HLA B7-DR15-DQ6

HLA B7-DR15-DQ6 is a multigene haplotype that covers a majority 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 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.

Multi-gene haplotype, human
HLA region on chromosome 6
HLA A3-B7-DR15-DQ6
Loci	Gene	Allele	Serotype
Class I centromeric	HLA-C	*0702	Cw7
	HLA-B	*0702	B7
HLA-DR	HLA-DRB1	*1501	DR15
	HLA-DRB5	*0101	DR51
HLA-DQ	HLA-DQA1	*0102	DQ1
	HLA-DQB1	*0602	DQ6
Nodes
PopulationMaxima			Freq.Max
Western Ireland			6.0%
Size and location
Genes	Location		size (kbps)
-	6	6p21.3	2500

HLA B7-DR15-DQ6 is a representation(by serotype) of a common HLA haplotype found in Western Eurasia. The haplotype can be written in an extended form covering the major histocompatibility loci as follows:

HLA Cw*0702 : B*0702 : DRB1*1501 : DQA1*0102 : DQB1*0602

The older literature may describe this haplotype in two different ways. One B7-DR2-DQ6 derives from the fact that DR15 is a split antigen of the DR2 broad antigen serotype. The other B7-DR2-DQ1 stems from the fact that DQ1 is an alpha chain serotype that is now covered by the beta chain type DQ5 and DQ6 (DQ1 pairs with DQ5 and DQ6 by cis-haplotype pairing).

There are two major subhaplotypes one that is preceded on its telomeric side by HLA A*0301 and the other by HLA A*0201. The A*0301 bearing haplotype (HLA A3-B7-DR15-DQ6) is described as the longest known multgene haplotype in humans.

HLA A2-B7-DR15-DQ6

The appendation of the B7::DQ6 haplotype creates the A2-B7::DQ6 haplotype. This haplotype if found often in Northern Spain, Switzerland, Netherlands.

HLA A*0201Cw*0702 : B*0702 : DRB1*1501 : DQA1*0102 : DQB1*0602

HLA A3-B7-DR15-DQ6

HLA A3-B7 haplotype frequencies

		freq		Rank in
ref.	Population	(%)		Pop.
[1]	Swiss	9.1		^1
[2]	Ireland	8.6
[3]	Austria	7.4		^1
[4]	Northern Ireland	6.5	^1
[5]	Netherlands	6.6
[3]	Belgium	6.0		^1
[3]	Swedish	5.7		3
[6]	German	5.7
[3]	Polish	4.9
[3]	Romanian	3.8
[3]	Armenia	3.7
[3]	Portuguese	3.4
[3]	British	3.4
[3]	Czech	3.1
[7]	Svans	2.7
[3]	Albania	2.7
[8]	Tuscan Italy	2.7
[3]	Spanish	2.6
[3]	Basque	2.5
[3]	Italy	1.6
[3]	Greek	1.3
[9]	Bulgaria	1.1
^1 Cw*0702 (Europe)

The gene-allele representation of the haplotype is:

HLA A*0301Cw*0702 : B*0702 : DRB1*1501 : DQA1*0102 : DQB1*0602

This is considered now the longest of the widely distributed ancestral haplotypes, its length is 4.8 million nucleotides and extends from TRIM27 gene . . . .The haplotype is nodal in Ireland but is also at high frequency in Switzerland, it has a subnode in the Pasiegos of northern Spain. There is some variance in the distribution of A3::DQ6 relative to A1::DQ2 in that there is more of a bias toward central and eastern Europe. Parts of the haplotype are spread into East Asia and even appear within the New world's indigeonous populations. DR15:DQ6 frequencies peak in central Asia, and it is suspect that this may be a point of Eurasian spread westward into Europe.

While there are some diseases associated with the haplotype, the frequency of association is less compared to A1::B8.

Disease Associations

HLA B7-DR15-DQ6 was found to have an association with postmenopausal osteoporosis in a Greek population.[10]

DR2 (15 or 16) -DQ6.2 has been found to associate with (idiopathic) narcolepsy-cataplexy [11] Hypocretin ligand deficiency in the brain and cerebrospinal fluid is also link to narcolepsy-cataplexy. DR15-DQ6 also shows an association with factors (including a genetic factor on chromosome 12p12) involved in familial multiple sclerosis[12][13] DR15-DQ6 is strongly associated with the development of choroidal neovascular lesions in presumed ocular histoplasmosis syndrome.[14]

The DR15-DQ6 haplotype may afford some greater protection against the progression of HIV.[15] However, the haplotype is a risk factor in cervical cancer.[16]

References

1. Grundschober C, Sanchez-Mazas A, Excoffier L, Langaney A, Jeannet M, Tiercy J (1994). "HLA-DPB1 DNA polymorphism in the Swiss population: linkage disequilibrium with other HLA loci and population genetic affinities". Eur J Immunogenet. 21 (3): 143–57. doi:10.1111/j.1744-313X.1994.tb00186.x. PMID 9098428.
2. Finch T, Lawlor E, Borton M, Barnes C, McNamara S, O'Riordan J, McCann S, Darke C (1997). "Distribution of HLA-A, B and DR genes and haplotypes in the Irish population". Exp Clin Immunogenet. 14 (4): 250–63. PMID 9523161.
3. 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.
4. Middleton D, Williams F, Hamill M, Meenagh A (2000). "Frequency of HLA-B alleles in a Caucasoid population determined by a two-stage PCR-SSOP typing strategy". Hum Immunol. 61 (12): 1285–97. doi:10.1016/S0198-8859(00)00186-5. PMID 11163085.
5. Schipper R, Schreuder G, D'Amaro J, Oudshoorn M (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.
6. <Müller C, Ehninger G, Goldmann S (2003). "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. doi:10.1016/S0198-8859(02)00706-1. PMID 12507825.
7. Sánchez-Velasco P, Leyva-Cobián F (2001). "The HLA class I and class II allele frequencies studied at the DNA level in the Svanetian population (Upper Caucasus) and their relationships to Western European populations". Tissue Antigens. 58 (4): 223–33. doi:10.1034/j.1399-0039.2001.580402.x. PMID 11782273.
8. Marroni F, Curcio M, Fornaciari S, Lapi S, Mariotti M, Scatena F, Presciuttini S (2004). "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. doi:10.1111/j.1399-0039.2004.00292.x. PMID 15361126.
9. Ivanova M, Rozemuller E, Tyufekchiev N, Michailova A, Tilanus M, Naumova E (2002). "HLA polymorphism in Bulgarians defined by high-resolution typing methods in comparison with other populations". Tissue Antigens. 60 (6): 496–504. doi:10.1034/j.1399-0039.2002.600605.x. PMID 12542743.
10. Douroudis K, Tarassi K, Athanassiades T, et al. (June 2007). "HLA alleles as predisposal factors for postmenopausal osteoporosis in a Greek population". Tissue Antigens. 69 (6): 592–6. doi:10.1111/j.1399-0039.2007.00833.x. PMID 17498269.
11. Nishino S, Kanbayashi T (August 2005). "Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system". Sleep Med Rev. 9 (4): 269–310. doi:10.1016/j.smrv.2005.03.004. PMID 16006155.
12. Stickler M, Valdes AM, Gebel W, et al. (January 2004). "The HLA-DR2 haplotype is associated with an increased proliferative response to the immunodominant CD4(+) T-cell epitope in human interferon-beta". Genes Immun. 5 (1): 1–7. doi:10.1038/sj.gene.6364027. PMID 14735143.
13. Vitale E, Cook S, Sun R, et al. (February 2002). "Linkage analysis conditional on HLA status in a large North American pedigree supports the presence of a multiple sclerosis susceptibility locus on chromosome 12p12". Hum. Mol. Genet. 11 (3): 295–300. doi:10.1093/hmg/11.3.295. PMID 11823448.
14. Dabil H, Kaplan HJ, Duffy BF, Phelan DL, Mohanakumar T, Jaramillo A (October 2003). "Association of the HLA-DR15/HLA-DQ6 haplotype with development of choroidal neovascular lesions in presumed ocular histoplasmosis syndrome". Hum. Immunol. 64 (10): 960–4. doi:10.1016/S0198-8859(03)00175-7. PMID 14522093.
15. Vyakarnam A, Sidebottom D, Murad S, et al. (May 2004). "Possession of human leucocyte antigen DQ6 alleles and the rate of CD4 T-cell decline in human immunodeficiency virus-1 infection". Immunology. 112 (1): 136–42. doi:10.1111/j.1365-2567.2004.01848.x. PMC 1782463. PMID 15096192.
16. Ghaderi M, Wallin KL, Wiklund F, et al. (August 2002). "Risk of invasive cervical cancer associated with polymorphic HLA DR/DQ haplotypes". Int. J. Cancer. 100 (6): 698–701. doi:10.1002/ijc.10551. PMID 12209609.