HLA A1-B8 haplotype

Mgh
haplotype = Class I, A1-Cw7-B8


image_source = HLA region on chromosome 6
chromosome = 6
location = 6p21.3
placement = right
chromosome = 6
location = 6p21.3
variable =
alias = "HL A1,8; HL A1,A8; HLA A1-B8;
HLA A*01-B*08, HLA A*0101-B*0801 . . "
othertype = Serotype
loci1name = HLA-F
to
HLA-A
loci1rows = 3
gene1name = HLA-F
gene1var = [http://www.ebi.ac.uk/cgi-bin/imgt/hla/get_allele.cgi?F*01010301 *0101]
type1var = -
loci2name =
loci2rows =
gene2name = HLA-G
gene2var = [http://www.ebi.ac.uk/cgi-bin/imgt/hla/get_allele.cgi?G*01010201 *0101]
type2var = -
loci3name =
loci3rows =
gene3name = HLA-A
gene3var = *0101
type3var = A1
loci4name = HLA-E
loci4rows = 1
gene4name = HLA-E
gene4var = [http://www.ebi.ac.uk/cgi-bin/imgt/hla/get_allele.cgi?E*01010101 *0101]
type4var = -
loci5name = Cw-B
loci5rows = 2
gene5name = HLA-C
gene5var = *0701
type5var = Cw7
loci6name = -
loci6rows =
gene6name = HLA-B
gene6var = *0801
type6var = B8
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") is a multigene that covers the MHC Class I region of the human major histocompatibility complex on chromosome 6. A multigene haplotype is set of inherited 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:

HLA A*0101 : Cw*0701 : B*0801

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 chromsome 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, in the European population.cite journal |author=Gazit E, Sartani A, Mizrachi Y, Ravid M |title=HLA antigen in Jewish patients with juvenile diabetes mellitus |journal=Diabete Metab |volume=3 |issue=1 |pages=55–8 |year=1977 |month=March |pmid=858444 |doi= |url=] cite journal |author=Vogten AJ, Shorter RG, Opelz G |title=HLA and cell-mediated immunity in HBsAg negative chronic active hepatitis |journal=Gut |volume=20 |issue=6 |pages=523–5 |year=1979 |month=June |pmid=89064 |pmc=1412459 |doi= |url=http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=89064] cite journal |author=Ercilla G, Parés A, Arriaga F, "et al" |title=Primary biliary cirrhosis associated with HLA-DRw3 |journal=Tissue Antigens |volume=14 |issue=5 |pages=449–52 |year=1979 |month=November |pmid=12731577 |doi= |url=] cite journal |author=Robinson BN, Roberts DF, Mather BA, Nelson R, Rowlatt AS |title=Coeliac disease and HLA: a family study |journal=J. Immunogenet. |volume=7 |issue=5 |pages=381–91 |year=1980 |month=October |pmid=7430678 |doi= |url=] cite journal |author=Tosi R, Vismara D, Tanigaki N, "et al" |title=Evidence that celiac disease is primarily associated with a DC locus allelic specificity |journal=Clin. Immunol. Immunopathol. |volume=28 |issue=3 |pages=395–404 |year=1983 |month=September |pmid=6192959 |doi= |url=] 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.

ystemic 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.cite journal |author=Goldberg MA, Arnett FC, Bias WB, Shulman LE |title=Histocompatibility antigens in systemic lupus erythematosus |journal=Arthritis Rheum. |volume=19 |issue=2 |pages=129–32 |year=1976 |pmid=1259797 |doi= |url=] 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.cite journal |author=Parks CG, Pandey JP, Dooley MA, "et al" |title=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 |journal=Hum. Immunol. |volume=65 |issue=6 |pages=622–31 |year=2004 |month=June |pmid=15219382 |doi=10.1016/j.humimm.2004.03.001 |url=]

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.cite journal |author=Noble JA, Martin A, Valdes AM, "et al" |title=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 |journal=Hum. Immunol. |volume=69 |issue=4-5 |pages=291–300 |year=2008 |pmid=18486765 |pmc=2505335 |doi=10.1016/j.humimm.2008.02.003 |url=] 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.cite journal | author = Noble J, Valdes A, Bugawan T, Apple R, Thomson G, Erlich H | title = The HLA class I A locus affects susceptibility to type 1 diabetes. | journal = Hum Immunol | volume = 63 | issue = 8 | pages = 657–64 | year = 2002 | pmid = 12121673 | doi = 10.1016/S0198-8859(02)00421-4] 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. cite journal |author=Soothill JF, Stokes CR, Turner MW, Norman AP, Taylor B |title=Predisposing factors and the development of reaginic allergy in infancy |journal=Clin. Allergy |volume=6 |issue=4 |pages=305–19 |year=1976 |month=July |pmid=963861 |doi= |url=] A1, B8 was found increased in children with bronchial asthma and low IgA.cite journal |author=Ostergaard PA, Eriksen J |title=Association between HLA-A1,B8 in children with extrinsic asthma and IgA deficiency |journal=Eur. J. Pediatr. |volume=131 |issue=4 |pages=263–70 |year=1979 |month=August |pmid=477683 |doi= |url=] However, some of this reaction can be attributed to the linkage of the HLA A1-B8-DR3-DQ2 haplotype to the IgA-less phenotype.cite journal |author=Ambrus M, Hernádi E, Bajtai G |title=Prevalence of HLA-A1 and HLA-B8 antigens in selective IgA deficiency |journal=Clin. Immunol. Immunopathol. |volume=7 |issue=3 |pages=311–4 |year=1977 |month=May |pmid=872455 |doi= |url=] A firmer association was found with atopies.cite journal |author=Dasgupta A, Misri N, Bala S |title=Population and family studies to demonstrate Ir genes: HLA haplotype in atopic allergy |journal=Monogr Allergy |volume=11 |issue= |pages=75–9 |year=1977 |pmid=327293 |doi= |url=] cite journal |author=MacKie RM, Dick HM |title=A study of HLA antigen distribution in families with atopic dermatitis |journal=Allergy |volume=34 |issue=1 |pages=19–23 |year=1979 |month=February |pmid=453484 |doi= |url=] cite journal |author=Heikkilä M, Koistinen J, Lohman M, Koskimies S |title=Increased frequency of HLA-A1 and -B8 in association with total lack, but not with deficiency of serum IgA |journal=Tissue Antigens |volume=23 |issue=5 |pages=280–3 |year=1984 |month=May |pmid=6611606 |doi= |url=] A1,B8 where found more frequently in hay fever complicated by asthma or atopia relative to just hay fever.cite journal |author=Turner MW, Brostoff TJ, Wells RS, Stokes CR, Soothill JF |title=HLA in eczema and hay fever |journal=Clin. Exp. Immunol. |volume=27 |issue=1 |pages=43–7 |year=1977 |month=January |pmid=849649 |pmc=1540890 |doi= |url=] cite journal |author=Jeannet M, Girard JP, Varonier HS, Mirimanoff P, Joye P |title=HLA antigens in grass pollinosis |journal=Monogr Allergy |volume=11 |issue= |pages=69–73 |year=1977 |pmid=876128 |doi= |url=] cite journal |author=Oehling A, Baena-Cagnani CE, Sanz ML, Crisci CD |title=HLA and pollinosis |journal=Allergol Immunopathol (Madr) |volume=7 |issue=6 |pages=423–6 |year=1979 |pmid=539526 |doi= |url=] Further asthmatic patients with negative skin tests tended toward higher A1,B8 serotypes.cite journal |author=Morris MJ, Vaughan H, Lane DJ, Morris PJ |title=HLA in asthma |journal=Monogr Allergy |volume=11 |issue= |pages=30–4 |year=1977 |pmid=876121 |doi= |url=]

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.cite journal |author=Steel CM, Ludlam CA, Beatson D, "et al" |title=HLA haplotype A1 B8 DR3 as a risk factor for HIV-related disease |journal=Lancet |volume=1 |issue=8596 |pages=1185–8 |year=1988 |month=May |pmid=2897006 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(88)92009-0] 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.cite journal |author=Kaslow RA, Duquesnoy R, VanRaden M, "et al" |title=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 |journal=Lancet |volume=335 |issue=8695 |pages=927–30 |year=1990 |month=April |pmid=1970024 |doi= |url=] The strongest associations were seen with A1-Cw7-B8 haplotype. C4 (compliment 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. cite journal |author=Cameron PU, Mallal SA, French MA, Dawkins RL |title=Major histocompatibility complex genes influence the outcome of HIV infection. Ancestral haplotypes with C4 null alleles explain diverse HLA associations |journal=Hum. Immunol. |volume=29 |issue=4 |pages=282–95 |year=1990 |month=December |pmid=1981061 |doi= |url=] The haplotype was further linked to false-tumor splenomegaly, CD8 lymphocytosis, and high IgG.cite journal |author=Oksenhendler E, Autran B, Gorochov G, D'Agay MF, Seligmann M, Clauvel JP |title=CD8 lymphocytosis and pseudotumoral splenomegaly in HIV infection |journal=Lancet |volume=340 |issue=8813 |pages=207–8 |year=1992 |month=July |pmid=1353138 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/0140-6736(92)90471-E]

Viral hepatitis

An association was seen between viral hepatitis and HLA-A1.cite journal |author=Hug G |title=Genetic factors and autoimmunity in viral hepatitis |journal=Am. J. Clin. Pathol. |volume=65 |issue=5 Suppl |pages=870–5 |year=1976 |month=May |pmid=218441 |doi= |url=] cite journal |author=Descamps B, Jungers P, Naret C, Degott C, Zingraff J, Bach JF |title=HLA-A1, B8-phenotype association and HBs antigenemia evolution in 440 hemodialyzed patients |journal=Digestion |volume=15 |issue=4 |pages=271–7 |year=1977 |pmid=67978 |doi= |url=] Though, the association of A1 with autoimmune hepatitis with no anti-viral antibody was stronger than with chronic active hepatitis with anti-viral titer.cite journal |author=Freudenberg J, Baumann H, Arnold W, Berger J, Büschenfelde KH |title=HLA in different forms of chronic active hepatitis. A comparison between adult patients and children |journal=Digestion |volume=15 |issue=4 |pages=260–70 |year=1977 |pmid=863130 |doi= |url=] The association with viral hepatitis was subsequently demonstrated and patients with antinuclear antibodies were more likely to have A1-B8-DR3.cite journal |author=Czaja AJ, Carpenter HA, Santrach PJ, Moore SB |title=Immunologic features and HLA associations in chronic viral hepatitis |journal=Gastroenterology |volume=108 |issue=1 |pages=157–64 |year=1995 |month=January |pmid=7806037 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0016508595000114] Currently studies point to association proximal the the Cw*0702-B*0801 loci.

Frequencies

References