvenile diabetes
haplotype2 = B8::DR3
disease2 = Systemic lupus erythematosus

In coeliac disease & dermatitis herpetiformis

Prior to refined typing for HLA-DQ and DR, the association with HLA-A1 and B8 was identified for coeliac disease in 1973 and dermatitis herpetiformis in 1976 .cite journal |author=Ludwig H, Polymenidis Z, Granditsch G, Wick G |title= [Association of HL-A1 and HL-A8 with childhood celiac disease] |language=German |journal=Z Immunitatsforsch Exp Klin Immunol |volume=146 |issue=2 |pages=158–67 |year=1973 |month=November |pmid=4282973 |doi= |url=] cite journal |author=Reunala T, Salo OP, Tiilikainen A, Mattila MJ |title=Histocompatibility antigens and dermatitis herpetiformis with special reference to jejunal abnormalities and acetylator phenotype |journal=Br. J. Dermatol. |volume=94 |issue=2 |pages=139–43 |year=1976 |month=February |pmid=1252348 |doi= |url=] Because of the haplotype it became possible to identify the genetic risk "even though disease causing genes, a DQ2 haplotype, was 1.3 million nucleotides away".

Aside from the highly studied link between DQ2.5 and coeliac disease, there are additional risk factors on the B8::DQ2 haplotype that increase risk of dermatitis herpetiformis in coeliac disease.cite journal |author=Ahmed AR, Yunis JJ, Marcus-Bagley D, "et al" |title=Major histocompatibility complex susceptibility genes for dermatitis herpetiformis compared with those for gluten-sensitive enteropathy |journal=J. Exp. Med. |volume=178 |issue=6 |pages=2067–75 |year=1993 |month=December |pmid=8245782 |pmc=2191293 |doi= |url=] The involvement of other A1::DQ2 gene-alleles in coeliac disease cannot be excluded, either. For example, MICA and MICB are mhc class 1 genes found expressed in the epithelium of the gut.

In insulin dependent diabetes mellitus

In type 1 diabetes both DR3 and DQ2 appear to play a role. DR3-DQ2.5 can be established to other genes like TNF-305A (TNF2) which may also increase the risk of autoimmune disease in both Coeliac Disease and Type 1 diabetes. In systemic lupus erythematosus (SLE) patients HLA DR3-DQ2.5-C4AQ0, which was strongly associated with SLE (odds ratio [OR] 2.8, 95% CI 1.7-4.5). A more recent paper shows that Inositol triphosphate receptor 3 gene which is ~ 1 million base pairs centromeric from DQ2.5 may also be associated with Type 1 diabetes. In addition the BAT1 and MICB variant is more common in type 1 diabetes when B8 is absent but DR3 is presentcite journal |author=Cheong KY, Allcock RJ, Eerligh P, "et al" |title=Localization of central MHC genes influencing type I diabetes |journal=Hum. Immunol. |volume=62 |issue=12 |pages=1363–70 |year=2001 |month=December |pmid=11756005 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0198-8859(01)00351-2] These studies suggest multiple factors on B8::DQ2 that are possessed by other haplotypes also confer susceptibility to type 1 diabetes. Type 1 diabetes has a risk associated with coxsackie 4B virus, there is a potential for involvement of class I loci, particularly those expressed in the GI tract.

In myasthenia gravis

In 1975, association with "HL-A1,8" (Current name: HLA A1-B8) was confirmed by serological typing of cells from myasthenics.cite journal |author=Hammarström L, Smith E, Möller E, Franksson C, Matell G, Von Reis G |title=Myasthenia gravis: studies on HL-A antigens and lymphocyte subpopulations in patients with myasthenia gravis |journal=Clin. Exp. Immunol. |volume=21 |issue=2 |pages=202–15 |year=1975 |month=August |pmid=1081023 |pmc=1538268 |doi= |url=] However, in a larger sample the risk association was found closer to "HL-A8" (Current name: HLA-B8).cite journal |author=Pirskanen R |title=Genetic associations between myasthenia gravis and the HL-A system |journal=J. Neurol. Neurosurg. Psychiatr. |volume=39 |issue=1 |pages=23–33 |year=1976 |month=January |pmid=1255208 |pmc=492209 |doi= |url=] This association later migrated to the "B8-DRw3" (Current: B8-DR3) region.cite journal |author=Keesey J, Naeim F, Lindstrom J, Zeller E, Herrmann C, Walford R |title=Correlation between acetylcholine receptor antibody titer and HLA-B8 and HLA-DRw3 antigens in myasthenia gravis |journal=Trans Am Neurol Assoc |volume=103 |issue= |pages=188–90 |year=1978 |pmid=757055 |doi= |url=] There are two major DR3 haplotypes in Europe, A1::DQ2 and A30-B18-DR3-DQ2. Linkage with disease could more firmly be attributed to B8::DQ2 portion of A1::DQ2 relative to A30-B18::DQ2, indicating some involvment of other B8-DR3 gene-alleles in disease.cite journal |author=Vieira ML, Caillat-Zucman S, Gajdos P, Cohen-Kaminsky S, Casteur A, Bach JF |title=Identification by genomic typing of non-DR3 HLA class II genes associated with myasthenia gravis |journal=J. Neuroimmunol. |volume=47 |issue=2 |pages=115–22 |year=1993 |month=September |pmid=8370765 |doi= |url=] The association of the B8::DQ2 region is primarily seen in females with age-relative thymic hyperplasia. Later the level of anti-acetylcholine receptor antibodies in disease were found to correlate with B8::DR3.cite journal |author=Naeim F, Keesey JC, Herrmann C, Lindstrom J, Zeller E, Walford RL |title=Association of HLA-B8, DRw3, and anti-acetylcholine receptor antibodies in myasthenia gravis |journal=Tissue Antigens |volume=12 |issue=5 |pages=381–6 |year=1978 |month=November |pmid=85353 |doi= |url=] Later it was found that both DQ2.5 and DQ2.2(A DQ haplotype of DR7-DQ2) were positively associated with disease.cite journal |author=Hjelmström P, Giscombe R, Lefvert AK, "et al" |title=Different HLA-DQ are positively and negatively associated in Swedish patients with myasthenia gravis |journal=Autoimmunity |volume=22 |issue=1 |pages=59–65 |year=1995 |pmid=8882423 |doi= |url=] There remains controversy over whether DR3 or DQ2 confers primary susceptibility to myasthenia gravis. In some studies no association with either has been observed. To segregate disease groups have attempted to further define population to earliest onset (presumbably most susceptibility) and females. In these studies link with B8 was greater than DR3, so that susceptibility moves from class II to Class III or Class I loci.cite journal |author=Price P, Witt C, Allcock R, "et al" |title=The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases |journal=Immunol. Rev. |volume=167 |issue= |pages=257–74 |year=1999 |month=February |pmid=10319267 |doi= |url=] The association with class I would be unusual since T-helper mediated autoantibody production is characteristic of disease, whereas class I mediated cytotoxicity is not. MICA and MICB are intestinally expressed. There are many genes that lie on either side of HLA-B, TNF alpha is over expressed. Closer to DR3, C4A is null in B8-DR3 haplotype.

In autoimmune hepatitis

In 1972, a link between "HLA A1,8" (current:HLA A1-B8) active chronic hepatitis, subsequently B8 better associated with autoimmune hepatitis.cite journal |author=Mackay IR, Morris PJ |title=Association of autoimmune chronic active hepatitis with HL-A1,8 |journal=Lancet |volume=2 |issue=7781 |pages=793–5 |year=1972 |month=October |pmid=4116233 |doi= |url=] cite journal |author=Freudenberg J, Baumann H, Arnold W, Berger J, Büschenfelde KH |title=HLA in different forms of chronic active hepatitis. A comparison between adult patients and children |journal=Digestion |volume=15 |issue=4 |pages=260–70 |year=1977 |pmid=863130 |doi= |url=] With the discovery of DR3, the linkage was extended to DR3 and subsequently to DQ2-DP4.cite journal |author=Donaldson PT, Doherty DG, Hayllar KM, McFarlane IG, Johnson PJ, Williams R |title=Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR4 and A1-B8-DR3 are independent risk factors |journal=Hepatology |volume=13 |issue=4 |pages=701–6 |year=1991 |month=April |pmid=2010165 |doi= |url=] cite journal |author=Manabe K, Donaldson PT, Underhill JA, "et al" |title=Human leukocyte antigen A1-B8-DR3-DQ2-DPB1*0401 extended haplotype in autoimmune hepatitis |journal=Hepatology |volume=18 |issue=6 |pages=1334–7 |year=1993 |month=December |pmid=8244257 |doi= |url=] While HLA A*0101, Cw*0701, and DPB1*0402 are linked to disease, the stongest association locates between B8 and DR3-DQ2, or the B8::DQ2 subregion.cite journal |author=Strettell MD, Thomson LJ, Donaldson PT, Bunce M, O'Neill CM, Williams R |title=HLA-C genes and susceptibility to type 1 autoimmune hepatitis |journal=Hepatology |volume=26 |issue=4 |pages=1023–6 |year=1997 |month=October |pmid=9328330 |doi=10.1002/hep.510260434 |url=] cite journal |author=Underhill JA, Donaldson PT, Doherty DG, Manabe K, Williams R |title=HLA DPB polymorphism in primary sclerosing cholangitis and primary biliary cirrhosis |journal=Hepatology |volume=21 |issue=4 |pages=959–62 |year=1995 |month=April |pmid=7705806 |doi= |url=] cite journal |author=Muratori P, Czaja AJ, Muratori L, "et al" |title=Genetic distinctions between autoimmune hepatitis in Italy and North America |journal=World J. Gastroenterol. |volume=11 |issue=12 |pages=1862–6 |year=2005 |month=March |pmid=15793882 |doi= |url=http://www.wjgnet.com/1007-9327/11/1862.asp] Other genes in the region, C4A-null and TNF may associated with autoimmune hepatitis [cite journal |author=Scully LJ, Toze C, Sengar DP, Goldstein R |title=Early-onset autoimmune hepatitis is associated with a C4A gene deletion |journal=Gastroenterology |volume=104 |issue=5 |pages=1478–84 |year=1993 |month=May |pmid=8482459 |doi= |url=] cite journal |author=Cookson S, Constantini PK, Clare M, "et al" |title=Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis |journal=Hepatology |volume=30 |issue=4 |pages=851–6 |year=1999 |month=October |pmid=10498633 |doi=10.1002/hep.510300412 |url=]

The appearance of anti-nuclear antibodies in autoimmune hepatitis was found to correlated with A1-B8-DR3.cite journal |author=Czaja AJ, Carpenter HA, Santrach PJ, Moore SB |title=Immunologic features and HLA associations in chronic viral hepatitis |journal=Gastroenterology |volume=108 |issue=1 |pages=157–64 |year=1995 |month=January |pmid=7806037 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0016508595000114] One of the problems with autoimmune hepatitis is there is an increased risk in coeliac disease.cite journal |author=Volta U, De Franceschi L, Molinaro N, "et al" |title=Frequency and significance of anti-gliadin and anti-endomysial antibodies in autoimmune hepatitis |journal=Dig. Dis. Sci. |volume=43 |issue=10 |pages=2190–5 |year=1998 |month=October |pmid=9790453 |doi= |url=http://www.kluweronline.com/art.pdf?issn=0163-2116&volume=43&page=2190] Primary biliary cirrhosis which often follows chronic active hepatitis is linked to "DRw3", DR3, gene.cite journal |author=Ercilla G, Parés A, Arriaga F, "et al" |title=Primary biliary cirrhosis associated with HLA-DRw3 |journal=Tissue Antigens |volume=14 |issue=5 |pages=449–52 |year=1979 |month=November |pmid=12731577 |doi= |url=] Celiac disease is often increased in autoimmune hepatitis and vise-versa. Recent studies indicate a more insidious association between gluten sensitivity and autoimmune hepatitis. In one study 65% of patients with end stage autoimmune hepatitis had coeliac associated HLA-DQ (DQ2, DQ8), of these half had anti-transglutaminase antibodies, but few had endomysial antibody.cite journal |author=Rubio-Tapia A, Abdulkarim AS, Wiesner RH, Moore SB, Krause PK, Murray JA |title=Celiac disease autoantibodies in severe autoimmune liver disease and the effect of liver transplantation |journal=Liver Int. |volume=28 |issue=4 |pages=467–76 |year=2008 |month=April |pmid=18339073 |doi=10.1111/j.1478-3231.2008.01681.x |url=] This could indicate an association with enteropathy, or alternatively the result of chronic viral infection which is known to also elevate anti-tranglutaminase antibody. A german study found that risk was more associated with B8 than DQ2, these conflicting results indicate that there are at least two risk associations in the B8::DQ2 region.cite journal |author=Teufel A, Wörns M, Weinmann A, "et al" |title=Genetic association of autoimmune hepatitis and human leucocyte antigen in German patients |journal=World J. Gastroenterol. |volume=12 |issue=34 |pages=5513–6 |year=2006 |month=September |pmid=17006990 |doi= |url=http://www.wjgnet.com/1007-9327/12/5513.asp]

In sarcoidosis

Like these other studies a link between "HL-A1,8" eventually leads to susceptibility close to the DR-DQ locus, Sarcoidosis appears to link to HLA-DR3-DQ2.

In systemic lupus erythromatosus

The "HL-A1,8 phenotype" was found to be associated with severe systemic lupus erythematosus (SLE) (renal and central nervous system involvement) in Caucasian patients.cite journal |author=Goldberg MA, Arnett FC, Bias WB, Shulman LE |title=Histocompatibility antigens in systemic lupus erythematosus |journal=Arthritis Rheum. |volume=19 |issue=2 |pages=129–32 |year=1976 |pmid=1259797 |doi= |url=] Two-point haplotype analysis between TNFB(B*01 allele) and HLA show that the allele is in linkage disequilibrium with HLA-A1, Cw7, B8, C4A(Null), DR3, DQ2.5.cite journal |author=Parks CG, Pandey JP, Dooley MA, "et al" |title=Genetic polymorphisms in tumor necrosis factor (TNF)-alpha and TNF-beta in a population-based study of systemic lupus erythematosus: associations and interaction with the interleukin-1alpha-889 C/T polymorphism |journal=Hum. Immunol. |volume=65 |issue=6 |pages=622–31 |year=2004 |month=June |pmid=15219382 |doi=10.1016/j.humimm.2004.03.001 |url=] The entire haplotype, A1-Cw7-B8-TNFB*1-C4A(Null)-DR3-DQ2, is increased in patients and the genetic susceptibility to SLE cannot be distinquished.cite journal |author=Bettinotti MP, Hartung K, Deicher H, "et al" |title=Polymorphism of the tumor necrosis factor beta gene in systemic lupus erythematosus: TNFB-MHC haplotypes |journal=Immunogenetics |volume=37 |issue=6 |pages=449–54 |year=1993 |pmid=8436420 |doi= |url=] Linkage could not be extended to HLA-DPB1 locus.cite journal |author=Bishof NA, Welch TR, Beischel LS, Carson D, Donnelly PA |title=DP polymorphism in HLA-A1,-B8,-DR3 extended haplotypes associated with membranoproliferative glomerulonephritis and systemic lupus erythematosus |journal=Pediatr. Nephrol. |volume=7 |issue=3 |pages=243–6 |year=1993 |month=June |pmid=8100139 |doi= |url=] Outside of Europe the DRB1*0301 and DR3-DQ2 loci have been linked to disease independently of A1::DQ2 haplotype.cite journal |author=Castaño-Rodríguez N, Diaz-Gallo LM, Pineda-Tamayo R, Rojas-Villarraga A, Anaya JM |title=Meta-analysis of HLA-DRB1 and HLA-DQB1 polymorphisms in Latin American patients with systemic lupus erythematosus |journal=Autoimmun Rev |volume=7 |issue=4 |pages=322–30 |year=2008 |month=February |pmid=18295738 |doi=10.1016/j.autrev.2007.12.002 |url=] DR3 is found to correlate with anti-Ro/La antibodies in SLE.cite journal |author=Christian N, Smikle MF, DeCeulaer K, Daniels L, Walravens MJ, Barton EN |title=Antinuclear antibodies and HLA class II alleles in Jamaican patients with systemic lupus erythematosus |journal=West Indian Med J |volume=56 |issue=2 |pages=130–3 |year=2007 |month=March |pmid=17910142 |doi= |url=]

In inclusion body myositis

HLA-DR3 has been consistently observed at high frequencies in inclusion body myositis in caucasians.cite journal |author=Hirsch TJ, Enlow RW, Bias WB, Arnett FC |title=HLA-D related (DR) antigens in various kinds of myositis |journal=Hum. Immunol. |volume=3 |issue=2 |pages=181–6 |year=1981 |month=October |pmid=6948801 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/0198-8859(81)90055-0] DR3 was found to correlate also with Jo-1 antiboidy presence.cite journal |author=Arnett FC, Hirsch TJ, Bias WB, Nishikai M, Reichlin M |title=The Jo-1 antibody system in myositis: relationships to clinical features and HLA |journal=J. Rheumatol. |volume=8 |issue=6 |pages=925–30 |year=1981 |pmid=6977032 |doi= |url=] Studies of sporadic inclusion body myositis indicate association with A1:DQ2 haplotype.cite journal |author=Price P, Santoso L, Mastaglia F, "et al" |title=Two major histocompatibility complex haplotypes influence susceptibility to sporadic inclusion body myositis: critical evaluation of an association with HLA-DR3 |journal=Tissue Antigens |volume=64 |issue=5 |pages=575–80 |year=2004 |month=November |pmid=15496200 |doi=10.1111/j.1399-0039.2004.00310.x |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0001-2815&date=2004&volume=64&issue=5&spage=575] More recent studies indicate that risk lies solely between B8-DR3 region, this includes 3 class I genes, the class III gene region, and 2 class II genes.cite journal |author=O'Hanlon TP, Carrick DM, Arnett FC, "et al" |title=Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: distinct HLA-A, -B, -Cw, -DRB1 and -DQA1 allelic profiles and motifs define clinicopathologic groups in caucasians |journal=Medicine (Baltimore) |volume=84 |issue=6 |pages=338–49 |year=2005 |month=November |pmid=16267409 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0025-7974&volume=84&issue=6&spage=338]

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