HLA A1-B8-DR3-DQ2
Encyclopedia
HLA A1-B8-DR3-DQ2 haplotype (Also: AH8.1, COX, Super B8, ancestral MHC 8.1 or 8.1 ancestral haplotype) is a multigene haplotype that covers a majority of the human major histocompatibility complex
on chromosome 6 (not to be confused with the HLA-DQ
heterodimer DQ8.1
). A multigene haplotype is set of inherited alleles 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:
Although there are many other gene-alleles within the haplotype. The haplotype contains more than 250 coding loci that produce transcripts.
At 4.7 million nucleotide
s in length, A1::DQ2 is the second longest haplotype identified within the human genome
. A1::DQ2 creates a conundrum for the evolutionary study of recombination. 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.
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. 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.
s, 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.
of chromosome 6's shorter arm. AH8.1 extends past the 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).
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.
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.
in 1973 and dermatitis herpetiformis in 1976 . 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. 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.
. With the discovery of DR3, the linkage was extended to DR3 and subsequently to DQ2-DP4. While HLA A*0101, Cw*0701, and DPB1*0402 are linked to disease, the strongest association locates between B8 and DR3-DQ2, or the B8::DQ2 subregion. Other genes in the region, C4A
-null and TNF
may associated with autoimmune hepatitis
The appearance of anti-nuclear antibodies in autoimmune hepatitis was found to correlated with A1-B8-DR3. One of the problems with autoimmune hepatitis is there is an increased risk in coeliac disease. Primary biliary cirrhosis which often follows chronic active hepatitis is linked to "DRw3", DR3, gene. Celiac disease is often increased in autoimmune hepatitis and vice 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. This could indicate an association with subclinical 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.
Studies of sporadic inclusion body myositis indicate association with A1:DQ2 haplotype.
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.
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
on chromosome 6 (not to be confused with the HLA-DQ
HLA-DQ
HLA-DQ is a cell surface receptor type protein found on antigen presenting cells. DQ is an αβ heterodimer of the MHC Class II type. The α and β chains are encoded by HLA-DQA1 and HLA-DQB1, respectively. These two loci are adjacent to each other on chromosome 6p21.3. Both the α-chain and β-chain...
heterodimer DQ8.1
HLA-DQ8
HLA-DQ8 is a human leukocyte antigen serotype within the HLA-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....
). A multigene haplotype is set of inherited alleles 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
Genetic recombination
Genetic recombination is a process by which a molecule of nucleic acid is broken and then joined to a different one. Recombination can occur between similar molecules of DNA, as in homologous recombination, or dissimilar molecules, as in non-homologous end joining. Recombination is a common method...
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 loci that produce transcripts.
At 4.7 million nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
s in length, A1::DQ2 is the second longest haplotype identified within the human genome
Human genome
The human genome is the genome of Homo sapiens, which is stored on 23 chromosome pairs plus the small mitochondrial DNA. 22 of the 23 chromosomes are autosomal chromosome pairs, while the remaining pair is sex-determining...
. A1::DQ2 creates a conundrum for the evolutionary study of recombination. 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.
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
HLA DR3-DQ2
HLA DR3-DQ2 is double serotype that specifically recognizes cells from individuals who carry a multigene HLA DR, DQ haplotype.Certain HLA DR and DQ genes have known involvementin autoimmune diseases. DR3-DQ2, a multigene...
with known associations to autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
, other factors within A1::DQ2 are believed to also contribute to autoimmune disease. 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 chromosomeChromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
s, 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.
Structure
A1::DQ2 is 4,731,878 nucleotides in length. The haplotype begins before the locus approximately 28.8 million nucleotides from the telomereTelomere
A telomere is a region of repetitive DNA sequences at the end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos "end" and merοs "part"...
of chromosome 6's shorter arm. AH8.1 extends past the 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 hundreds of years ago.Resistance to recombination
A1::DQ2 is found in Iceland, PomorsPomors
Pomors or Pomory are Russian settlers and their descendants on the White Sea coast. It is also term of self-identification for the descendants of Russian, primarily Novgorod, settlers of Pomorye , living on the White Sea coasts and the territory whose southern border lies on a watershed which...
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
Neolithic
The Neolithic Age, Era, or Period, or New Stone Age, was a period in the development of human technology, beginning about 9500 BC in some parts of the Middle East, and later in other parts of the world. It is traditionally considered as the last part of the Stone Age...
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
Younger Dryas
The Younger Dryas stadial, also referred to as the Big Freeze, was a geologically brief period of cold climatic conditions and drought between approximately 12.8 and 11.5 ka BP, or 12,800 and 11,500 years before present...
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. 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.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.In organ transplantion
A1::DQ2 was at the forefront of histocompatibility science, A1 was the first numerical antigen HL-A1 identified in the late 1960s. 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.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 diseaseCoeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
in 1973 and dermatitis herpetiformis in 1976 . 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. 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 present 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. However, in a larger sample the risk association was found closer to "HL-A8" (Current name: HLA-B8). This association later migrated to the "B8-DRw3" (Current: B8-DR3) region. 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 involvement of other B8-DR3 gene-alleles in disease. 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. Later it was found that both DQ2.5 and DQ2.2(A DQ haplotype of DR7-DQ2) were positively associated with disease. 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. 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 hepatitisAutoimmune hepatitis
Autoimmune Hepatitis is a disease of the liver that occurs when the body's immune system attacks cells of the liver. Anomalous presentation of human leukocyte antigen class II on the surface of hepatocytes, possibly due to genetic predisposition or acute liver infection, causes a cell-mediated...
. With the discovery of DR3, the linkage was extended to DR3 and subsequently to DQ2-DP4. While HLA A*0101, Cw*0701, and DPB1*0402 are linked to disease, the strongest association locates between B8 and DR3-DQ2, or the B8::DQ2 subregion. Other genes in the region, C4A
C4A
Complement C4-A is a protein that in humans is encoded by the C4A gene.-Further reading:...
-null and TNF
Tumor necrosis factors
Tumor necrosis factors refers to a group of cytokines family that can cause cell death . The first two members of the family to be identified were:...
may associated with autoimmune hepatitis
The appearance of anti-nuclear antibodies in autoimmune hepatitis was found to correlated with A1-B8-DR3. One of the problems with autoimmune hepatitis is there is an increased risk in coeliac disease. Primary biliary cirrhosis which often follows chronic active hepatitis is linked to "DRw3", DR3, gene. Celiac disease is often increased in autoimmune hepatitis and vice 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
Autoimmune hepatitis
Autoimmune Hepatitis is a disease of the liver that occurs when the body's immune system attacks cells of the liver. Anomalous presentation of human leukocyte antigen class II on the surface of hepatocytes, possibly due to genetic predisposition or acute liver infection, causes a cell-mediated...
had coeliac associated HLA-DQ (DQ2, DQ8), of these half had anti-transglutaminase antibodies
Anti-transglutaminase antibodies
Anti-transglutaminase antibodies are autoantibodies against the transglutaminase protein. Antibodies serve an important role in the immune system by detecting cells and substances that the rest of the immune system then eliminates. These cells and substance can be foreign and also can be producd...
, but few had endomysial antibody. This could indicate an association with subclinical 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.
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. 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. 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. Linkage could not be extended to HLA-DPB1 locus. Outside of Europe the DRB1*0301 and DR3-DQ2 loci have been linked to disease independently of A1::DQ2 haplotype. DR3 is found to correlate with anti-Ro/La antibodies in SLE.In inclusion body myositis
HLA-DR3 has been consistently observed at high frequencies in inclusion body myositis in caucasians. DR3 was found to correlate also with Jo-1 antiboidy presence.Studies of sporadic inclusion body myositis indicate association with A1:DQ2 haplotype.
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.