HLA-DR4

HLA-DR4 (DR4) is an HLA-DR serotype that recognizes the DRB1*04 gene products. The DR4 serogroup is large and has a number of moderate frequency alleles spread over large regions of the world.

human major histocompatibility complex, class II, DR4
Haplotypes groups DRA*01:DRB1*0401 to DRA*01:DRB1*0413
Structure (See HLA-DR)
Identifiers
alpha *0101
Symbol(s) HLA-DRA
EBI-HLA DRA*0101
Identifiers
beta 1 *0401 to *0413
Symbol(s) HLA-DRB1
EBI-HLA DRB1*0401
EBI-HLA DRB1*0402
EBI-HLA DRB1*0403
EBI-HLA DRB1*0404
EBI-HLA DRB1*0405
EBI-HLA DRB1*0406
EBI-HLA DRB1*0407
EBI-HLA DRB1*0408
EBI-HLA DRB1*0409
EBI-HLA DRB1*0410
EBI-HLA DRB1*0411
EBI-HLA DRB1*0412
EBI-HLA DRB1*0413
Shared data
Locus chr.6 6p21.31

Serology
DR4 serological recognition of the gene products of some DRB1*04 alleles[1]
DRB1*DR4 Sample
allele%size (N)
04:01985118
04:02921029
04:0392748
04:04892164
04:0591505
04:068983
04:0786846
04:0886258
04:099513
04:108429
04:119376
04:12>501
04:13>303

The serological identification of DR4 is good. The serology of DRB1*04:17 to *04:60 is unknown.

Disease associations

By serotype

DR4 is associated with extraarticular[2] rheumatoid arthritis,[3] hydralazine-induced female systemic lupus erythematosus,[4] pemphigoid gestationis,[5] pemphigus foliaceus,[6] obstructive hypertrophic cardiomyopathy,[7] IgA nephropathy,[8] 'shared syndrome'-systemic sclerosis/rheumatoid arthritis[9] and polymyalgia rheumatica.[10]

By allele

DRB1*04 is associated with increased risk for alopecia areata.[11]

DRB1*04:01 is associated with multiple sclerosis,[12] rheumatoid arthritis,[13] type 1 diabetes,[14][15] lyme disease induced arthritis.[16]

DRB1*04:02: drug-triggered[17]/idiopathic pemphigus vulgaris,[18][19] type 1 diabetes,[15] SLE associated anti-cardiolipin and anti-β2 glycoprotein I.[20]

DRB1*04:03: polycystic ovary syndrome,[21] SLE associated anti-cardiolipin and anti-β2 glycoprotein I.[22]

DRB1*04:04: anti-citrullinated fibrinogen[23] in rheumatoid arthritis,[13] autoimmune hepatitis.[24]

DRB1*04:05: rheumatoid arthritis,[25] Autoimmune hepatitis,[26] type 1 diabetes.[14][15]

DRB1*04:06: caspase-8 autoantibodies silicosis-systemic sclerosis (SSc)-systemic lupus erythematosus (SLE).[27]

DRB1*04:09: T. cruzi infection with cardiomyopathy.[28]

By haplotype

DR4-DQ8 is a risk factor for papillary thyroid carcinoma,[29] juvenile diabetes, coeliac disease and rheumatoid arthritis.[30]

DRB1*04:DQA1*03:03-DQB1*04:01 haplotype: type III autoimmune polyglandular syndrome,[31] autoimmune hepatitis,[32] autoimmune pancreatitis.[33]

DRB1*04:DQA1*03-DQB1*03:02 haplotype: Type 1 diabetes[34][35] with DRB1*04:01, *04:05, *04:02 increasing risk when DQ8 is present.[36]

By genotype

DRB1*01:01/*04:04 and *01:01/*04:01 increases risk of mortality in rheumatoid arthritis, with ischemic heart disease and smoking.[37] these same genotypes are associated with rheumatoid vasculitis.[38]

Genetic linkage
DR4 Haplotypes
Serotypes DRADRB1DRB4
DR4-DR53 *0101*0401*0103
*0101*0402*01
*0101*0403*01
*0101*0404*01
*0101*0405*01
Serotypes DQA1DQB1DRB1
DR4-DQ7 (7.3, 3) *0303*0301*0401
DR4-DQ7 (8.1, 3) *0301*0302*0401
*0301*0302*0402
*0301*0302*0404
DR4-DQ4 (4.3) *0303*0401*0405
Serotypes HLA-AHLA-CHLA-BDRB1
A2-Cw10-B62(15)-DR4*0201*0304*1501*0401
A2-Cw10-B60(40)-DR4*0201*0304*4001*0402
A2-Cw5-B44(16)-DR4*0201*0501*4402*0401

References
  1. derived from IMGT/HLA
  2. Roudier J (2006). "HLA-DRB1 genes and extraarticular rheumatoid arthritis". Arthritis Research & Therapy. 8 (1): 103. doi:10.1186/ar1886. PMC 1526581. PMID 16542468.
  3. Winchester R (1981). "Genetic aspects of rheumatoid arthritis". Springer Semin Immunopathol. 4 (2): 89–102. doi:10.1007/BF01857089. PMID 6459655.
  4. Batchelor J, Welsh K, Tinoco R, Dollery C, Hughes G, Bernstein R, Ryan P, Naish P, Aber G, Bing R, Russell G (1980). "Hydralazine-induced systemic lupus erythematosus: influence of HLA-DR and sex on susceptibility". Lancet. 1 (8178): 1107–9. doi:10.1016/S0140-6736(80)91554-8. PMID 6103441.
  5. Shornick J, Jenkins R, Artlett C, Briggs D, Welsh K, Kelly S, Garvey M, Black M (1995). "Class II MHC typing in pemphigoid gestationis". Clin Exp Dermatol. 20 (2): 123–6. doi:10.1111/j.1365-2230.1995.tb02668.x. PMID 8565245.
  6. Matsuyama M, Hashimoto K, Yamasaki Y, Shirakura R, Higuchi R, Miyajima T, Amemiya H (1981). "HLA-DR antigens in pemphigus among Japanese". Tissue Antigens. 17 (2): 238–9. doi:10.1111/j.1399-0039.1981.tb00689.x. PMID 7233418.
  7. Sakurami T, Ueno Y, Iwaki Y, Park M, Terasaki P, Saji H (1982). "HLA-DR specificities among Japanese with several autoimmune diseases". Tissue Antigens. 19 (2): 129–33. doi:10.1111/j.1399-0039.1982.tb01428.x. PMID 6954729.
  8. Kashiwabara H, Shishido H, Tomura S, Tuchida H, Miyajima T (1982). "Strong association between IgA nephropathy and HLA-DR4 antigen". Kidney Int. 22 (4): 377–82. doi:10.1038/ki.1982.185. PMID 6217371.
  9. Szücs G, Szekanecz Z, Zilahi E, et al. (2007). "Systemic sclerosis-rheumatoid arthritis overlap syndrome: a unique combination of features suggests a distinct genetic, serological and clinical entity". Rheumatology (Oxford, England). 46 (6): 989–93. doi:10.1093/rheumatology/kem021. PMID 17384178.
  10. Page 255 in: Elizabeth D Agabegi; Agabegi, Steven S. (2008). Step-Up to Medicine (Step-Up Series). Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 978-0-7817-7153-5.
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  12. Laroni A, Calabrese M, Perini P, Albergoni M, Ranzato F, Tiberio M, Battistin L, Gallo P (2006). "Multiple sclerosis and autoimmune diseases : Epidemiology and HLA-DR association in North-east Italy". J Neurol. 253 (5): 636–9. doi:10.1007/s00415-006-0084-4. PMID 16502215.
  13. Angelini G, Morozzi G, Delfino L, Pera C, Falco M, Marcolongo R, Giannelli S, Ratti G, Ricci S, Fanetti G (1992). "Analysis of HLA DP, DQ, and DR alleles in adult Italian rheumatoid arthritis patients". Hum Immunol. 34 (2): 135–41. doi:10.1016/0198-8859(92)90039-P. PMID 1429034.
  14. Fernandez-Viña M, Ramirez L, Raskin P, Stastny P (1993). "Genes for insulin-dependent diabetes mellitus (IDDM) in the major histocompatibility complex (MHC) of African-Americans". Tissue Antigens. 41 (2): 57–64. doi:10.1111/j.1399-0039.1993.tb01980.x. PMID 8475491.
  15. Undlien D, Friede T, Rammensee H, Joner G, Dahl-Jørgensen K, Søvik O, Akselsen H, Knutsen I, Rønningen K, Thorsby E (1997). "HLA-encoded genetic predisposition in IDDM: DR4 subtypes may be associated with different degrees of protection". Diabetes. 46 (1): 143–9. doi:10.2337/diabetes.46.1.143. PMID 8971095.
  16. Gross D, Forsthuber T, Tary-Lehmann M, Etling C, Ito K, Nagy Z, Field J, Steere A, Huber B (1998). "Identification of LFA-1 as a candidate autoantigen in treatment-resistant Lyme arthritis". Science. 281 (5377): 703–6. doi:10.1126/science.281.5377.703. PMID 9685265.
  17. Matzner Y, Erlich H, Brautbar C, Sanilevitch A, Landau M, Brenner S, Friedmann A (1995). "Identical HLA class II alleles predispose to drug-triggered and idiopathic pemphigus vulgaris". Acta Derm Venereol. 75 (1): 12–4. PMID 7747528.
  18. Sáenz-Cantele AM, Fernández-Mestre M, Montagnani S, Calebotta A, Balbas O, Layrisse Z (2007). "HLA-DRB1*0402 haplotypes without DQB1*0302 in Venezuelan patients with pemphigus vulgaris". Tissue Antigens. 69 (4): 318–325. doi:10.1111/j.1399-0039.2007.00826.x. PMID 17389015.
  19. Lee E, Lendas K, Chow S, Pirani Y, Gordon D, Dionisio R, Nguyen D, Spizuoco A, Fotino M, Zhang Y, Sinha A (2006). "Disease relevant HLA class II alleles isolated by genotypic, haplotypic, and sequence analysis in North American Caucasians with pemphigus vulgaris". Hum Immunol. 67 (1–2): 125–39. doi:10.1016/j.humimm.2005.09.003. PMID 16698434.
  20. Galeazzi M, Sebastiani G, Tincani A, Piette J, Allegri F, Morozzi G, Bellisai F, Scorza R, Ferrara G, Carcassi C, Font J, Passiu G, Smolen J, Papasteriades C, Houssiau F, Nebro A, Ramon Garrido E, Jedryka-Goral A, Marcolongo R (2000). "HLA class II alleles associations of anticardiolipin antibodies". Lupus. 9 (1): 47–55. doi:10.1177/096120330000900109. PMID 10715100.
  21. Kaibe M, Takakuwa K, Murakawa H, Ishii K, Tamura M, Tanaka K (2006). "Studies on the human leukocyte antigens in patients with polycystic ovary syndrome in a Japanese population--possible susceptibility of HLA-A11 and -DRB1*0403 to patient population with polycystic ovary syndrome". Am J Reprod Immunol. 55 (4): 301–6. doi:10.1111/j.1600-0897.2006.00369.x. PMID 16533342.
  22. Galeazzi M, Sebastiani G, Tincani A, Piette J, Allegri F, Morozzi G, Bellisai F, Scorza R, Ferrara G, Carcassi C, Font J, Passiu G, Smolen J, Papasteriades C, Houssiau F, Nebro A, Ramon Garrido E, Jedryka-Goral A, Marcolongo R (2000). "HLA class II alleles associations of anticardiolipin and anti-beta2GPI antibodies in a large series of European patients with systemic lupus erythematosus". Lupus. 9 (1): 47–55. doi:10.1177/096120330000900109. PMID 10715100.
  23. Auger I, Sebbag M, Vincent C, Balandraud N, Guis S, Nogueira L, Svensson B, Cantagrel A, Serre G, Roudier J (2005). "Influence of HLA-DR genes on the production of rheumatoid arthritis-specific autoantibodies to citrullinated fibrinogen". Arthritis Rheum. 52 (11): 3424–32. doi:10.1002/art.21391. PMID 16255019.
  24. Vázquez-García M, Aláez C, Olivo A, Debaz H, Pérez-Luque E, Burguete A, Cano S, de la Rosa G, Bautista N, Hernández A, Bandera J, Torres L, Kershenobich D, Alvarez F, Gorodezky C (1998). "MHC class II sequences of susceptibility and protection in Mexicans with autoimmune hepatitis". J Hepatol. 28 (6): 985–90. doi:10.1016/S0168-8278(98)80347-4. PMID 9672174.
  25. Al-Swailem R, Al-Rayes H, Sobki S, Arfin M, Tariq M (2006). "HLA-DRB1 association in Saudi rheumatoid arthritis patients". Rheumatol Int. 26 (11): 1019–24. doi:10.1007/s00296-006-0119-2. PMID 16673133.
  26. Ota M, Seki T, Kiyosawa K, Furuta S, Hino K, Kondo T, Fukushima H, Tsuji K, Inoko H (1992). "A possible association between basic amino acids of position 13 of DRB1 chains and autoimmune hepatitis". Immunogenetics. 36 (1): 49–55. doi:10.1007/BF00209292. PMID 1350267.
  27. Ueki A, Isozaki Y, Kusaka M (2005). "Anti-caspase-8 autoantibody response in silicosis patients is associated with HLA-DRB1, DQB1 and DPB1 alleles". J Occup Health. 47 (1): 61–7. doi:10.1539/joh.47.61. PMID 15703453.
  28. García Borrás S, Diez C, Cotorruelo C, et al. (2006). "HLA class II DRB1 polymorphism in Argentinians undergoing chronic Trypanosoma cruzi infection". Ann. Clin. Biochem. 43 (Pt 3): 214–6. doi:10.1258/000456306776865205. PMID 16704757.
  29. Porto T, Coelho I, Boavida J, et al. (2006). "Association of HLA DQ4-DR8 haplotype with papillary thyroid carcinomas". Clin. Endocrinol. 64 (2): 179–83. doi:10.1111/j.1365-2265.2006.02445.x. PMID 16430717.
  30. Singal D, Green D, Reid B, Gladman D, Buchanan W (1992). "HLA-D region genes and rheumatoid arthritis (RA): importance of DR and DQ genes in conferring susceptibility to RA". Ann Rheum Dis. 51 (1): 23–8. doi:10.1136/ard.51.1.23. PMC 1004612. PMID 1371662.
  31. Hashimoto K, Maruyama H, Nishiyama M, Asaba K, Ikeda Y, Takao T, Iwasaki Y, Kumon Y, Suehiro T, Tanimoto N, Mizobuchi M, Nakamura T (2005). "Susceptibility alleles and haplotypes of human leukocyte antigen DRB1, DQA1, and DQB1 in autoimmune polyglandular syndrome type III in Japanese population". Horm Res. 64 (5): 253–60. doi:10.1159/000089293. PMID 16254435.
  32. Yoshizawa K, Ota M, Katsuyama Y, Ichijo T, Matsumoto A, Tanaka E, Kiyosawa K (2005). "Genetic analysis of the HLA region of Japanese patients with type 1 autoimmune hepatitis". J Hepatol. 42 (4): 578–84. doi:10.1016/j.jhep.2004.12.019. hdl:10091/219. PMID 15763345.
  33. Kawa S, Ota M, Yoshizawa K, Horiuchi A, Hamano H, Ochi Y, Nakayama K, Tokutake Y, Katsuyama Y, Saito S, Hasebe O, Kiyosawa K (2002). "HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population". Gastroenterology. 122 (5): 1264–9. doi:10.1053/gast.2002.33022. PMID 11984513.
  34. Park Y, Tait B, Kawasaki E, Rowley M, Mackay I (2004). "Closer association of IA-2 humoral autoreactivity with HLA DR3/4 than DQB1*0201/*0302 in Korean T1D patients". Ann N Y Acad Sci. 1037: 104–9. doi:10.1196/annals.1337.015. PMID 15699500.
  35. Hermann R, Turpeinen H, Laine A, Veijola R, Knip M, Simell O, Sipilä I, Akerblom H, Ilonen J (2003). "HLA DR-DQ-encoded genetic determinants of childhood-onset type 1 diabetes in Finland: an analysis of 622 nuclear families". Tissue Antigens. 62 (2): 162–9. doi:10.1034/j.1399-0039.2003.00071.x. PMID 12889996.
  36. Thomson G, Valdes AM, Noble JA, et al. (2007). "Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis". Tissue Antigens. 70 (2): 110–27. doi:10.1111/j.1399-0039.2007.00867.x. PMID 17610416.
  37. Mattey DL, Thomson W, Ollier WE, et al. (2007). "Association of DRB1 shared epitope genotypes with early mortality in rheumatoid arthritis: results of eighteen years of followup from the early rheumatoid arthritis study". Arthritis Rheum. 56 (5): 1408–16. doi:10.1002/art.22527. PMID 17469097.
  38. Gorman JD, David-Vaudey E, Pai M, Lum RF, Criswell LA (2004). "Particular HLA-DRB1 shared epitope genotypes are strongly associated with rheumatoid vasculitis". Arthritis Rheum. 50 (11): 3476–84. doi:10.1002/art.20588. PMID 15529352.
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