HLA-A*02

α (A*02:01 gene product), β2-microglobulin, and HIV peptide.
AboutProteintransmembrane receptor/ligandStructureαβ heterodimerSubunitsHLA-A*02--, β2-microglobulinOlder namesHL-A2Subtypes
Subtype
allele
Available structures
A2.1 *02:01 3hla​, 2gj6​, 2git​, 2clr​, 2bsv​, 2c7u​, 2bsu​, 2av1​, 2av7​, 1tvb​, 1tvh​, 1s8d​, 1s9w​, 1s9x​, 1s9y​, 1t1w​, 1t1x​, 1t1y​, 1t1z​, 1t20​, 1t21​, 1t22​, 1qse​, 1qr1​, 1qrn​, 1p7q​, 1jf1​, 1jht​, 1i1f​, 1i1y​, 1i4f​, 1i7r​, 1i7t​, 1i7u​, 1im3​, 1akj​, 1ao7​, 1b0g​, 1b0r​, 1bd2​, 1duy​, 1duz​, 1eey​, 1eez​, 1hhg​, 1hhh​, 1hhi​, 1hhj​, 1hhk​, 1hla​
A2.2F *02:02
A2.3, A203 *02:03
A2.2Y *02:05
A2.4a *02:06
Rare alleles
Subtype
allele
Available structures
A2.4 *02:04
A2.4b *02:07
A2.5 *02:11
Alleles link-out to IMGT/HLA database at EBI

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.[1] 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.[2]

HLA-A*02 is one particular class I major histocompatibility complex (MHC) allele group at the HLA-A locus. The A*02 allele group can code for many proteins; as of December 2013 there are 456 different HLA-A*02 proteins.[3] Serotyping can identify as far as HLA-A*02, which is typically enough to prevent transplant rejection (the original motivation for HLA identification). Genes can further be separated by genetic sequencing and analysis. HLAs can be identified with as many as nine numbers and a letter (ex. HLA-A*02:101:01:02N).[2] HLA-A*02 is globally common, but particular variants of the allele can be separated by geographic prominence.

Serotype

The serotyping for the most abundant A*02 alleles is good. For A*02:03, A*02:06, A*02:07 serotyping is borderline useful. There is a separate serotyping for A203 and A210. As of December 2013, there are 456 alleles identified (mostly by sequence homology) as being A2, of those 27 are nulls, and a large majority have unknown serotypes, although it is highly probable that they will all return A2 serotypes.[3]

A2 recognition of some HLA A*02 gene products[4]
A*02 A2 Sample
allele % size (N)
*02:01 98 6315
*02:02 81  859
*02:03 64  472
*02:05 81  462
*02:06 68  636
*02:07 80  135
*02:11 74  228

Disease associations

HLAs serve as the primary link between the immune system and interior of cells. Thus any alteration to the HLA that induces decreased binding to a certain peptide or increased binding to a certain peptide, is expressed as, respectively, increased susceptibility to disease or decreased susceptibility to disease. In other words, certain HLAs may be incapable of binding any of the short peptides produced by proteolysis of pathogenic proteins. If HLAs bind none of the peptides produced by a pathogen, then there is no way for the immune system to tell that a cell is infected. Thus the infection can proliferate largely unchecked. It works the other way too. Some HLAs bind pathogenic peptide fragments with very high affinity. This in essence "supercharges" their immune system in regards to that particular pathogen, allowing them to easily control an infection that might otherwise be devastating.[5]

Spontaneous abortion

The HLA-A*02 antigen has been associated with spontaneous abortion in infertile couples. In essence, there are indicators, albeit from a small study comparing HLA expression in fertile and infertile couples, that HLA-A*02 may induce increased maternal immune response to the fetus. This immune response could be compared to an allergic reaction, and, if severe enough, induces abortion of the fetus.[6] Although this is a very interesting correlation, the study which first uncovered this link was quite small and more work needs to be done to verify this hypothesis.

Human immunodeficiency virus

HLA-A*02 appears to stimulate peripheral blood mononuclear cells in a manner that inhibits HIV replication. This could be the reason for a documented 9-fold reduced risk of HIV transmission to infants during childbirth.[7] HIV has evolved mechanisms to combat immune recognition. HIV produces a protein called Nef that binds to the cytoplasmic tail of HLA-A and B and diverts it to the lysosomes for destruction. This prevents the HLAs from being expressed on the cell surface and then functioning properly.[8] In addition, there are several HLA-A*02 haplotypes that appear to contribute heavily to higher or lower viral loads in HIV patients. HLA-A*02-C*16 and HLA-A*02-B*45 have been shown to contribute to significantly increased viral loads (greater than 100,000 copies per milliliter).[9] In summation, HLA-A*02 appears to be somewhat less effective than other HLA-As at protecting against HIV infections.

Hodgkin lymphoma

HLA-A*02 has been linked with decreased risk of developing Epstein-Barr virus (EBV)-positive Hodgkin lymphoma(HL). Among patients with EBV+ HL, only 35.5% of people expressed HLA-A*02 compared to 50.9% in the EBV-HL group and 53% in the control group. This is a significant decrease and is almost certainly a result of the abnormally efficient binding of HLA-A*02 to peptides originating from EBV.[10] This high affinity increases the probability of CD8+ t-cell recognition of EBV peptides held by HLA-A*02 complexes. This, in turn, enhances the immune system's ability to control and clear the EBV, which decreases the change of developing Hodgkin Lymphoma as a result of the infection.

By haplotype

A*02:Cw*16 is associated with increased higher viral load in HIV[9]

Alleles

A*02:01 allele frequency
HLA A*02:01 frequencies
Study populationFreq.
 (in %)[11]
Mexico Sonora Seri54.5
USA Arizona Pima43.6
USA New Mexico Canoncito ...37.8
Finland34.4
Mexico Mestizos34.1
Georgia Tbilisi Georgian...31.0
Bulgaria30.0
Philippines Ivatan30.0
Spain Catalonia Girona29.9
USA South Dakota Lakota S...29.7
Portugal North29.3
Italy North pop 128.9
Mexico Zaptotec Oaxaca28.4
Italy Bergamo28.0
Czech Republic27.4
Ireland Northern27.4
USA Caucasian (2)27.2
Spain Basque Gipuzkoa Pro...27.0
Belgium26.6
Croatia26.3
Australia New South Wales26.1
Portugal Centre26.0
Turkey (1)25.7
Mexico Chihuahua State Ta...25.0
Romanian25.0
Ireland South24.6
Mexico Guadalajara Mestizo22.3
China Tibet21.8
USA North American Native...21.7
USA South Texas Hispanics21.7
Oman21.6
Venezuela Perja Mountain ...21.6
Georgia Svaneti Svans21.3
Brazil Terena20.8
Iran Baloch20.2
Japan Ainu Hokkaido20.0
Brazil19.2
China Beijing18.7
Uganda Kampala18.4
Morocco Nador Berber17.8
Australia Indig. Cape Yor...17.5
Tunisia17.5
Sudanese17.3
South Korea (3)16.5
Mongolia Buriat14.3
Burkina Faso Rimaibe13.8
Jordan Amman13.4
Zambia Lusaka12.8
USA African Americans (3)12.1
Japan (3)11.6
India Tamil Nadu Nadar10.7
Japan Okinawa Ryukyuan10.2
Zimbabwe Harare Shona9.1
Ecuador Cayapa9.0
Kenya8.7
Georgia Tbilisi Kurds8.3
Mali Bandiagara8.3
Senegal Niokholo Mandenka8.1
Cameroon Yaounde7.1
Singapore Riau Malay6.5
India North Hindus5.8
Taiwan Hakka5.5
Taiwan Pazeh5.5
China South Han5.3
Burkina Faso Fulani5.1
Sri Lanka Colombo Sinhalese4.9
China Guangxi Maonan4.6
Singapore Javanese Indonesian4.0
Taiwan Paiwan3.9
India Andhra Pradesh Goll...3.4
Singapore Thai3.1
Taiwan Rukai3.0
Taiwan Tsou2.9
Pakistan Karachi Parsi2.8
Taiwan Ami2.6
South African Natal Zulu2.5
New Caledonia2.4
USA Alaska Yupik Natives2.4
PNG Wanigela2.1
Taiwan Puyuma2.0
Taiwan Tao2.0
India Mumbai Marathas1.9
Thailand1.8
South Africa Natal Tamil1.0
Allele frequencies presented, only
A*02:02 allele frequency
HLA A*02:02 frequencies
Study populationFreq.
 (in %)[11]
Cameroon Bamileke10.4
Senegal Niokholo Mandenka9.1
Cameroon Yaounde8.2
Mali Bandiagara7.6
Guinea Bissau6.2
Cameroon Beti6.0
Burkina Faso Rimaibe5.3
Kenya4.9
Georgia Svaneti Svans3.8
USA African Americans (2)3.7
Zimbabwe Harare Shona3.6
South African Natal Zulu3.5
Uganda Kampala3.4
Saudi Arabia Guraiat and ...2.4
Pakistan Brahui2.3
Zambia Lusaka2.3
Israel Arab Druse2.0
Sudanese1.8
India North Delhi1.7
Pakistan Karachi Parsi1.7
China Qinghai Hui1.4
Portugal North1.1
Georgia Tbilisi Georgian...1.0
Tunisia1.0
Allele frequencies presented, only
A*02:03 allele frequency
HLA A*02:03 frequencies
Study populationFreq.
 (in %)[11]
China Guangxi Maonan17.6
China Yunnan Lisu15.2
Thailand Northeast12.2
China South Han10.8
China Guangzhou9.8
Singapore Javanese Indonesian9.0
China Yunnan Nu8.2
Thailand7.7
Taiwan Minnan pop 16.4
Taiwan Puyuma6.0
Taiwan Siraya5.9
Singapore Riau Malay5.2
India Khandesh Pawra5.0
India West Bhils5.0
Taiwan Pazeh4.5
USA Asian4.2
India Mumbai Marathas3.7
Taiwan Hakka3.6
China North Han2.4
Sri Lanka Colombo Sinhalese2.4
China Qinghai Hui2.3
Burkina Faso Rimaibe1.1
Taiwan Saisiat1.0
Allele frequencies presented, only
A*02:05 allele frequency
HLA A*02:05 frequencies
Study populationFreq.
 (in %)[11]
Burkina Faso Fulani9.2
Kenya Nandi8.7
Sudanese6.5
Saudi Arabia Guraiat and ...6.1
Italy North (1)5.8
South African Natal Zulu5.5
Cameroon Pygmy Baka5.0
Georgia Tbilisi Kurds5.0
Burkina Faso Rimaibe4.3
Israel Arab Druse4.0
Cameroon Sawa3.8
Turkey (1)3.5
Mongolia Buriat3.2
Zimbabwe Harare Shona3.1
India New Delhi3.0
USA African America3.0
Bulgaria2.7
Cameroon Bamileke2.6
Kenya Luo2.6
Pakistan Sindhi2.5
Tunisia2.5
Cuban Mulatto2.4
Czech Republic2.4
Spain Catalonia Girona2.3
Cameroon Yaounde2.2
Mali Bandiagara2.2
Uganda Kampala2.2
Italy Bergamo2.1
Oman2.1
USA African Americans (2)1.7
China North Han1.4
Georgia Tbilisi Georgian...1.4
Kenya1.4
Ireland Northern1.2
Cameroon Beti1.1
India North Delhi1.1
Senegal Niokholo Mandenka1.1
USA Caucasians (3)1.1
India North Hindus1.0
Mexico Mixtec Oaxaca1.0
Portugal Centre1.0
Spain Basque Gipuzkoa Pro...1.0
Allele frequencies presented, only
A*02:06 allele frequency
HLA A*02:06 frequencies
Study populationFreq.
 (in %)[11]
Mexico Mixe Oaxaca34.9
Mexico Zaptotec Oaxaca26.1
Mexico Mixtec Oaxaca21.6
Pakistan Kalash21.6
Japan Ainu Hokkaido20.0
Japan Okinawa Ryukyuan18.3
USA Alaska Yupik Natives16.5
USA Hawaii Okinawa14.3
American Samoa13.0
Mexico Chihuahua State Ta...12.5
Taiwan Puyuma12.0
USA South Dakota Lakota S...10.5
Taiwan Atayal9.4
Japan pop38.7
Japan pop58.4
India North Delhi7.7
Japan Central7.7
USA Arizona Pima7.6
Taiwan Bunun7.4
USA South Texas Hispanics7.3
USA North American Native...7.2
China North Han7.1
South Korea pop 37.1
Russia Tuva pop 26.9
Mexico Mestizos6.1
Pakistan Burusho6.0
Taiwan Taroko5.5
Singapore Chinese Han5.2
USA Asian5.0
USA New Mexico Canoncito ...4.9
China Beijing4.8
China Beijing Shijiazhuan...4.7
Hong Kong Chinese4.7
China Guangxi Maonan4.6
Mongolia Buriat4.3
China Guangzhou4.0
Philippines Ivatan4.0
Singapore Chinese4.0
Taiwan Pazeh3.6
China South Han3.5
Taiwan Thao3.3
Pakistan Sindhi3.2
USA Hispanic3.2
Pakistan Pathan3.1
India New Delhi3.0
Taiwan Rukai3.0
India North Hindus2.9
Taiwan Minnan pop 12.9
Taiwan Paiwan2.9
India Andhra Pradesh Goll...2.8
Taiwan Hakka2.7
Papua New Guinea Eastern ...2.6
Thailand2.5
Sri Lanka Colombo Sinhalese2.4
Pakistan Brahui2.3
Papua New Guinea Wanigela2.1
Singapore Javanese Indone...2.0
Singapore Riau Malay2.0
Singapore Thai2.0
Taiwan Saisiat2.0
Taiwan Siraya2.0
Pakistan Baloch1.6
Taiwan Ami1.5
Zambia Lusaka1.2
Iran Baloch1.1
Pakistan Karachi Parsi1.1
Allele frequencies presented, only
A*02:07 allele frequency
HLA A*02:07 frequencies
Study populationFreq.
 (in %)[11]
Thailand Northeast15.7
China Guangxi Maonan13.4
Hong Kong Chinese13.1
Singapore Chinese13.1
Singapore Thai12.2
Singapore Chinese Han11.6
Taiwan Minnan pop 111.3
Thailand10.9
China South Han9.4
China Guangzhou9.3
China Yunnan Nu8.2
Taiwan Hakka8.2
Taiwan Siraya6.9
China Beijing6.7
USA Asian6.6
Taiwan Pazeh6.4
China North Han4.3
China Qinghai Hui3.6
Japan (3)3.4
South Korea (3)3.0
China Inner Mongolia2.5
China Yunnan Lisu2.2
Mongolia Buriat2.1
Singapore Riau Malay2.0
Taiwan Thao1.7
China Tibet Autonomous Region1.6
Russia Tuva pop 21.6
USA Hawaii Okinawa1.4
Burkina Faso Fulani1.0
Japan Ainu Hokkaido1.0
Singapore Javanese Indonesian1.0
Allele frequencies presented, only
A*02:11 allele frequency
HLA A*0211 frequencies
Study populationFreq.
 (in %)[11]
India Khandesh Pawra16.0
South Africa Natal Tamil13.0
India Andhra Pradesh Goll...9.7
India Mumbai Marathas8.6
Sri Lanka Colombo Sinhale...7.4
India North Hindus6.7
Ecuador Cayapa4.8
India West Bhils4.0
Pakistan Sindhi2.5
Pakistan Brahui2.3
Pakistan Pathan2.0
Singapore Javanese Indonesian2.0
India North Delhi1.7
Pakistan Baloch1.6
Singapore Riau Malay1.2
Iran Baloch1.1
Pakistan Burusho1.1
Allele frequencies presented, only

A2-B haplotypes

A2-B7 (Node in Netherlands) A2-B5

  • A2-B51
  • A2-B52

A2-B8
A2-B13
A2-B14

  • A2-B64
  • A2-B65

A2-B15

  • A2-B62
  • A2-B63
  • A2-B70,71,75,76
  • A2-B46 (Node in Southern China, may be most abundant haplotype)

A2-B16

A2-B18
A2-B27
A2-B35
A2-B37 A2-B39 (Node in North American Amerinds)
A2-B40

  • A2-B60
  • A2-B61

A2-B46

A2-Cw5-B44

HLA A2-B44 haplotype frequencies
freq Rank in
ref. Population (%) Pop.
[12] Cornish 11.4 1 1
[13] Ireland 9.2 2
[14] Northern Ireland 8.0 1 2
[12] Sweden 7.2 2
[15] Swiss 6.9 2
[12] Polish 6.2 1
[12] Spanish 5.9 1
[12] Ukraine 5.9 1
[16] Dutch Netherlands 5.9 3
[12] Dane 4.8 1
[12] Czech 4.7 3
[12] Basque 4.7 3
[12] Greek 4.5 3
[12] Yugoslavian 4.4
[12] Hungarian 3.5
[12] British 2.6 4
[1] Romania 2.5
[12] Austria 2.4
1Cw*0501 (Eur.)

A2-Cw5-B44 is the multi-serotype designation for the haplotype HLA-A*02:01~C*05:01~B*4402, the class I portion, of an ancestral haplotype (A2~B44~DR4~DQ8). The full haplotype is (for relative distances) see Human leukocyte antigens:

A*02:01 ~ C*05:01 ~ B*44:02 ~ DRB1*04:01 ~ DQA1*03:01 ~ DQB1*03:02

Another haplotype that is more common in Central Europe is the (A2-B44-DR7-DQ2)

A*02:01 ~ C*05:01 ~ B*44:02 ~ DRB1*07:01 ~ DQA1*02:01 ~ DQB1*02:02

Over northwestern Europe A2-B44 shows a single common ancestor which contributed the Cw5 allele to the haplotype. The haplotype appears to have been introduced early in European prehistoric period, frequencies of the haplotype generally correlate with A1-Cw7-B8 and A2-B7. The haplotype is considerably more equilibrated relative to A1-B8 and a possible reason is gene flow from iberia or the east with related haplotypes after initial migrations.

References

  1. ^ Arce-Gomez B, Jones EA, Barnstable CJ, Solomon E, Bodmer WF (Feb 1978). "The genetic control of HLA-A and B antigens in somatic cell hybrids: requirement for beta2 microglobulin". Tissue Antigens. 11 (2): 96–112. doi:10.1111/j.1399-0039.1978.tb01233.x. PMID 77067.
  2. ^ a b "HLA Nomenclature @ hla.alleles.org". Anthony Nolan Research Institute. 10 Nov 2013. Retrieved 8 Dec 2013.
  3. ^ a b "Allele Search Tool". European Molecular Biology Laboratory. 2013. Retrieved 20 December 2013.
  4. ^ Allele Query Form IMGT/HLA - European Bioinformatics Institute
  5. ^ Daniel M. Davis (2014). The Compatibility Gene. How Our Bodies Fight Disease, Attract Others, and Define Our Selves. Oxford: Oxford University Press. ISBN 978-0-19-931641-0.
  6. ^ Komlos L, Klein T, Korostishevsky M (Aug 2007). "HLA-A2 class I antigens in couples with recurrent spontaneous abortions". International Journal of Immunogenetics. 34 (4): 241–6. doi:10.1111/j.1744-313X.2007.00682.x. PMID 17627758. S2CID 12367668.
  7. ^ Grene E, Pinto LA, Cohen SS, Trivett MT, Simonis TB, Liewehr DJ, Steinberg SM, Shearer GM (Feb 2001). "Generation of alloantigen-stimulated anti-human immunodeficiency virus activity is associated with HLA-A*02 expression". The Journal of Infectious Diseases. 183 (3): 409–16. doi:10.1086/318085. PMID 11133372.
  8. ^ Mann JK, Byakwaga H, Kuang XT, Le AQ, Brumme CJ, Mwimanzi P, Omarjee S, Martin E, Lee GQ, Baraki B, Danroth R, McCloskey R, Muzoora C, Bangsberg DR, Hunt PW, Goulder PJ, Walker BD, Harrigan PR, Martin JN, Ndung'u T, Brockman MA, Brumme ZL (16 September 2013). "Ability of HIV-1 Nef to downregulate CD4 and HLA class I differs among viral subtypes". Retrovirology. 10 (1): 100. doi:10.1186/1742-4690-10-100. PMC 3849644. PMID 24041011.
  9. ^ a b Tang J, Tang S, Lobashevsky E, Myracle AD, Fideli U, Aldrovandi G, Allen S, Musonda R, Kaslow RA (Aug 2002). "Favorable and unfavorable HLA class I alleles and haplotypes in Zambians predominantly infected with clade C human immunodeficiency virus type 1". Journal of Virology. 76 (16): 8276–84. doi:10.1128/JVI.76.16.8276-8284.2002. PMC 155130. PMID 12134033.
  10. ^ Niens M, Jarrett RF, Hepkema B, Nolte IM, Diepstra A, Platteel M, Kouprie N, Delury CP, Gallagher A, Visser L, Poppema S, te Meerman GJ, van den Berg A (Nov 2007). "HLA-A*02 is associated with a reduced risk and HLA-A*01 with an increased risk of developing EBV+ Hodgkin lymphoma" (PDF). Blood. 110 (9): 3310–5. doi:10.1182/blood-2007-05-086934. PMID 17630352. S2CID 24567105.
  11. ^ a b c d e f g Middleton, D.; Menchaca, L.; Rood, H.; Komerofsky, R. (2003). "New allele frequency database: http://www.allelefrequencies.net". Tissue Antigens. 61 (5): 403–407. doi:10.1034/j.1399-0039.2003.00062.x. PMID 12753660.
  12. ^ a b c d e f g h i j k l m Sasazuki, Takehiko; Tsuji, Kimiyoshi; Aizawa, Miki (1992). HLA 1991: proceedings of the eleventh International Histocompatibility Workshop and Conference, held in Yokohama, Japan, 6-13 November, 1991. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-262390-7.
  13. ^ Finch T, Lawlor E, Borton M, Barnes CA, McNamara S, O'Riordan J, McCann SR, Darke C (1997). "Distribution of HLA-A, B and DR genes and haplotypes in the Irish population". Experimental and Clinical Immunogenetics. 14 (4): 250–63. PMID 9523161.
  14. ^ Middleton D, Williams F, Hamill MA, Meenagh A (Dec 2000). "Frequency of HLA-B alleles in a Caucasoid population determined by a two-stage PCR-SSOP typing strategy". Human Immunology. 61 (12): 1285–97. doi:10.1016/S0198-8859(00)00186-5. PMID 11163085.
  15. ^ Grundschober C, Sanchez-Mazas A, Excoffier L, Langaney A, Jeannet M, Tiercy JM (Jun 1994). "HLA-DPB1 DNA polymorphism in the Swiss population: linkage disequilibrium with other HLA loci and population genetic affinities". European Journal of Immunogenetics. 21 (3): 143–57. doi:10.1111/j.1744-313X.1994.tb00186.x. PMID 9098428. S2CID 29932752.
  16. ^ Schipper RF, Schreuder GM, D'Amaro J, Oudshoorn M (Nov 1996). "HLA gene and haplotype frequencies in Dutch blood donors". Tissue Antigens. 48 (5): 562–74. doi:10.1111/j.1399-0039.1996.tb02670.x. PMID 8988539.
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