HLA MHC Genetics Evolution Biostatistics Glossary Homepage
HLA-DR53 Fact File
M.Tevfik Dorak, M.D., Ph.D.
Contents:
Brief review of HLA-DR53 / DRB4
Disease Associations
Sequences
References
Links
PowerPoint presentation on MHC & Leukemia Associations in Humans
Latest paper reporting rs2395185 as a marker for the HLA-DRB4/DR53 lineage: Kennedy, Singh & Dorak. JNCI 2012
See below for disease associations of HLA-DR53 and rs2395185
HLA-DR53 specificity -encoded by HLA-DRB4- is exclusively found in association with haplotypes encoding the DR4, DR7 and DR9 broad specificities (i.e., all DRB1*04, *07, *09 alleles). It was originally called BR4x7, Hon7, MT3 and DRw53 1. HLA-DR53 is an HLA class II supertypic antigen expressed at somewhat lower level than the private HLA-DR antigens encoded by HLA-DRB1 2-6. The HLA-DRB4 promoter polymorphism is associated with differential expression of this locus 4 and this occurs at the level of mRNA production 3. No such difference between the transcripts of the HLA-DRB1 and HLA-DRB3 genes were found for the HLA-DR52/DRB3 haplotypes 7 which shows the highest transcriptional activity 6-8.
HLA-DR53 is not expressed on the HLA-B57DR7Dw11DQ9 (DQA1*02:01, DQB1*03:03) haplotype (as in the cell line DBB (IHW 9052) representing the conserved extended haplotype (CEH) 57.1) due to a base substitution at the 3' end of the first intron of the gene 9;10. In fact, the null allele of the HLA-DRB4 gene (DRB4*0103102N) is transcribed, but it is an aberrant protein due to the lack of splicing out of the first exon 11. An exception has been reported as an unexpected expression of HLA-DR53 in a DR7 (Dw11) : DQ9 - positive leukemia patient 12. More recently, further unusual associations have also been reported. The null allele DRB4*0103102N has been found on HLA-DRB1*04:01, *04:02 and *04:04 haplotypes 13;14. The reference cell lines for this allele are DBB and JHO2821 15;16.
The gene encoding the HLA-DR53 antigen is HLA-DRB4 which exists only on DRB1*04, *07 and *09 haplotypes. In HLA-DRB4, allelic differences occur and are not limited to exon 2 (b1 domain) but involve exon 3 (b2 domain) too. All expressed alleles belong to the DRB4*01 allelic series (see the Table below). The three main alleles (DRB4*0101101 [MOU-MANN, LKT3, LBUF-LBF, BSM and PRIESS cell lines]; *0102 [CML cell line], and *0103101 [BOLETH, JHAF, DKB and SUD cell lines]) differ by one amino acid substitution. DRB4*0102 differs from the others in codon 76 of the b1 domain (Asp to Gly substitution - creating a Bsp1286 I (or SduI) site), and DRB4*0103101 differs from the others in codon 135 of the b2 domain (Ser to Gly substitution - creating an EaeI (or CfrI) site). The rare alleles DRB4*0104 and DRB4*0105 have also been recognized 17-22. The null alleles which are not expressed are: DRB4*0103102N [DBB and 12762 cell lines], DRB4*0201N [GN016 cell line] and DRB4*0301N [GN017 cell line] 16;17;20;21. For the alignment of DRB4 allelic sequences, see the IMGT/HLA Sequence Database alignment page. The latest list of officially recognized HLA-DRB alleles can be found at the ANRC site.
Serological equivalents of HLA-DRB4 alleles
(From HLA Dictionary 2008 and Nomenclature Reports 1998, 2000 (Ref.22), 2002):
DRB4*01
DRB4*0101101 [DR53]
DRB4*0102 [DR53]
DRB4*0103101 [DR53]
DRB4*0103102N [null]
DRB4*01032 [DR53] [cell line W778R]
DRB4*01033 [equivalent to DRB4*0103101; Ref. 23]
DRB4*0104 [No serological equivalent is defined]
DRB4*0105 [DR53]
DRB4*02
DRB4*0201N [null]
DRB4*03
DRB4*0301N [null]
There is a high degree of diversity in the DRB1-DRB4 haplotypes 24. This is not surprising as these two genes have different evolutionary histories (see below). Some DRB1 alleles are associated with more than one DRB4 allele. This is exemplified by the association of DRB1*04:01 with either DRB4*01:01:101 or DRB4*01:03:101 (as in the cell lines BOLETH and SUD). In Caucasians and also in patients with rheumatoid arthritis, the commonest DRB4 allele is DRB4*01:03 25.
Common HLA-DRB4 haplotypes
|
Ancestral Haplotype
|
B/DRB1/DQB1
|
DRB4 |
Bw4/6 |
BF |
TNFB |
HSPA1B |
Frequency (%)
|
|
44.1 |
44/0401/0301 |
0101 |
4 |
S |
1 |
183 |
5.1 |
|
44.2 |
44/07/0201 |
0101 |
4 |
F |
2 |
183 |
3.9 |
|
57.1 |
57/07/03032 |
0103102N |
4 |
S |
2 |
183 |
2.7 |
|
60.1 |
60/0404/0302 |
0101 |
6 |
S |
2 |
- |
2.6 |
|
64.1 |
64/07/0201 |
0101 |
6 |
S |
2 |
- |
1.7 |
|
62.1 |
62/0401/0302 |
0101/0103 |
6 |
S |
2 |
183 |
1.5 (B62.X) |
|
62.2 |
62/0401/0302 |
0103 |
6 |
S |
2 |
183 |
|
|
62.4 |
62/0401/0302 |
0103 |
6 |
S |
2 |
183 |
|
|
13.1 |
13/07/0201 |
0101 |
4 |
S |
2 |
188 |
1.0 |
|
38.1 |
38/0402/0302 |
0101 |
4 |
S |
2 |
183 |
< 0.5 |
|
47.1 |
47/07/0201 |
0101 |
4 |
F |
2 |
183 |
< 0.5 |
|
50.1 |
50/07/0201 |
0101 |
6 |
S |
1 |
- |
< 0.5 |
|
51.1 |
51/0404/0301 |
0103 |
4 |
F |
2 |
183 |
< 0.5 |
|
(DKB) |
40/0901/0303 |
0103 |
6 |
S |
2 |
183 |
< 0.5 |
As exemplified in the cell lines BOLETH and BSM, the DRB4 may differ on the CEH 62.1 despite identity at DRB1 and DQB1. The haplotypes are shown in decreasing frequency order (in the Welsh population, Ref. 26) and those with a frequency of > 0.5% are shown in bold. The frequency column shows the haplotype frequencies for HLA-BDRDQ parts of the ancestral haplotypes in an adult Welsh population 26. The HSPA1B (HSP70-2) genotypes are from our own studies (Dorak et al. 2006) with confirmation from another report by Corzo et al. 27. TNF and BF genotypes are from Refs. 28, 29. Further information of the typings of IHW / 4AOH cell lines can be found at ECACC, IMGT and IHWG Cell Bank websites. See also Complete List of HLA-DR53 Homozygous Cell Lines.
Brief evolutionary history of the HLA-DRB haplotypes
Although there are different scenarios, the ancestor of the human HLA-DRB genes appears to have been HLA-DRB1*04-like (Figueroa, 1994; Satta, 1996a, Satta, 1996b) 30;31. Both DRB1*04- like ancestor and the ancestor of the DRB1*03 cluster have been estimated to be older than 85 mya (Figueroa, 1994) 30. This estimate derives from the fact that DRB1*04 alleles are found in Prosimian species (note that the mouse lineage separated about 75-80 mya). It is possible that DRB2 (on DR52 haplotypes), DRB4 (on DR53 haplotypes and most closely resembles DRB2), and DRB6 (on DR51 haplotypes) might be the diverged copies of a single ancestral DRB gene 32-34. Available evidence suggests that the different HLA-DRB genes arose by duplication that was followed by homogenization through gene conversions 35. The DR51 and DR52 haplotypes may share a common ancestry and the lineages separated after an ERV9 LTR insertion about 40-60 mya 33.
The DRB4 gene may have arisen 46 mya by a deletion from the DRB1 and DRB2 genes 31. The DRB9 locus is about 58 mya old 36 and the DRB4 lineage-specific pseudogenes DRB7 and DRB8 arose after DRB9 37. The remaining HLA-DR haplotypes, the DR1/10 and DR8 groups, probably evolved from the DR51 and DR52 haplotypes, respectively, after more recent deletion events 33. All DR53 haplotypes carry the DRB1, DRB4, DRB7, DRB8 and DRB9. genes. The DRB1 and DRB4 genes of the DR53 haplotypes have distinct evolutionary histories 38. It has to be noted that phylogenetic analysis results may vary depending on which part of the gene is analyzed. There is strong evidence that the present day HLA haplotypes derived from three main haplotypes corresponding to HLA-DR51, -DR52, and -DR53 haplotypes (Satta, 1996a) 31. This grouping is agreed by others too: an evolutionary grouping encompasses the HLA class II haplotype families characterized by the second expressed DRB genes encoding the supertypes, i.e., DRB5, DRB3 and DRB4 haplotype groups (Andersson, 1994). Since DR51 (incl. DR1/10) and DR52 (incl. DR8) haplotypes seem to share a common ancestor 33, it is possible to divide the HLA-DR haplotypes into two evolutionarily related groups: DR53 group and non-DR53 group as direct descendants of the two primordial DRB genes more than 85 mya old (but see below). In summary, two main, evolutionarily old branches of HLA-DR haplotypes exist in human population. The DR53 supertypic group represents one main branch, and the second branch consists of the DR51 and DR52 supertypic groups as well as the -DR1 and -DR8 lineages 33;39. The second branch (DR51/52 group) is characterized by the ERV9 LTR insertions at the identical position in the intron 5 of the expressed DRB genes (DRB1*01, *15, *0301, *0802; DRB3*0101) 33;39. However, note that the DRB5 lineage appears closer to the DRB3 group when intron 1 sequences are used (Hughes, 2000).
By direct comparison of exon 2 nucleotide sequences of DRB1 alleles, two groups of HLA class II haplotypes (HLA-DRB4/DRB5 and ‑DRB3) can be distinguished (Klein, 1990; Kasahara, 1992; Ayala, 1994; Svensson, 1995; Satta, 1996). The evolutionary tree of 58 HLA-DRB1 alleles show that these alleles coalesced into 44 lineages by 1.7 million years ago (Ayala, 1994; Fig 3). They further coalesced into two ancestral lineages about 25 to 30 million years ago with the exception of HLA-DRB1*0701. One of these lineages contains all HLA-DRB1*03, *11/12, *13/14 and *08 alleles examined (the DRB3 group and DRB1*08), while the other one contains all DRB1*04, *09, *15/16, *01 and *10 alleles examined (DRB4/5group and DRB1*01/*10).
Analysis of DRB gene sequences from primates showed that the age of polymorphism for DRB4 is very old, in fact, its age is only exceeded by DQB1 and DQA1 loci 40. The DRB4 locus is polymorphic also in Chimpanzees but not in other primates examined, and is subject to selection 40. This is suggested by a high dn/ds ratio (number of non-synonymous substitutions / synonymous substitutions). Also in humans, the HLA-DRB4 gene shows a very high dn/ds ratio only in the peptide-binding regions but not in the remainder of the gene 41. Therefore, the appearance of polymorphism accompanied by a high dn/ds ratio supports the notion that balancing selection is the driving force behind the maintenance of the polymorphism.
The most ancient polymorphic class II locus is likely to be HLA-DQA1 (Gyllensten & Erlich, 1989) 40;42. The polymorphism of this locus also correlates to the MHC class II supertypical groupings (Moriuchi, 1985) 43. This is most obvious in the HLA-DQA1 / TaqI RFLP patterns as used in an HLA-leukemia association study 44. The supertypes' being the ancient allelic lineages of MHC is also evident from the cross-reactivities among them in different species 45-49. Most interestingly, HLA-DR53 is cross-reactive with the corresponding supertype H‑2Ek 48;49. The HVR3 epitope of HLA-DR53 is shared by HLA-DR1 and HLA-DR10 50;51. This explains an earlier finding that an antibody specific for H-2Ek was found to be cross-reactive with HLA-DR1 when HLA-DR53 had not been recognized yet 52.
Extra DNA and pseudogenes on HLA-DR53 haplotypes
One exclusive feature of the DRB4-carrying haplotypes (haplotypes with all DRB1*04, *07 and *09 alleles) is that they have an extra amount of DNA compared to the DR3 haplotype irrespective of the DRB1 type 53-56. It is not yet known whether this DNA contains novel genes besides the lineage-specific pseudogenes DRB7 and DRB8. Although the sequencing of a human MHC haplotype was completed in 1999 57, the haplotype used in that study belongs to the shortest HLA-DR52 family. The Sanger Centre has also sequenced the class II region of a DR53 haplotype 57;58. Recently, processed pseudogenes (PRKRAP1) 59;60 and (FAM8A5P) (Jamain, 2001) have been identified that are exclusive to the DRB4/DR53 haplotypes. Sequencing of eight HLA haplotypes has now been completed (MHC Haplotype Project), but the final report does not comment on the additional DNA content of the HLA-DRB4 region (Horton, 2008). However, the MHC Haplotype Project has reported identification of three novel pseudogenes ((DASS–218M11.1, DASS–23B5.1, and DASS–23B5.2; nucleotide sequence, cDNA sequence) (Horton, 2008) with DASS–23B5.1 corresponding to PRKRAP1, and others presumably to LOC100294188 and LOC100507714. According to these findings, in the HLA-DRB4 region, there are at least four unique pseudogenes located between HLA-DRA and ‑DQA1. Their role, if any, in any biologic phenomenon is yet unknown. A novel feature of the pseudogenes within the HLA complex is the high (70%) transcription rate (Vandiedonck, 2011). These pseudogenes may therefore be transcribed too. Please note that the reference sequence used for the HLA region derives from the PGF cell line which belongs to the HLA-DRB5/DR51 family and does not contain the DRB4-specific pseudogenes. Thus, these pseudogenes, in fact not even DRB4, are not included in common maps of the region (but see the links given for these pseudogenes (PRKRAP1, FAM8A5P, LOC100294188, LOC100507714) to locate them within the DRB4 haplotype).
Immunological function of HLA-DR53
The HLA-DR53 molecule has a unique peptide-binding motif and indeed binds peptides (most frequently an autoantigen calreticulin 'p278-292' involved in class I peptide presentation pathway, L-plastin 'p581-595', gliadin 'various peptides', a melanocyte antigen gp100, and a cancer antigen 'NY-ESO-1') 61-69. In a diabetic patient, an autoreactive T cell clone has been shown to recognize a fragment of HLA-DR4 presented by HLA-DR53 64. The putative peptide binding motif of HLA-DR53 is a positively charged residue (K) at position 1, a hydrophobic residue (I) at position 4, a positively charged residue (R or K) at position 8 or 9, and another hydrophobic residue (I) at position 10 (the C-terminus) 62;65; but another study found no preference for P1; while F, I, M, T are favorable residues for P4; F, A, I, T are for P6; I, T are for P9; and D for P10 67. The crucial residues on the HLA-DRb molecules are residues 86 and 57. In the HLA-DR53 molecule, b57 is D and b86 is V (the tyrosine at b81 is unique to HLA-DR53 and may indirectly alter the specificity of pocket 1 by providing a higher flexibility to the peptide 67. It is thought that the hydrophobic b86V has an influence on the HLA-DR53 binding motif composed of a positively charged residue at the N-terminus; and the negatively charged b57D (and/or b9E) interacts with the positively charged residues at the C-terminus of the peptide 62.
Among the peptides eluted from HLA-DR4/DR9/DR53, the most interesting is calreticulin. It is a peptide-binding cytoplasmic molecular chaperone which behaves like a tumor-rejection antigen by eliciting CTL response against bound peptides 70;71. Calreticulin is also implicated in a number of autoimmune disorders 72. The peptide fragment of calreticulin found bound to HLA-DR53/DR4 61;73 is as follows:
(278/295) DNPEY SPDPS IYAYD (292/309)
The residues in bold correspond to relative positions 1 and 6 of anchor residues in HLA-DR4 / HLA-DR53. This sequence is not found in any other human protein listed on the SwissPort database (as of May 2006).
Another peptide which binds to HLA-DRB4*0101 for presentation is dihydrolipoamide acetyltransferase component of pyruvate dehydrogenase complex (PDC-E2 also known as 70 kDa mitochondrial autoantigen of primary biliary cirrhosis) peptide 65:
(163) GDLLAEIETDKATI (176)
The crucial amino acids in binding of this peptide to HLA-DR53 are shown in bold. This peptide sequence is not shared by another human protein in the SwissPort database either. Despite binding of these peptides to the DR53 molecule, if you do a search for DR53-specific epitopes in these sequences using the HLA-peptide binding motif scanner, it does not find any epitope that would bind to DR53.
The peptide binding motifs of the individual HLA-DR53 family members, HLA-DR4, ‑DR7 and ‑DR9, are known 61;63;74-77.
HLA-DR53 is immunologically functional and no different from any other HLA-DR antigen. HLA-DR53 acts as a restriction element in antigen presentation 48;64;65;78-83. Among the antigens for which it is a restriction element are Hsp70 of M. leprae (Mustafa, 1994; Adams, 1997) 81;82 (see also Joko, 1995 and White, 1997 for protective role of HLA-DR53 in leprosy), the PDC-E2 (mitochondrial autoantigen of primary biliary cirrhosis) (Shigematsu H, 2000) 65;80, a Chlamydia trachomatis antigen 78 (see also White, 1997 for protective role of HLA-DR53 in blinding trachoma), glutamic acid decarboxylase [an autoantigen in diabetes] 83, TARP (prostate and breast tumor antigen) (Kobayashi, 2005), and most interestingly the HLA-DR4 molecule 64. Beta2-glycoprotein I (beta2GPI)-specific CD4+ T cells preferentially recognize the antigenic peptide containing the major phospholipid (PL)-binding site in the context of DR53, and autoreactive CD4+ T cells to beta2-glycoprotein I (beta2GPI) that promote production of pathogenic antiphospholipid antibodies (Kuwana, 2004).
The HLA-DR53 molecule is known to have poor interaction with CD4 which is determined by the polymorphic residues between positions beta 180 and 189 (Fleury, 1995) 84. Another feature of the HLA-DR53 molecule is its low affinity for superantigen binding (Herman, 1991; Karp & Long, 1992) 85;86. The DR53 family molecules DR4 and DR7 are associated with low IFN-g production in an MLR context (but also DR3 and DR5) 87.
The residues 80 to 83 of HLA-DRb chain (residues 80 RHNY 83) control the post-Golgi entry of class II molecules into endosomes 88. This sequence is highly conserved among all HLA-DRB alleles except HLA-DRB4*01 (80 RYNY 83). It is not known what effect this may have on the intracellular transport of the HLA-DRb4 chain. Although the effect of this difference has not been studied specifically, it is known that a single amino acid change at position 81 (where HLA-DRB4*01 differs from the rest) severely affects the intracellular transport of the mutant HLA-DRb chain and possibly also its peptide presentation ability 88. One other segment that is unique to all HLA-DRB4 alleles lies between residues 39 and 42 of b1 domain encoded by exon 2. The consensus amino acid sequence of this segment is Arg-Phe-Asp-Ser (RFDS) in all DRB1 (except *0433, *10011 and *10112), DRB3, DRB5, DQB1 and DPB1 alleles (IMGT database). It is, however, Arg-Tyr-Asn-Ser (RYNS) in all HLA-DRB4 alleles (Young, 1987) 89. The importance of this finding is that this segment may be important for T-cell recognition 90.
The above-mentioned studies suggest that although there is no doubt that HLA-DR53 is an immunologically functional HLA molecule, the functionality of DR53 itself and that of the DR alleles who are the members of the DR53 family may be somewhat lower than other HLA-DR alleles. These features of the HLA-FR53 family of haplotypes may be the immunological mechanism of the homozygous HLA-DR53 association in CML, CLL and childhood ALL (see PowerPoint presentation on MHC & Leukemia Associations in Humans).
Cross-reaction with H-2Ek
Several monoclonal antibodies react with various epitopes of HLA-DR53. Among these, 17-3-3s also reacts with the mouse class II supertype H-2Ek (r=0.88; p=10-12) 49, and 109d6 recognizes the HVR3-encoded epitope and detects it as a susceptibility marker for adult acute myeloblastic leukemia 91 and rheumatoid arthritis 92. The cross-reaction with H-2Ek may be of functional significance as H-2k haplotype is invariably associated with increased risk for spontaneous and virus-induced mouse leukemia 93-95.
Molecular mimicry
The HVR3-encoded epitope is mimicked in its entirety (67 LLERRRA 74, exon 2) by the E3-14.7K protein of adenovirus and the large tegument protein of EBV 96. The HVR3 epitope is identical in all DRB4 variants. The following DRB1 alleles also share this epitope: DRB1*0101, 0102, 0104, 0105, 0106, 0404, 0405, 0408, 0410, 0419, 0423, 0428, 0430, 0440, 0442, 1134, 1344, 1402, 1406, 1409, 1413, 1420, 1429, 1430, 1433. DRB1*1001 shares the epitope with the exception of a single conservative amino acid change in position 70 (Q70R). A large group of DRB1*14 alleles show the same conservative amino acid change from the DR53 HVR3 epitope. These are 1401, 1407, 1408, 1410, 1411, 1414, 1418, 1423, 1426, 1428, 1431, 1432, 1434, 1435, 1436, 1438 and 1439. Therefore, it 4can be said that the mimicry by several oncogenic viruses of the HVR3 epitope of DR53 extends to DRB1*01, *10 and *14 alleles.
This is the greatest molecular mimicry ever reported between an HLA molecule and a non-HLA protein. Given the fact that HLA-DR53 or HLA-DR4/7/9 are associated with a number of diseases including all major leukemias and several other malignancies, it is likely that this molecular mimicry is operative in the pathogenesis of these diseases. It has been proposed that molecular mimicry with adenovirus, together with other features of HLA-DR53, may play a role in the development of childhood acute lymphoblastic leukemia 97. A recent study has shown an increased frequency of antibodies against EBV in childhood acute lymphoblastic leukemia, which suggests the involvement of EBV in the development of this leukemia 98.
Disease associations
A number of autoimmune, viral and malignant diseases are associated with HLA-DR53 or HLA-DR4/7/9:
* Rheumatoid arthritis (DRB1*04 and DRB4*01 susceptibility; DRB1*07 protection) 92;99-111 (homozygosity for HLA-DR4 in young males 110;111; HLA-DR4,7 genotype more frequent in males 112; association with ancestral HLA-DR haplotypes in males only 99)
* Felty syndrome (DR4) 113
* Early-onset psoriatic arthritis (DR4, DR53) 114
* Pemphigus vulgaris (DRB1*04) 115
* Polymyalgia rheumatica 116
* Giant cell arteritis 117-119, in one study HLA-DR7 association in males only 120
* Primary antiphospholipid syndrome (DRB1*07 and DRB4*01) 121-124 (see also Kuwana, 2004 for the molecular mechanism)
* Recurrent spontaneous pregnancy loss associated with the presence of anticardiolipin (antiphospholipid) antibodies 125
* Recurrent spontaneous pregnancy loss (DR4) 126, and pre-eclampsia (DR4) 127;128 or B44DR7 129;130
* Intrauterine growth retardation (B44DR7) 129
* IDDM (DRB1*04 and DRB1*03) 131. Under 13 yr, an excess of females in the DR3+/DR4- group; and an excess of males in DR3-/DR4+ group 132;133.
* Myasthenia gravis in Japan (DR53 in early-onset disease in females) 134
* Hashimoto thyroiditis 135;136
* Graves disease (DR9) (in China and in males only) 137;138
* Crohn disease in Japan: HLA-DR53 & DRB1*0402, *0405, *0410 139-141
* Protection from ulcerative colitis: DRB4*0101 140 (replicated as a protective association with rs2395185: Silverberg, 2009)
* Celiac disease 66
* Sympathetic ophthalmia: HLA DRB1*04 and DQA1*03 (Kilmartin, 2000)
* Vogt-Koyanagi-Harada syndrome 142-146
* Churg-Strauss syndrome (Vaglio, 2007)
* 70kd U1-snRNP antibody-positive connective tissue disease 147;148
* HTLV-1-associated HAM/TSP: B*54,DRB1*0405 149
* Rheumatic fever 150;151
* Protection from multiple sclerosis (together with HLA-DR1) 152
* Development of antibodies against IFN-beta treatment in multiple sclerosis: HLA-DRB1*0401 & *0408 (Hoffmann, 2008 & Buck, 2011); DRB1*07 (Barbosa, 2006)
* Erythema multiforme [herpes virus related] 153-155
* CMV infections in AIDS: (B44)DR7 156;157
* Persistence of hepatitis C infection 158;159, lack of response to interferon treatment in hepatitis C infection 160 (B*54,DRB1*0405 in Japan)
* Unresponsiveness to hepatitis B surface antigen: B*54,DRB1*0405 haplotype in the Japanese 161, DRB1*07 in Caucasians 162
* Autoimmune hepatitis in Japan (HLA-B54, DRB1*0405) 163
* Actinic prurigo (DRB1*0407) 164
* Atopy (DR4, DR7) 165
* Drug reaction to Abacavir 166
* Rapidly progressing periodontitis (DR4) 167
* Podoconiosis (a tropical lymphedema) risk & DRB1*0701 (Ayele et al, 2012)
* Long-QT syndrome (DR7, in males only) 168
* Autism (the HVR3 shared epitope of HLA-DRB1*0401 and *0404) 169
* Anti-glomerular basement membrane disease (DRB1*04 susceptibility / DRB1*07 protection) 170
* Thrombotic thrombocytopenic purpura/adult hemolytic uremic syndrome (protective) 171 (replicated by Scully et al, 2010)
* Immune thrombocytopenic purpura: DRB1*0410 in Japan 172
* Vitiligo (in blacks) 173
* Creutzfeldt-Jakob disease (CJD) in Japan 174
* Longevity: negative association with homozygosity for DR53 in males only 175; increased DR7 and decreased DR4 in the elderly (above 75 years) 176; increased DR7 in male centenarians 177.
* Protective association in leprosy (Joko, 1995 & White, 1997) and blinding trachoma (White, 1997).
Malignancies
* Lymph node metastasis in gastric cancer (DR4) 178;179
* Gall bladder cancer (DR4) 180
* Breast cancer in Russia (DR4) 181
* Skin cancer (DR7) 182;183, in post-transplant patients 184
* Melanoma (DR4) 185
* Thyroid cancer (DR7) 186
* Germ-cell testis tumors (obviously in males only) (DR7) 187-189 and DR4 190;191
* Burkitt lymphoma (DR7) 192
* Cervical cancer in HPV-16-positive patients (DR7) 193;194
* Protective effect from renal cell carcinoma in the Japanese (DRB1*0405 and *0101) 195
Leukemia & Lymphoma (PPT)
* Adult acute myeloblastic leukemia risk (DR53 HVR3 epitope) 91
* Childhood acute lymphoblastic leukemia risk (homozygosity for DR53 in males only) 196;197 (Dorak et al, 1999; replicated using rs2395185; Dorak et al. unpublished)
* Childhood acute lymphoblastic leukemia risk (homozygosity for DR7) 198
* Chronic myeloid leukemia risk (DR53) 44 (Oguz et al, 2003)
* Chronic lymphoid leukemia risk (A2B44DR7) 199 and (DR53) 200;201
* Large granular lymphocyte leukemia with arthritis (DRB1*04) [Coakley G et al., BSHI98 abstract]
* Worse prognosis following BMT 202 (HLA-DR4 is also a marker for worse prognosis after BMT for lymphoma: Aggarwal et al, 2008)
* Strongest (protective) marker for Hodgkin lymphoma (Urayama et al, 2012; see also the related correspondence)
rs2395185 associations
* Strongest (protective) marker for Hodgkin lymphoma (Urayama et al, 2012; see also the related correspondence)
* Childhood acute lymphoblastic leukemia risk (Dorak et al, unpublished)
* Ulcerative colitis (variant allele T protective; common allele G risk) (originally in a European population, Silverberg et al, 2009); replicated in Japan (Asano, 2009), Italy (Latiano, 2011) and India (Juyal, 2011)
* Asthma risk (Li, 2012)
* High-density lipoprotein and waist-to-hip ratio in metabolic syndrome (Min et al, 2012)
* Trans associations with the expression levels of AOAH (inverse correlation) and ARHGAP24 in monocytes (Fairfax et al, 2012); AOAH and TRBV18 in whole peripheral blood (Fehrmann, 2011); B4GALT2, ASB5, STK32A, OXT, CSRP3, and LGALS4 in lymphoblastoid cell lines (Nica, 2010); CACNA1H (inverse); SPC25 (Suppl Table 6 in Stranger, 2007) in HapMap populations.
* Cis effect (inverse correlation) on HLA-DQA1 gene expression levels (see Additional File 1 in Heap, 2009; Suppl Table 3 in Stranger, 2007); identified as a master regulator of HLA class II gene (HLA-DRB1, -DQA1) expression levels (Suppl Table 3 in Dixon, 2007).
(Links to PubMed and dbSNP-PubMed for rs2395185 associations; rs2395185 in 1000 Genomes Browser)
Appendix
The aa sequence of DRB4*0103 (accession number: NP_068818; GI: 18641373)
1 MVCLKLPGGS CMAALTVTLT VLSSPLALAG DTQPRFLEQA KCECHFLNGT ERVWNLIRYI 61 YNQEEYARYN SDLGEYQAVT ELGRPDAEYW NSQKDLLERR RAEVDTYCRY NYGVVESFTV 121 QRRVQPKVTV YPSKTQPLQH HNLLVCSVNG FYPGSIEVRW FRNSQEEKAG VVSTGLIQNG 181 DWTFQTLVML ETVPRSGEVY TCQVEHPSMM SPLTVQWSAR SESAQSKMLS GVGGFVLGLL 241 FLGTGLFIYF RNQKGHSGLQ PTGLLS
The mRNA sequence of DRB4 (accession number: NM_021983; GI: 52630343)
1 ggggggccat agttctccct gattgagact tgcctgctgc tgtgaccact ggtcttgtcc
61 tcttctccag catggtgtgt ctgaagctcc ctggaggctc ctgtatggca gcgctgacag
121 tgacattgac ggtgctgagc tccccactgg ctttggctgg ggacacccaa ccacgtttct
181 tggagcaggc taagtgtgag tgtcatttcc tcaatgggac ggagcgagtg tggaacctga
241 tcagatacat ctataaccaa gaggagtacg cgcgctacaa cagtgacctg ggggagtacc
301 aggcggtgac ggagctgggg cggcctgacg ctgagtactg gaacagccag aaggacctcc
361 tggagcggag gcgggccgag gtggacacct actgcagata caactacggg gttgtggaga
421 gcttcacagt gcagcggcga gtccaaccta aggtgactgt gtatccttca aagacccagc
481 ccctgcagca ccacaacctc ctggtctgct ctgtgaatgg tttctatcca ggcagcattg
541 aagtcaggtg gttccggaac ggccaggaag agaaggctgg ggtggtgtcc acaggcctga
601 tccagaatgg agactggacc ttccagaccc tggtgatgct ggaaacagtt cctcggagtg
661 gagaggttta cacctgccaa gtggagcatc caagcatgat gagccctctc acggtgcaat
721 ggagtgcacg gtctgaatct gcacagagca agatgctgag tggagtcggg ggctttgtgc
781 tgggcctgct cttccttggg acagggctgt tcatctactt caggaatcag aaaggacact
841 ctggacttca gccaacagga ctcttgagct gaagtgcaga tgaccacatt caaggaagaa
901 ccttctgccc cagctttgca agatgaaaag ctttcccact tggctcttat tcttccacaa
961 gagctttgtc aggaccaggt tgttactggt tcagcaactc tgcagaaaat gtcctccctt
1021 gtggcttcct tagctcctgt tcttggcctg aagcctcaca gctttgatgg cagtgcctca
1081 tcttcaactt ttgtgcttcc ctttacctaa actgtcctgc ctcccgtgca tctgtactcc
1141 ccttgtgcca cacattgcat tattaaatgt ttctcaaaca tggagttaaa aaa
Genomic sequence of DRB4 (accession number: M20555; GI: 188433): The polymorphic exons 2 and 3 are nt 878-1147 and nt 3888-4160, respectively. See also a chromosome 6 draft sequence which includes the DRB4 gene (GI:29804596).
Genomic sequence of the DR subregion of the DR53 haplotype (DRA to DRB1; 150447 bp): accession number: NG_002433.1; GI:28212470. Compare DR53 with DR51 and DR52 haplotypes using PAIRWISE BLAST.
References
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Frequently Asked Questions about HLA-DR53 and Leukemia
SNP analysis of HLA-DRB4 Entrez-Gene: HLA-DRB4 dbSNP: HLA-DRB4
UniGene- HLA-DRB4: Hs.723344 & Hs.716081 Protein Database: HLA-DRB4 GeneCards: HLA-DRB4
HLA-DR53 monoclonal antibody: ABIN228535 & LS-C24567
Affymetrix Gene Expression Microarray Probe IDs: 215666 & 209728
Address for bookmark: http://www.dorak.info/hla/hla-dr53.html
M.Tevfik Dorak, M.D., Ph.D.
14 July 2013
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