haplotype = HLA DR3-DQ2

image_source = HLA region on chromosome 6
chromosome = 6
location = 6p21.3
variable =
alias = HLA DRB1*0301:DQA1*0501:DQB1*0201
othertype = Serotype
loci1name = HLA-DR
loci1rows = 3
gene1name = HLA-DRA
gene1var = [http://www.ebi.ac.uk/cgi-bin/imgt/hla/get_allele.cgi?DRA*0102 *0101]
type1var =
loci2name = HLA-DR
loci2rows =
gene2name = HLA-DRB1
gene2var = HDR1A|0301
type2var = DR3
loci3name =
loci3rows =
gene3name = HLA-DRB3
gene3var = HDR3A|0101
type3var = DR52
loci4name = HLA-DQ
loci4rows = 2
gene4name = HLA-DQA1
gene4var = HQAA|0501
type4var =
loci5name =
loci5rows =
gene5name = HLA-DQB1
gene5var = HQBA|0201
type5var = DQ2
popMax = Sardinia
freqMax = 22%
length = 300
haplotype1 = DQ2.5
disease1 = Coeliac disease
haplotype2 = DR3-DQ2
disease2 = Juvenile diabetes
haplotype3 = DR3-DQ2
disease3 = Sarcoidosis
NumLoci = 5

HLA DR3-DQ2 is double serotype that specifically recognizes cells from individuals who carry a multigene HLA DR,DQ haplotype. Certain HLA DR and DQ genes have known involvementin autoimmune diseases. DR3-DQ2, a multigene haplotype, stands out in prominence because it is a factor in several prominent diseases, namely coeliac disease and juvenile diabetes. In coeliac disease, the DR3-DQ2 haplotype is associated with highest risk for disease in first degree relatives, highest risk is conferred by DQA1*0501:DQB1*0201 homozygotes and semihomozygotes of DQ2, and represents the overwhelming majority of risk. HLA DR3-DQ2 encodes DQ2.5cis isoform of HLA-DQ, this isoform is described frequently as 'the DQ2 isoform', but in actuality there are two major DQ2 isoform. The DQ2.5 isoform, however, is many times more frequently associated with autoimmune disease, and as a result to contribution of DQ2.2 is often ignored.

The frequency of both diseases changes with respect to both the environment (diet) and the frequency of the DR3-DQ2. With coeliac disease risk is increased with the consumption of "Triticeae" glutens, and this also increases risk in juvenile diabetes whereas other cereals also appear to play a role. More importantly the risk of disease is greatest in homozygotes and linear increases in haplotype resulting in several fold increases of disease risk. This increased risk is most prominent in a rare cancer, enteropathy associated T-cell lymphoma. HLA-DR3-DQ2 is found in HLA A1-B8-DR3-DQ2 haplotype in Northern Europeans (including the British Ilse, Ireland, Iceland).

Genetic Linkage

HLA DR3-DQ2 is the serotypic representation of a HLA-DRB1:DQA1:DQB1cis-chromosomal haplotype on human 6p21.3 in a region known as the HLA complex. The DR3-DQ2 haplotype is notable because of the very strong linkage between genes that extends into the HLA-A, -B and -C regions of the HLA gene complex in northern and northwestern Europe. The linked haplotype is HLA A1-B8-DR3-DQ2 (AH8.1 in the most recent literature)

Because of its strong linkage disequilbrium, each of the genes in the haplotype are markers for probable presence of adjacent genes. However serotyping does not recognize genes, but clusters of gene products. For example DQ2 recognizes both DQB1*0201, DQB1*0202, DQB1*0203. DQB1*0202 is not genetically linked to DQA1*0501 and its cis-haplotype isoform infrequently mediates coeliac disease or type 1 diabetes. For serotypic identification of the DQ2.5cis isoform requires the DR3 (or HLA-DR17 or HLA-DR18) and DQ2 serotypes.

An example of phenotypes that can mediate CD and T1D, the DR3-DQ2/X serotypes and the DR5-DQ7/DR7-DQ2 serotypes can mediate celiac disease with equal efficiency but the DR5-DQ7/DR7-DQ2 cannot mediate T1D as successfully as DR4-DQ8 or DR3-DQ2 (X is not DR3-DQ2 or DR7-DQ2).


HLA DR3-DQ2 is not spread evenly in the among humans. It is has a substantially higher frequency in the western world, except indigenous Native American (see tables). It is virtually absent in some Asian populations. It current world distribution suggest that it spread from Africa with a wave that spread late in human evolution which reached central Asia more recently, a possibility is that it spread with agrarian cultures that migrated from Africa. [Note some population test DR3 or DQA1:DQB1, the DR3-DQ2 serotype is generally synonymous in frequency with DQ2.5]

Frequencies in Africa

Based on frequencies in Central and East Asia, DR3_DQ2 appears to have spread eastward recently. Of particular interest to the West African/Central Asian comparison, not only is DQ3-DQ2.5 elevated in both places, but a linked HLA A-B haplotype, A33-B58, is found in West Africans and both the A33 and B58 alleles show more allelic and haplotype diversity in West Africa. This similarity would be remarkable if this haplotype came with migrations 50,000 to 130,000 years ago, since considerable equilibration and long range migrations are expected over this time frame. Ironically, there is no convincing route of travel between West Africa and Central Asia suggested by gene frequencies in the peoples between the two. This recent migation hypothesis is supported by HLA-A36 which shows a similar African/Central Asian bimodal distribution. One population that might have been related to this migration are non-caucasians of northern Africa.

DR3-DQ2 is notably higher in W. Mongolia, Kazahkstan and W. China. One eastern haplotype is "A33-B58" and has some punctuated distribution in Western Europe at relatively low levels, and is also in extreme disequilibrium where it is found, elsewhere. In Thailand it is elevated, particularly in the Thai Chinese, but in the south and most parts of Indonesia its frequency is zero. Elevated DR3-DQ2 levels in the Muong suggest a similar North to South spread.

DR3-DQ2 presence in the Koreans and lack thereof in the Japanese suggest a recent spread into Western Pacific Rim of Asia. By HLA, Y chromosome, or mitochondrial DNA the Japanese are about 60-85% of post-Jōmon period Korean origin, and the level of DR3-DQ2 in Japanese is about 1/10th that of Koreans suggesting that DR3-DQ2 did not spread in the Yayoi and that it spread recently with Mongol spread in Eastern Asia, it is rare both east and south of China (except in regions with strong historic migrations of Chinese), rare in Indigenous Austronesians, and isolated Indigeonous American groups.

The importance of the estimates

Currently, in assessing diseases like Coeliac disease a definite diagnosis is often not possible and statistical considerations are relied upon. The knowledge of frequencies in populations, particularly among ancestors of immigrants can aid patient and physician as to the potential risks.cite journal | author = Hadithi M, von Blomberg BM, Crusius JB, "et al" | title = Accuracy of serologic tests and HLA-DQ typing for diagnosing celiac disease | journal = Ann. Intern. Med. | volume = 147 | issue = 5 | pages = 294–302 | year = 2007 | pmid = 17785484 | doi = ] An example, one publication states that the western regions of Ireland have the highest coeliac disease rate in the world [cite journal | author = Zhong F, McCombs C, Olson J, Elston R, Stevens F, McCarthy C, Michalski J | title = An autosomal screen for genes that predispose to celiac disease in the western counties of Ireland. | journal = Nat Genet | volume = 14 | issue = 3 | pages = 329–33 | year = 1996 | pmid = 8896565 | doi = 10.1038/ng1196-329] . Plotting the frequency of DQ2.5 from any part of Western Europe to the Irish one sees the frequency gradient progressing toward the north and west of Ireland; therefore, a high rate of coeliac disease is not unexpected in Western Ireland. People with many common ancestors from Ireland share similar risks of disease.

In the case of juvenile diabetes a clear distinction of DR3-DQ2 from DR7-DQ2 is necessarybecause both DR3 and DQ2 confer risk of disease. And DR3-DQ2/DR4-DQ8 individuals who have type 1 diabetes (late onset) are often mistaken for type-2 diabetes.

Associated Diseases

DR3-DQ2 is associated with probably the greatest frequency of autoimmune occurrence relative to any other haplotype. The DQA1*0501:DQB1*0201 (DQ2.5) locus confers susceptibility to Gluten Sensitive Enteropathy (GSE)and (Type 1 Diabetes ) but has also been linked to other rarer autoimmune diseases like myasthenia gravis.

Type 1 diabetes

In type 1 diabetes both DR3 and DQ2 appear to play a role.

*DR3-DQ2.5 can be established to other genes like TNF-305A (TNF2) which may also increase the risk of autoimmune disease in both Coeliac Disease and Type 1 diabetes. In systemic lupus erythematosus (SLE) patients HLA DR3-DQ2.5-C4AQ0, which was strongly associated with SLE (odds ratio [OR] 2.8, 95% CI 1.7-4.5) [cite journal | author = Jönsen A, Bengtsson A, Sturfelt G, Truedsson L | title = Analysis of HLA DR, HLA DQ, C4A, FcgammaRIIa, FcgammaRIIIa, MBL, and IL-1Ra allelic variants in Caucasian systemic lupus erythematosus patients suggests an effect of the combined FcgammaRIIa R/R and IL-1Ra 2/2 genotypes on disease susceptibility. | journal = Arthritis Res Ther | volume = 6 | issue = 6 | pages = R557–62 | year = 2004 | pmid = 15535834 | doi = 10.1186/ar1224] .

* A more recent paper shows that Inositol triphosphate receptor 3 gene which is ~ 1 million base pairs from DQ2.5 is also associated with Type 1 diabetes [cite journal | author = Roach J, Deutsch K, Li S, Siegel A, Bekris L, Einhaus D, Sheridan C, Glusman G, Hood L, Lernmark A, Janer M | title = Genetic mapping at 3-kilobase resolution reveals inositol 1,4,5-triphosphate receptor 3 as a risk factor for type 1 diabetes in Sweden. | journal = Am J Hum Genet | volume = 79 | issue = 4 | pages = 614–27 | year = 2006 | pmid = 16960798 | doi = 10.1086/507876] .


A relationship between HLA and sarcoidosis has been known for 30+ years.cite journal |author=Rybicki BA, Iannuzzi MC |title=Sarcoidosis and human leukocyte antigen class I and II genes: it takes two to tango? |journal=Am. J. Respir. Crit. Care Med. |volume=169 |issue=6 |pages=665–6 |year=2004 |month=March |pmid=15003948 |doi=10.1164/rccm.2401005 |url=] However, the association is weak and has not been reproducible in all studies. A common serologically defined haplotype in Europeans is HLA A1-B8-DR3-DQ2.5 (see above). In non-persistent sarcoidosis this haplotype was found to be increased in sarcoidosis, and further study eliminated risk contributed by A1-Cw7-B8 indicating DR3-DQ2 haplotype contains risk of disease (OR = 11.8)cite journal |author=Grunewald J, Eklund A, Olerup O |title=Human leukocyte antigen class I alleles and the disease course in sarcoidosis patients |journal=Am. J. Respir. Crit. Care Med. |volume=169 |issue=6 |pages=696–702 |year=2004 |month=March |pmid=14656748 |doi=10.1164/rccm.200303-459OC |url=]

Extended linkage

* DQ2.5 is also linked to the IgA-less phenotype which may or may not increase susceptibility to diseases [cite journal | author = Schaffer F, Palermos J, Zhu Z, Barger B, Cooper M, Volanakis J | title = Individuals with IgA deficiency and common variable immunodeficiency share polymorphisms of major histocompatibility complex class III genes. | journal = Proc Natl Acad Sci U S A | volume = 86 | issue = 20 | pages = 8015–9 | year = 1989 | pmid = 2573059 | doi = 10.1073/pnas.86.20.8015] [cite journal | author = Klemola T, Savilahti E, Koskimies S, Pelkonen P | title = HLA antigens in IgA deficient paediatric patients. | journal = Tissue Antigens | volume = 32 | issue = 4 | pages = 218–23 | year = 1988 | pmid = 3217938] . This imposes a problem for understanding autoimmunity in DQ2.5, since many genes linked to disease with partial contributions are some degree of disequilibration with DQ2.5 loci and thus DQ2.5 masks genetic association via it positive association with some many diseases.



Coeliac Disease
* [http://www.coeliac.co.uk/ Coeliac UK] (charity)
* [http://www.celiac.org/ The Celiac Disease Foundation] (U.S.)
* [http://digestive.niddk.nih.gov/ddiseases/pubs/celiac/ National Digestive Diseases Clearinghouse] - page on coeliac disease
* [http://www.celiacawareness.org National Foundation for Celiac Awareness] (U.S.)
* [http://www.celiaccenter.org/ University of Maryland Center for Celiac Research]

Type 1 Diabetes
* [http://www.childrenwithdiabetes.com/ Children with Diabetes]
* [http://www.diabetes.org/type-1-diabetes.jsp Type 1 Diabetes] at the American Diabetes Association

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