HLA-DQ1

HLA-DQ1 is a serotype that covers a broad range of HLA-DQ haplotypes. Historically it was identified as a DR-like alpha chain called DC1^[1], later, it was among 3 types DQw1 (later DQ1, and split into DQ5 and DQ6), DQw2 and DQw3. Of these three serotyping specificities only DQw1 recognized DQ alpha chain.^[2] The serotype is positive in individuals who bear the DQA1*01 alleles. The most frequently found within this group are: DQA1*0101, *0102, *0103, and *0104. In the illustration on the left, DQ1 serotyping antibodies recognizes the DQ α (magenta), where antibodies to DQA1* gene products bind variable regions close to the peptide binding pocket.

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Serotypes

The serotyping efficiency of DQ1 recognition relative to DQ5 and DQ6 is listed below. Since DQ1 recognizes alpha, the DQ5 and DQ6 recognition are to beta chain. Meaning that DQ1 is corecognized with DQ5 and DQ6.

The table to the left shows some of the serotyping efficiencies. Efficient recognition of a genotyped allele approaches 100%. Compared to DQ2 serotyping of DQB1*0201 positive individuals (98%), the efficiency of DQ1 recognition is relatively low and error prone.

For this reason DQ1 serotyping is a poor method of typing for transplantation or disease association prediction or study. Nonetheless, it is still widely used and association proported in the literature.

Alleles

DQA1*0101

DQA1*0101 is commonly linked to haplotypes of DQB1*05, the common DQA1*0101:DQB1*0501 haplotype which is part of a braoder DR1-DQ1 haplotype.

DQA1*0102

DQA1*0102 is associated with both DR5 and DR6.

DQA1*0102:DQA1*0502 has a bimodal distribution. It is found in the Philippines in high frequency and on the Mediterranean island of Sardinia.

DQA1*0102:DQA1*0602 is a very common haplotype in Eurasia, with higher frequency in central Asia relative to elsewhere. It is part of an European ancestral haplotype B7-DR15-DQ1 that appears to have expanded asymmetrically into Europe. The A3-B7-DR15-DQ1 haplotype indicates relationships in Eurasia that span from Korea to Ireland, indicating some common ancestry in recent times.

DQA1*0102:DQB1*0604 much less frequently found but spread widely.

DQA1*0103

DQA1*0103 (*0103) shows a negative (protective) association with many autoimmune disease, this association is apparent in Japanese studies in the *0103:DQB1*0601 haplotype, and in Europe with the *0103:DQB1*0603 haplotype, indicating the protective effect is influenced by the alpha chain of DQ. DQA1*0103 is protective against Behçet's disease^[4][5], pemphigus vulgaris ^[6], juvenile diabetes,^[7][8] steroid-sensitive nephrotic syndrome,^[9] myasthenia gravis^[10] coeliac disease^[11] multiple sclerosis,^[12] chronic active hepatitis C,^[13] and Vogt-Koyanagi-Harada syndrome.^[14] However, it may predispose carriers to chronic infection such as leprosy,^[15] Helicobacter pylori-positive gastric lymphoma,^[16] and AIDS^[17].

DQA1*0103:DQB1*0601 is part of a multigene haplotype (DRB1*1502:DRB5*0102:DQA1*0103:DQB1*0601:DPA1*02:DPB1*0901) linked to Takayasu arteritis in Japanese.^[18] Another haplotype, DR8-DQ1 which contains this haplotype may be associated with primary biliary cirrhosis,^[19], Grave's disease^[20] There is a negative association of this DR15-DQ1 haplotype in Japanese with inflammatory bowel disease.^[21]

DQA1*0103:DQB1*0603 is part of a DR-DQ haplotype (DR13-DQ1) that increases for primary sclerosing cholangitis^[22][23] The same haplotype shows a negative association with rheumatic heart disease,^[24]

The DQ1-Gluten sensitive neuropathy controversy

Is DQ1 associated IGS?. In 2002, a team of British neurologists sorted the gluten sensitive idiopathic neuropathy(131 individuals) with 41% (58 inds) that were AGA reactive.^[25] Although N was not given on DQ studies one assumes that the DQ serotyping was on the set or subset of this 58 individuals or less. Of these 70% (41) were DQ2, of the remaining, 9% (5 of 58) were DQ8+, and the remaining (12) were DQ1. Although the authors made no remarkable claim about DQ1, the claim has propagated among off-clinical testing groups. This study has been the primary support for the DQ1 association. DQ1 typing is notoriously inaccurate, and undertyping and mistyping are common (for example DQB1*0502 in serological efficiency table above). The presentation was not statistically analyzed for significance and was reported in an editorial. A number of DQ2 or DQ8 patients are either CD, undetected CD, or GSE (testing for the full scale of GSE in 2002 was not technically possible); however the observed normal frequency of DQ2 in Kent was 35%. Therefore we can assume many, but not all DQ2 where GSE. The number of DQ8 was unremarkable relative to the normal DQ8 frequency, the number of DQ2 homozygotes was not disclosed nor the second serotype (every person has two serotypes although some have one apparent as they are homozygotes) for DQ2, DQ8 or DQ1. The normal frequency for DQ1 in Britain is 36.9%. Assuming that All DQ2 and DQ8 were GSE associated the random probability of a DQ1 is 0.008 (Fisher exact Test 61,40,12,0) indicating a significance of positive association. However, the authors made no attempt to remove GSEA patients from the group. Given an observed frequency of 70% DQ2, based on the random frequency of DQ2 of 35% the expected numbers of GSEA-DQ2 and -DQ8 are at maximum likelihood of 60%(~35), and the remainder are IGS(23). The Fisher exact probability of 0.5 is obtained with DQ1 lower than expected however this analysis is burdened by not knowing the second serotypes of patients. Tentatively, therefore when one eliminates only DQ2 and DQ8 that are likely part of GSE, and then considers DQ1 the association of DQ1 completely disappears. However, a likely 35% of these non-GSE, AGA+ neuropathies and probably result from other immunological conditions, possibly allergies to gluten or extension of an allergic response to include IgA and IgG.^[26] But, the typical markers for ataxia such as anti-Purkinje cell or anti-neuronal nuclear antibodies appear not to be the targets of these gluten sensitive responses^[27]

References