HLA A1-B8 haplotype explained

Haplotype:Class I, A1-Cw7-B8
Image Source:HLA region on chromosome 6
Placement:right
Chromosome:6
Location:6p21.3
Alias:"HL A1,8; HL A1,A8; HLA A1-B8;
HLA A*01-B*08, HLA A*01:01-B*08:01"
Othertype:Serotype
Loci1name:HLA-F
to
HLA-A
Loci1rows:3
Gene1var:
  • 0101
Type1var:-
Gene2var:
  • 0101
Type2var:-
Gene3name:HLA-A
Gene3var:
  • 0101
Loci4name:HLA-E
Loci4rows:1
Gene4var:
  • 0101
Type4var:-
Loci5name:Cw-B
Loci5rows:2
Gene5name:HLA-C
Gene5var:
  • 0701
Type5var:Cw7
Loci6name:-
Gene6name:HLA-B
Gene6var:
  • 0801
Popmax:Western Ireland
Freqmax:>15.0%
Length:1400
Numloci:-

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.

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] 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.

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

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] Ireland 14.4 1
Slovak 11.9 1
[35] Northern Ireland 11.51 1
Swedish 11.5 1
[36] Dutch Netherlands 9.8
Yugoslavian 9.7 1
British 9.7 1
Hungarian 9.4 1
[37] CEPH France 8.51 1
[38] German 8.3 1
Czech 7.8 1
[39] Swiss 6.7 3
Belgium 5.5 2
Austria 4.5 2
[40] Tuscan Italy 4.3
Ukraine 4.3 3
Italy 4.2 1
Basque 4.2
Portuguese 4.2 2
Polish 4.0
[41] Uganda 3.7 1
Uralic 3.13
Spanish 2.84
https://web.archive.org/web/20070927005011/http://www.allelefrequencies.net/test/searchHaplotypePart3.asp?Population=RomanianRomania 2.8
Albania 2.5
Greek 2.3
http://www.allelefrequencies.net/test/searchHaplotypePart3.asp?Population=Greece%20North Northern Greece 2.1
[42] Crete 1.9
Luo Kenya 1.7 2
Nandi Kenya 1.4 2
[43] Oman Arabia 1.4
Japanese 0.1
1Cw*0701 (Eur.), ²Cw*0704 (Afr.)

Notes and References

  1. Clarke AK, Galbraith RM, Hamilton EB, Williams R . Rheumatic disorders in primary biliary cirrhosis . Ann. Rheum. Dis. . 37 . 1 . 42–7 . February 1978 . 305233 . 1000187 . 10.1136/ard.37.1.42.
  2. Lada G, Gyódi E, Gláz E . HLA antigens in patients with adrenocortical hyperfunction . Acta Med Acad Sci Hung . 34 . 4 . 213–26 . 1977 . 618054 .
  3. Ludwig H, Polymenidis Z, Granditsch G, Wick G . [Association of HL-A1 and HL-A8 with childhood celiac disease] . de . Z Immunitatsforsch Exp Klin Immunol . 146 . 2 . 158–67 . November 1973 . 4282973 .
  4. Mackay IR, Morris PJ . Association of autoimmune active chronic hepatitis with HL-A1,8 . Lancet . 2 . 7781 . 793–5 . October 1972 . 4116233 . 10.1016/S0140-6736(72)92149-6.
  5. Feltkamp TE, van den Berg-Loonen PN, Engelfriet CP, etal . [HL-A typing and autoantibodies in patients with myasthenia gravis] . nl . Ned Tijdschr Geneeskd . 118 . 23 . 895–6 . June 1974 . 4839444 .
  6. Hammarström L, Smith E, Möller E, Franksson C, Matell G, Von Reis G . Myasthenia gravis: studies on HL-A antigens and lymphocyte subpopulations in patients with myasthenia gravis . Clin. Exp. Immunol. . 21 . 2 . 202–15 . August 1975 . 1081023 . 1538268 .
  7. Gazit E, Sartani A, Mizrachi Y, Ravid M . HLA antigen in Jewish patients with juvenile diabetes mellitus . Diabete Metab . 3 . 1 . 55–8 . March 1977 . 858444 .
  8. Vogten AJ, Shorter RG, Opelz G . HLA and cell-mediated immunity in HBsAg negative chronic active hepatitis . Gut . 20 . 6 . 523–5 . June 1979 . 89064 . 1412459 . 10.1136/gut.20.6.523.
  9. Ercilla G, Parés A, Arriaga F, etal . Primary biliary cirrhosis associated with HLA-DRw3 . Tissue Antigens . 14 . 5 . 449–52 . November 1979 . 12731577 . 10.1111/j.1399-0039.1979.tb00874.x.
  10. Robinson BN, Roberts DF, Mather BA, Nelson R, Rowlatt AS . Coeliac disease and HLA: a family study . European Journal of Immunogenetics . 7 . 5 . 381–91 . October 1980 . 7430678 . 10.1111/j.1744-313X.1980.tb00732.x.
  11. Tosi R, Vismara D, Tanigaki N, etal . Evidence that celiac disease is primarily associated with a DC locus allelic specificity . Clin. Immunol. Immunopathol. . 28 . 3 . 395–404 . September 1983 . 6192959 . 10.1016/0090-1229(83)90106-X.
  12. Goldberg MA, Arnett FC, Bias WB, Shulman LE . Histocompatibility antigens in systemic lupus erythematosus . Arthritis Rheum. . 19 . 2 . 129–32 . 1976 . 1259797 . 10.1002/art.1780190201.
  13. Parks CG, Pandey JP, Dooley MA, etal . Genetic polymorphisms in tumor necrosis factor (TNF)-alpha and TNF-beta in a population-based study of systemic lupus erythematosus: associations and interaction with the interleukin-1alpha-889 C/T polymorphism . Hum. Immunol. . 65 . 6 . 622–31 . June 2004 . 15219382 . 10.1016/j.humimm.2004.03.001 .
  14. Noble JA, Martin A, Valdes AM, etal . Type 1 diabetes risk for human leukocyte antigen (HLA)-DR3 haplotypes depends on genotypic context: association of DPB1 and HLA class I loci among DR3- and DR4-matched Italian patients and controls . Hum. Immunol. . 69 . 4–5 . 291–300 . 2008 . 18486765 . 2505335 . 10.1016/j.humimm.2008.02.003 .
  15. Noble J, Valdes A, Bugawan T, Apple R, Thomson G, Erlich H . The HLA class I A locus affects susceptibility to type 1 diabetes. . Hum Immunol . 63 . 8 . 657–64 . 2002 . 12121673 . 10.1016/S0198-8859(02)00421-4. 4049513 .
  16. Soothill JF, Stokes CR, Turner MW, Norman AP, Taylor B . Predisposing factors and the development of reaginic allergy in infancy . Clinical & Experimental Allergy . 6 . 4 . 305–19 . July 1976 . 963861 . 10.1111/j.1365-2222.1976.tb01911.x.
  17. Ostergaard PA, Eriksen J . Association between HLA-A1,B8 in children with extrinsic asthma and IgA deficiency . Eur. J. Pediatr. . 131 . 4 . 263–70 . August 1979 . 477683 . 10.1007/BF00444347.
  18. Ambrus M, Hernádi E, Bajtai G . Prevalence of HLA-A1 and HLA-B8 antigens in selective IgA deficiency . Clin. Immunol. Immunopathol. . 7 . 3 . 311–4 . May 1977 . 872455 . 10.1016/0090-1229(77)90062-9.
  19. Dasgupta A, Misri N, Bala S . Population and family studies to demonstrate Ir genes: HLA haplotype in atopic allergy . Monogr Allergy . 11 . 75–9 . 1977 . 327293 .
  20. MacKie RM, Dick HM . A study of HLA antigen distribution in families with atopic dermatitis . Allergy . 34 . 1 . 19–23 . February 1979 . 453484 . 10.1111/j.1398-9995.1979.tb01996.x.
  21. Heikkilä M, Koistinen J, Lohman M, Koskimies S . Increased frequency of HLA-A1 and -B8 in association with total lack, but not with deficiency of serum IgA . Tissue Antigens . 23 . 5 . 280–3 . May 1984 . 6611606 . 10.1111/j.1399-0039.1984.tb00046.x.
  22. Turner MW, Brostoff TJ, Wells RS, Stokes CR, Soothill JF . HLA in eczema and hay fever . Clin. Exp. Immunol. . 27 . 1 . 43–7 . January 1977 . 849649 . 1540890 .
  23. Jeannet M, Girard JP, Varonier HS, Mirimanoff P, Joye P . HLA antigens in grass pollinosis . Monogr Allergy . 11 . 69–73 . 1977 . 876128 .
  24. Oehling A, Baena-Cagnani CE, Sanz ML, Crisci CD . HLA and pollinosis . Allergol Immunopathol (Madr) . 7 . 6 . 423–6 . 1979 . 539526 .
  25. Morris MJ, Vaughan H, Lane DJ, Morris PJ . HLA in asthma . Monogr Allergy . 11 . 30–4 . 1977 . 876121 .
  26. Steel CM, Ludlam CA, Beatson D, etal . HLA haplotype A1 B8 DR3 as a risk factor for HIV-related disease . Lancet . 1 . 8596 . 1185–8 . May 1988 . 2897006 . 10.1016/S0140-6736(88)92009-0.
  27. Kaslow RA, Duquesnoy R, VanRaden M, etal . A1, Cw7, B8, DR3 HLA antigen combination associated with rapid decline of T-helper lymphocytes in HIV-1 infection. A report from the Multicenter AIDS Cohort Study . Lancet . 335 . 8695 . 927–30 . April 1990 . 1970024 . 10.1016/0140-6736(90)90995-H.
  28. Cameron PU, Mallal SA, French MA, Dawkins RL . Major histocompatibility complex genes influence the outcome of HIV infection. Ancestral haplotypes with C4 null alleles explain diverse HLA associations . Hum. Immunol. . 29 . 4 . 282–95 . December 1990 . 1981061 . 10.1016/0198-8859(90)90042-N.
  29. Oksenhendler E, Autran B, Gorochov G, D'Agay MF, Seligmann M, Clauvel JP . CD8 lymphocytosis and pseudotumoral splenomegaly in HIV infection . Lancet . 340 . 8813 . 207–8 . July 1992 . 1353138 . 10.1016/0140-6736(92)90471-E.
  30. Hug G . Genetic factors and autoimmunity in viral hepatitis . Am. J. Clin. Pathol. . 65 . 5 Suppl . 870–5 . May 1976 . 218441 .
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  32. Freudenberg J, Baumann H, Arnold W, Berger J, Büschenfelde KH . HLA in different forms of chronic active hepatitis. A comparison between adult patients and children . Digestion . 15 . 4 . 260–70 . 1977 . 863130 . 10.1159/000198011.
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  35. Middleton D, Williams F, Hamill M, Meenagh A . Frequency of HLA-B alleles in a Caucasoid population determined by a two-stage PCR-SSOP typing strategy. . Hum Immunol . 61 . 12 . 1285–97 . 2000 . 11163085 . 10.1016/S0198-8859(00)00186-5.
  36. Schipper R, Schreuder G, D'Amaro J, Oudshoorn M . HLA gene and haplotype frequencies in Dutch blood donors. . Tissue Antigens . 48 . 5 . 562–74 . 1996 . 8988539 . 10.1111/j.1399-0039.1996.tb02670.x.
  37. Bugawan T, Klitz W, Blair A, Erlich H . High-resolution HLA class I typing in the CEPH families: analysis of linkage disequilibrium among HLA loci. . Tissue Antigens . 56 . 5 . 392–404 . 2000 . 11144287 . 10.1034/j.1399-0039.2000.560502.x.
  38. Müller C, Ehninger G, Goldmann S . Gene and haplotype frequencies for the loci hLA-A, hLA-B, and hLA-DR based on over 13,000 German blood donors. . Hum Immunol . 64 . 1 . 137–51 . 2003 . 12507825 . 10.1016/S0198-8859(02)00706-1.
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  40. Marroni F, Curcio M, Fornaciari S, Lapi S, Mariotti M, Scatena F, Presciuttini S . Microgeographic variation of HLA-A, -B, and -DR haplotype frequencies in Tuscany, Italy: implications for recruitment of bone marrow donors. . Tissue Antigens . 64 . 4 . 478–85 . 2004 . 15361126 . 10.1111/j.1399-0039.2004.00292.x.
  41. Cao K, Moormann A, Lyke K, Masaberg C, Sumba O, Doumbo O, Koech D, Lancaster A, Nelson M, Meyer D, Single R, Hartzman R, Plowe C, Kazura J, Mann D, Sztein M, Thomson G, Fernández-Viña M . Differentiation between African populations is evidenced by the diversity of alleles and haplotypes of HLA class I loci. . Tissue Antigens . 63 . 4 . 293–325 . 2004 . 15009803 . 10.1111/j.0001-2815.2004.00192.x.
  42. Arnaiz-Villena A, Iliakis P, González-Hevilla M, Longás J, Gómez-Casado E, Sfyridaki K, Trapaga J, Silvera-Redondo C, Matsouka C, Martínez-Laso J . The origin of Cretan populations as determined by characterization of HLA alleles. . Tissue Antigens . 53 . 3 . 213–26 . 1999 . 10203014 . 10.1034/j.1399-0039.1999.530301.x.
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