HLA A1-B8-DR3-DQ2

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HLA A1-B8-DR3-DQ2
HLA-mini.png
HLA region on chromosome 6
Nicknames
"Super-B8", "AH8.1", "ancestral MHC 8.1"
Loci
LociGeneAlleleSerotype
Class I HLA-A *0101 A1
HLA-C *0701 Cw7
HLA-B *0801 B8
HLA-DR HLA-DRB1 *0301 DR3
HLA-DRB3 *0101 DR52
HLA-DQ HLA-DQA1 *0501
HLA-DQB1 *0201 DQ2
Nodes
PopulationMaximaWestern Ireland
Freq.Max>11.0%
Size and location
Genes311
Chromosome 6
Location6p21.3
Size (kbps)4700
Associated diseases
Haplotype
(gene)		Disease(s)
DQ2.5 Coeliac disease
DR3-DQ2 Juvenile diabetes, Sarcoidosis
B8::DQ2 Autoimmune hepatitis, Primary biliary cirrhosis, Myasthenia gravis, Dermatitis herpetiformis

HLA A1-B8-DR3-DQ2 haplotype (Also: AH8.1, COX, [1] Super B8, ancestral MHC 8.1 [2] or 8.1 ancestral haplotype [3] ) 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.

Contents

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

There are many other gene-alleles within the haplotype, including more than 250 coding loci that produce transcripts.

At 4.7 million nucleotides in length, A1::DQ2 is the second longest haplotype identified within the human genome. [1] 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. [3] A1::DQ2 is the most frequent haplotype of its length found in US Caucasians, ~15% carry this common haplotype. [4]

Studies indicate that A1::DQ2 prominence is likely due to positive selection in the pre-Neolithic period and isolation in countries where 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. [3] 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 unique chromosomes, unless they are identical twins. These unique chromosomes are produced by recombination of each unique chromosome passed 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. [1] The haplotype begins before the TRIM27 locus approximately 28.8 million nucleotides from the telomere of chromosome 6's shorter arm. AH8.1 extends past the 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 [4] 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, 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 effect 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. [5] 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. [5] 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 an inherited (genetic) linkage between A1 and B1, this was extended to Cw7 locus. [6]

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 do not 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 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.

B8-DR3
Nicknames
"B8-DR3"; "B8-DR3"
"B*0801:DRB1*0301""
Loci
LociGeneAlleleIsoform
centomeric Class I regionHLA-BB*0801B8
MICA *0801 MICA5.1
MICB *0801 MICB24
RCCX HVR,
Class III		 TNFA --
TNFB --
C4A NullC4AQ0
C4B C4BS
Nodes
PopulationMaximaWestern Ireland
Freq.Max>15.0%
Size and location
Genes-
Chromosome 6
Location6p21.3
Size (kbps)1400
Associated diseases
Haplotype
(gene)		Disease(s)
B8::DQ2 Autoimmune hepatitis, Primary biliary cirrhosis, Juvenile diabetes
B8::DR3 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 . [7] [8] 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. [9] The involvement of other A1::DQ2 gene-alleles in coeliac disease cannot be excluded, either. [3] 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 [10] 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. [11] However, in a larger sample the risk association was found closer to "HL-A8" (Current name: HLA-B8). [12] This association later migrated to the "B8-DRw3" (Current: B8-DR3) region. [13] 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. [14] 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. [15] Later it was found that both DQ2.5 and DQ2.2(A DQ haplotype of DR7-DQ2) were positively associated with disease. [16] 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. [3] 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. [17] [18] With the discovery of DR3, the linkage was extended to DR3 and subsequently to DQ2-DP4. [19] [20] 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. [21] [22] [23] Other genes in the region, C4A-null and TNF may be associated with autoimmune hepatitis. [24] [25]

The appearance of anti-nuclear antibodies in autoimmune hepatitis was found to correlate with A1-B8-DR3. [26] One of the problems with autoimmune hepatitis is there is an increased risk in coeliac disease. [27] Primary biliary cirrhosis which often follows chronic active hepatitis is linked to "DRw3", DR3, gene. [28] 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. [29] 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. [30]

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. [31] 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. [32] The entire haplotype, A1-Cw7-B8-TNFB*1-C4A(Null)-DR3-DQ2, is increased in patients and the genetic susceptibility to SLE cannot be distinguished. [33] Linkage could not be extended to HLA-DPB1 locus. [34] Outside of Europe the DRB1*0301 and DR3-DQ2 loci have been linked to disease independently of A1::DQ2 haplotype. [35] DR3 is found to correlate with anti-Ro/La antibodies in SLE. [36]

In inclusion body myositis, polymyositis and dermatomyositis

HLA-DR3 has been consistently observed at high frequencies in inclusion body myositis in caucasians. [37] DR3 was found to correlate also with Jo-1 antibody presence. [38] Studies of sporadic inclusion body myositis indicate association with A1:DQ2 haplotype. [39] 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. [40] Research published in October 2015 by the National Institute of Environmental Health Sciences compared 1,710 cases of either adult- or juvenile-onset myositis, with 4,724 control subjects. They found that multiple genes that make up AH8.1 define the genetic risk for all types of myositis. [41]

See also

Suggested reading

Related Research Articles

<span class="mw-page-title-main">Human leukocyte antigen</span> Genes on human chromosome 6

The human leukocyte antigen (HLA) system or complex is a complex of genes on chromosome 6 in humans which encode cell-surface proteins responsible for regulation of the immune system. The HLA system is also known as the human version of the major histocompatibility complex (MHC) found in many animals.

<span class="mw-page-title-main">HLA-DQ</span> Cell surface receptor protein found on antigen-presenting cells.

HLA-DQ (DQ) is a cell surface receptor protein found on antigen-presenting cells. It is an αβ heterodimer of type MHC class II. The α and β chains are encoded by two loci, HLA-DQA1 and HLA-DQB1, that are adjacent to each other on chromosome band 6p21.3. Both α-chain and β-chain vary greatly. A person often produces two α-chain and two β-chain variants and thus 4 isoforms of DQ. The DQ loci are in close genetic linkage to HLA-DR, and less closely linked to HLA-DP, HLA-A, HLA-B and HLA-C.

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 involvement in autoimmune diseases. DR3-DQ2, a multigene haplotype, stands out in prominence because it is a factor in several prominent diseases, namely coeliac disease and juvenile diabetes. In coeliac disease, the DR3-DQ2 haplotype is associated with highest risk for disease in first degree relatives, highest risk is conferred by DQA1*0501:DQB1*0201 homozygotes and semihomozygotes of DQ2, and represents the overwhelming majority of risk. HLA DR3-DQ2 encodes DQ2.5cis isoform of HLA-DQ, this isoform is described frequently as 'the DQ2 isoform', but in actuality there are two major DQ2 isoform. The DQ2.5 isoform, however, is many times more frequently associated with autoimmune disease, and as a result to contribution of DQ2.2 is often ignored.

<span class="mw-page-title-main">HLA-DQ8</span>

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.

<span class="mw-page-title-main">HLA-DQ2</span>

HLA-DQ2 (DQ2) is a serotype group within HLA-DQ (DQ) serotyping system. The serotype is determined by the antibody recognition of β2 subset of DQ β-chains. The β-chain of DQ is encoded by HLA-DQB1 locus and DQ2 are encoded by the HLA-DQB1*02 allele group. This group currently contains two common alleles, DQB1*0201 and DQB1*0202. HLA-DQ2 and HLA-DQB1*02 are almost synonymous in meaning. DQ2 β-chains combine with α-chains, encoded by genetically linked HLA-DQA1 alleles, to form the cis-haplotype isoforms. These isoforms, nicknamed DQ2.2 and DQ2.5, are also encoded by the DQA1*0201 and DQA1*0501 genes, respectively.

<span class="mw-page-title-main">HLA-DQ5</span>

HLA-DQ5 (DQ5) is a human leukocyte antigen serotype subgroup within HLA-DQ(DQ) serotypes. The serotype is determined by the antibody recognition of β5.x subset of DQ β-chains. The β-chain of DQ is encoded by HLA-DQB1 locus and DQ5 are encoded by the HLA-DQB1*05 allele group. This group currently contains 4 common alleles, DQB1*0501, *0502, *0503, and *0504. HLA-DQ5 and HLA-DQB1*05 are almost synonymous in meaning. DQ5 β-chains combine with α-chains, encoded by genetically linked HLA-DQA1 alleles, to form the cis-haplotype isoforms. These isoforms, are all HLA-DQ1 encoded by the DQA1*01 allele group.

<span class="mw-page-title-main">HLA-DQ6</span>

HLA-DQ6 (DQ6) is a human leukocyte antigen serotype within HLA-DQ (DQ) serotype group. The serotype is determined by the antibody recognition of β6 subset of DQ β-chains. The β-chain of DQ isoforms are encoded by HLA-DQB1 locus and DQ6 are encoded by the HLA-DQB1*06 allele group. This group currently contains many common alleles, DQB1*0602 is the most common. HLA-DQ6 and DQB1*06 are almost synonymous in meaning. DQ6 β-chains combine with α-chains, encoded by genetically linked HLA-DQA1 alleles, to form the cis-haplotype isoforms. For DQ6, however, cis-isoform pairing only occurs with DQ1 α-chains. There are many haplotypes of DQ6.

<span class="mw-page-title-main">HLA-DQ7</span>

HLA-DQ7 (DQ7) is an HLA-DQ serotype that recognizes the common HLA DQB1*0301 and the less common HLA DQB1*0304 gene products. DQ7 is a form of 'split antigen' of the broad antigen group DQ3 which also contains DQ8 and DQ9.

<span class="mw-page-title-main">HLA-DQ1</span> Serotype that covers a broad range of HLA-DQ haplotypes.

HLA-DQ1 is a serotype that covers a broad range of HLA-DQ haplotypes. Historically it was identified as a DR-like alpha chain called DC1; later, it was among 3 types DQw1, DQw2 and DQw3. Of these three serotyping specificities only DQw1 recognized DQ alpha chain. The serotype is positive in individuals who bear the DQA1*01 alleles. The most frequently found within this group are: DQA1*0101, *0102, *0103, and *0104. In the illustration on the right, DQ1 serotyping antibodies recognizes the DQ α (magenta), where antibodies to DQA1* gene products bind variable regions close to the peptide binding pocket.

<span class="mw-page-title-main">HLA-DR53</span>

HLA-DR53 is an HLA-DR serotype that recognizes gene products of HLA-DRB4 locus. There are 13 alleles at this locus that encode 7 proteins.

<span class="mw-page-title-main">HLA-DR17</span>

HLA-DR17 (DR17) is an HLA-DR serotype that recognizes the DRB1*0301 and *0304 gene products. DR17 is found at high frequency in Western Europe. DR17 is part of the broader antigen group HLA-DR3 and is very similar to the group HLA-DR18.

<span class="mw-page-title-main">HLA-DR3</span>

HLA-DR3 is composed of the HLA-DR17 and HLA-DR18 split 'antigens' serotypes. DR3 is a component gene-allele of the AH8.1 haplotype in Northern and Western Europeans. Genes between B8 and DR3 on this haplotype are frequently associated with autoimmune disease. Type 1 diabetes mellitus is associated with HLA-DR3 or HLA-DR4. Nearly half the US population has either DR3 or DR4, yet only a small percentage of these individuals will develop type 1 diabetes.

<span class="mw-page-title-main">HLA-A1</span>

HLA-A1 (A1) is a human leukocyte antigen serotype within HLA-A "A" serotype group. The serotype is determined by the antibody recognition of α1 subset of HLA-A α-chains. For A1, the alpha "A" chain are encoded by the HLA-A*01 allele group and the β-chain are encoded by B2M locus. This group currently is dominated by A*01:01. A1 and A*01 are almost synonymous in meaning. A1 is more common in Europe than elsewhere, it is part of a long haplotype that appears to have been frequent in the ancient peoples of Northwestern Europe. A1 is a frequent component of the AH8.1 haplotype. A1 serotype positivity is roughly linked to a large number of inflammatory diseases and conditions believed to have immune system involvement. Because of its linkage within the AH8.1 haplotype many studies showed association with A1 or A1,B8 only later to show the association drift toward the class II region gene alleles, DR3 and DQ2.5. While it is not clear what role A1 has in infectious disease, some linkage with infection rates in HIV remain associated within the A1 region of the haplotype.

<span class="mw-page-title-main">HLA-A3</span>

HLA-A3 (A3) is a human leukocyte antigen serotype within HLA-A serotype group. The serotype is determined by the antibody recognition of α3 subset of HLA-A α-chains. For A3, the alpha, "A", chain are encoded by the HLA-A*03 allele group and the β-chain are encoded by B2M locus. This group currently is dominated by A*03:01. A3 and A*03 are almost synonymous in meaning. A3 is more common in Europe, it is part of the longest known multigene haplotype, A3~B7~DR15~DQ6.

<span class="mw-page-title-main">HLA-A33</span>

HLA-A33 (A33) is a human leukocyte antigen serotype within HLA-A serotype group. The serotype is determined by the antibody recognition of α33 subset of HLA-A α-chains. For A33, the alpha "A" chain are encoded by the HLA-A*33 allele group and the β-chain are encoded by B2M locus. A33 and A*33 are almost synonymous in meaning. A33 is a split antigen of the broad antigen serotype A19. A33 is a sister serotype of A29, A30, A31, A32, and A74.

Human leukocyte antigens (HLA) began as a list of antigens identified as a result of transplant rejection. The antigens were initially identified by categorizing and performing massive statistical analyses on interactions between blood types. This process is based upon the principle of serotypes. HLA are not typical antigens, like those found on surface of infectious agents. HLAs are alloantigens, they vary from individual to individual as a result of genetic differences. An organ called the thymus is responsible for ensuring that any T-cells that attack self proteins are not allowed to live. In essence, every individual's immune system is tuned to the specific set of HLA and self proteins produced by that individual; where this goes awry is when tissues are transferred to another person. Since individuals almost always have different "banks" of HLAs, the immune system of the recipient recognizes the transplanted tissue as non-self and destroys the foreign tissue, leading to transplant rejection. It was through the realization of this that HLAs were discovered.

HLA A1-B8 is a multigene haplotype that covers the MHC Class I region of the human major histocompatibility complex on chromosome 6. A multigene haplotype is set of inherited alleles covering several genes, or gene-alleles; common multigene haplotypes are generally the result of identity by descent from a common ancestor. Chromosomal recombination fragments multigene haplotypes as the distance to that ancestor increases in number of generations.

HLA-Cw7 (Cw7) is a human leukocyte antigen serotype within HLA-C serotype group. Cw7 is determined by the antibody recognition of α7 subset of HLA-Cw α-chains. For the serotype Cw7, the alpha chain are encoded by the HLA-Cw*07 allele group and the β-chain are encoded by B2M locus. Cw7 and Cw*07 are almost synonymous in meaning. Cw7 is more common in West Africa to Ireland. Cw7 in Europe is part of the AH8.1 and HLA B7-DR15-DQ6 haplotypes. The class I region of these supertype is HLA A1-B8 haplotype, HLA A3-B7, HLA-A2-B7 and HLA A24-B7.

HLA B7-DR15-DQ6 is a multigene haplotype that covers a majority of the human major histocompatibility complex on chromosome 6. 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. Chromosomal recombination fragments multigene haplotypes as the distance to that ancestor increases in number of generations.

HLA A30-Cw5-B18-DR3-DQ2 (A30::DQ2) is a multigene haplotype that extends across a majority of the major histocompatibility complex on human chromosome 6. A multigene haplotype is a set of inherited alleles covering several genes, or gene-alleles. Long haplotypes, like A30::DQ2, are generally the result of descent by common ancestry. As haplotypes increase in size, Chromosomal recombination fragments them in a generation dependent process.

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