HLA A1-B8 haplotype

Last updated
Class I, A1-Cw7-B8
HLA-mini.png
HLA region on chromosome 6
Nicknames
"HL A1,8; HL A1,A8; HLA A1-B8;
HLA A*01-B*08, HLA A*01:01-B*08:01"
Loci
LociGeneAlleleSerotype
HLA-F
to
HLA-A		 HLA-F *0101 -
HLA-G *0101 -
HLA-A*0101 A1
HLA-E HLA-E *0101 -
Cw-BHLA-C*0701Cw7
HLA-B*0801 B8
Nodes
PopulationMaximaWestern Ireland
Freq.Max>15.0%
Size and location
Genes-
Chromosome 6
Location6p21.3
Size (kbps)1400

HLA A1-B8 (Also:HL A1,8; HL A1,A8; HLA A1-Cw7-B8; HLA A*01-B*08, HLA A*0101-B*0801, HLA A*0101-Cw*0701-B*0801; HLA A*01:01-C*07:01-B*08:01) 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 (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*01:01 : Cw*07:01 : B*08:01

However, there are many other gene-alleles within the haplotype. In Europe A1-B8 is found, generally as part of the HLA A1-B8-DR3-DQ2 haplotype. This haplotype is 4.7 million nucleotides in length and the second longest haplotype identified within the human genome. In Africa A1-B8 and India A1-B8 is associated with other genes and other variants of A*01 and B*08

Disease associations

Philosophically, A1-B8 is more than just two gene-alleles. These gene-alleles are markers for a haplotype, a stretch of chromosome 6 that contains many gene alleles. In its natural history this haplotype underwent some atypical selection, at the end of the period of evolution it became the predominant haplotypes in North/Western European ancestors. Today however the collection of genes is associated with increased incidences of certain diseases. Despite the fact that the associations have been known almost as long as A1 and "A8" were known, the role of factors affecting disease are still not clear.

A1-B8 and autoimmune diseases

A1-B8 serotype was associated with a number of diseases as "HL-A"' antigens were first being described. Among these were coeliac disease, autoimmune active chronic hepatitis, myasthenia gravis, Adrenocortical hyperfunction-Cushing's syndrome, primary biliary cirrhosis. [1] [2] [3] [4] [5] [6]

Lymphotoxin alpha is encoded with HLA A-B region PBB Protein LTA image.jpg
Lymphotoxin alpha is encoded with HLA A-B region

However, as study sizes increased and D serotypes were described in more detail, the association of these loci moved from the MHC class I loci to the MHC class II loci. Underlying this move was the HLA A1-B8-DR3-DQ2 haplotype, a haplotype that is in acute linkage disequilibrium in the European population. [7] [8] [9] [10] [11] This disequilibrium made it appear that A1 and other class I gene-alleles were disease factors, when these alleles were only attached to a long segment of conserved DNA that had disease associated genes on the other end. In at least 2 diseases, the risk of autoimmune disease extends beyond the class II region of the haplotype.

Systemic lupus erythematosus

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. [12] 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. [13]

Type 1 diabetes

While type 1 diabetes shows an extended association on the HLA A1-B8-DR3-DQ2 haplotype, the association appears not to extend beyond the HLA-B locus. [14] A recent study of DR3-DQ2/DR4-DQ8 phenotype found that A1-cw7-B8 was actually lower than expected relative to other A-B types, indicating that risk associated genes are located between B8 and DR3. A*0101 appears to alter risk for type 1 diabetes but not Cw7-B8. [15] The type 1 diabetes example shows the inherent difficulty in the use of linkage analysis alone to cipher risk.

IgA-less or absent phenotype is associated with a number of inflammatory diseases Ig A.jpg
IgA-less or absent phenotype is associated with a number of inflammatory diseases

A1-B8 and allergic disease

In allergic disease A1,B8 were found to associate with allergic reactions in new-borns. [16] A1, B8 was found increased in children with bronchial asthma and low IgA. [17] However, some of this reaction can be attributed to the linkage of the HLA A1-B8-DR3-DQ2 haplotype to the IgA-less phenotype. [18] A firmer association was found with atopies. [19] [20] [21] A1,B8 where found more frequently in hay fever complicated by asthma or atopia relative to just hay fever. [22] [23] [24] Further asthmatic patients with negative skin tests tended toward higher A1,B8 serotypes. [25]

A1-B8 and infectious disease

Complement 4A gene is deleted within A1-B8 PBB Protein C4A image.jpg
Complement 4A gene is deleted within A1-B8

HIV

In the mid-1980s the association with A1-B8-DR3 and HIV progression appeared shortly after the discover of the virus. [26] A1-B8 associated with more rapid progression to seropositivity, and was strongly associated with a rapid decline in T4 cells and development of HIV-related symptoms within four years of infection. [27] The strongest associations were seen with A1-Cw7-B8 haplotype. C4 (complement 4) produces a null allele at on locus C4AQ. This locus in part of the HLA A1-B8-DR3-DQ2 haplotype (markers are A1, CW7, B8, BfS, C4AQ0, C4B1, DR3, DQ2) therefore one study concluded that C4AQ0 could explain the increased infectivity to HIV. [28] The haplotype was further linked to false-tumor splenomegaly, CD8 lymphocytosis, and high IgG. [29]

Viral hepatitis

An association was seen between viral hepatitis and HLA-A1. [30] [31] Though, the association of A1 with autoimmune hepatitis with no anti-viral antibody was stronger than with chronic active hepatitis with anti-viral titer. [32] The association with viral hepatitis was subsequently demonstrated and patients with antinuclear antibodies were more likely to have A1-B8-DR3. [33] Currently studies point to association proximal the Cw*0702-B*0801 loci.

Frequencies

HLA A1-B8 frequencies
[34] Ireland14.41
Slovak11.91
[35] Northern Ireland11.511
Swedish11.51
[36] Dutch Netherlands9.8
Yugoslavian9.71
British9.71
Hungarian9.41
[37] CEPH France8.511
[38] German8.31
Czech7.81
[39] Swiss6.73
Belgium5.52
Austria4.52
[40] Tuscan Italy4.3
Ukraine4.33
Italy4.21
Basque4.2
Portuguese4.22
Polish4.0
[41] Uganda3.71
Uralic3.13
Spanish2.84
Romania2.8
Albania2.5
Greek2.3
Archived 2007-09-27 at the Wayback Machine Northern Greece2.1
[42] Crete1.9
[41] Luo Kenya1.72
[41] Nandi Kenya1.42
[43] Oman Arabia1.4
Japanese0.1
1Cw*0701 (Eur.), ²Cw*0704 (Afr.)

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 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-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-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-DR11</span>

HLA-DR11 (DR11) is a HLA-DR serotype that recognizes the DRB1*1101 to *1110. DR11 serotype is a split antigen of the older HLA-DR5 serotype group which also contains the similar HLA-DR12 antigens.

<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> Human leukocyte antigen serotype

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-A*02</span> Human leukocyte antigen serotype within the HLA-A serotype group

HLA-A*02 (A*02) is a human leukocyte antigen serotype within the HLA-A serotype group. The serotype is determined by the antibody recognition of the α2 domain of the HLA-A α-chain. For A*02, the α chain is encoded by the HLA-A*02 gene and the β chain is encoded by the B2M locus. In 2010 the World Health Organization Naming Committee for Factors of the HLA System revised the nomenclature for HLAs. Before this revision, HLA-A*02 was also referred to as HLA-A2, HLA-A02, and HLA-A*2.

<span class="mw-page-title-main">HLA-A33</span> Human leukocyte antigen serotype

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.

HLA-Cw*16 (Cw*16) is an HLA-C allele-group. The serotype identifies the more common HLA-Cw*16 gene products. This allele group is most commonly found in West Africa, but A single Haplotype of Cw16 is found in Western Europe at unusually high frequencies. There is no useful serology for Cw*16.

<span class="mw-page-title-main">HLA-B8</span> Human leukocyte antigen serotype

HLA-B8 (B8) is an HLA-B serotype. The serotype identifies the HLA-B*08 gene products. HLA-B8, previously known as HL-A8 was one of the first identified of the HLA antigens. It coined the "Super B8" haplotype, also called the ancestral European haplotype because of its common occurrence in Europe, particular the isles and Scandinavia. B8 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.

<span class="mw-page-title-main">HLA-B7</span> Human leukocyte antigen serotype

HLA-B7 (B7) is an HLA-B serotype. The serotype identifies the more common HLA-B*07 gene products. B7, previously HL-A7, was one of the first 'HL-A' antigens recognized, largely because of the frequency of B*0702 in Northern and Western Europe and the United States. B7 is found in two major haplotypes in Europe, where it reaches peak frequency in Ireland. One haplotype A3-B7-DR15-DQ1 can be found over a vast region and is in apparent selective disequilibrium. B7 is a risk factor for cervical cancer, sarcoidosis, and early-onset spondylarthropathies.

HLA A1-B8-DR3-DQ2 haplotype 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 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.

References

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