Major Histocompatibility Complex, Class II, DR Alpha

Alternative Names

  • HLA-DRA
  • HLA-DRA1
  • HLA-DR Histocompatibility Type
  • HLA-D Histocompatibility Type
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OMIM Number

142860

Gene Map Locus
6p21.3

Description

MHC Class II molecules are proteins integrally involved in the immune system and are found on the surface of specialized cells, including macrophages, dendritic cells, and B lymphocytes. These molecules present peptides derived from foreign bodies to immune cell effectors. HLA-DR is one of the MHC Class II molecules, and like all others, is an alpha-beta heterodimer, both chains being encoded by genes within the MHC.

Various polymorphisms are seen in the DR genes, many of which are associated with certain disease conditions. These diseases include autoimmune disorders like rheumatoid arthritis, schizophrenia, pemphigus, psoriasis, Hashimoto's thyroiditis, systemic lupus erythematosus, insulin dependent diabetes mellitus, and multiple sclerosis.

Molecular Genetics

The HLA-DRA gene, which codes for the alpha chain of the HLA-DR mature protein, spans a length of 5.3 Kb and consists of five exons. In the mRNA, the 5' untranslated region, the leader peptide, and the first two NH2-terminal amino acids are fused into the first exon. Exons 2 and 3 represent two extracellular coding domains of the mature protein. The transmembrane domain, cytoplasmic domain, and part of the 3' untranslated region are merged into the fourth exon. The rest of the 3' untranslated region lies in exon 5. The N-terminal domain of the mature protein forms an alpha-helix that forms the exposed part of the binding groove, while the C-terminal cytoplasmic region interacts with the other chain forming a beta-sheet under the binding groove. Most of the peptide contact positions are within the first 80 residues of the protein. Most polymorphisms are also directed at these positions.

Epidemiology in the Arab World

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Other Reports

Kuwait

Zaki et al. (1994) carried out a case control study involving a group of 48 Arab children with steroid responsive childhood nephritic syndrome and a control group consisting of healthy Arab children, to see if there was any HLA association in this population. HLA-DR7 was found to be significantly increased in the patient group.

Mahmoud (1998) compared the expression frequencies of the major histocompatibilty complex (MHC) in 26 Kuwaiti psoriatic patients with 60 controls matched for age, sex, and ethnic origin. The study revealed significantly decreased expression of HLA-DR5 and DR2 in the cases versus the controls.

Haider et al. (1999) performed typing of HLA-DR alleles in 212 normal healthy Kuwaitis. DR3 was found to be the most common type in the Kuwaiti general population (28%) and DRB1*0301 was detected in 41% of the individuals with DR3 specificity.

Oman

Agarwal et al. (1996) compared the frequencies of HLA-D antigens in 50 Omani patients diagnosed with Idiopathic Dilated Cardiomyopathy, with those of 247 healthy Omani control subjects. Data obtained were statistically analyzed by chi square test or the Fisher exact test (where appropriate) with the Bonferroni correction obtained by multiplying the P value by the numbers of antigens tested to correct the P value for any chance associations (PC). The antigens tested for included HLA-DR 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 14, 15, 16, and w52 and HLA-DQ 1, 2, 3, and 7. None of these antigens showed a significant difference in frequency between the patient and control groups. Earlier studies performed in Anglo-Scandinavian populations had indicated HLA-DR4 to be connected to dilated cardiomyopathy. However, Agarwal et al. (1996) could not find any such correlation in this study. They also suggested that racial or ethnic origin of the patients may be an important factor in the pathophysiology of the disease.

White et al. (1999) determined the frequency of HLA-DR antigens in 283 donors, studied Class II DNA polymorphisms in 126 subjects with low-resolution sequence-specific primer (SSP) DNA typing, and compared those results with those recorded from Saudi Arabia and Kuwait. By serological typing, it was found that HLA-DR2 (66%) was very high and was significantly more frequent in Oman than in Saudi Arabia and Kuwait, while HLA-DR4 (13%), DR7 (11%) and DR53 (19%) were significantly lower in Oman than in the other two countries. Comparison of the results obtained by serology with those of sequence-specific primer (SSP) DNA typing in 126 subjects revealed disparity in the levels of DR4 and DR51, being more expressed by the DNA typing (14% and 70%, respectively, when compared to 8% and 53%, respectively by serology typing), and White et al. (1999) explained this as due to the different subtypes defined by both techniques in case of DR4. As already known, those who were DR15 and DR16 positive should also be DR51 positive, but this was not the case in some of the subjects as out of the 109 subjects with positive DR15 and 16, only 88 were DR51 positive. HLA-DR2 had associated antigens (DR15 and 16) whose frequencies were determined by HLA SSP/DNA typing and were 63% for DR16, and 18% for DR15, while 6% had both antigens giving a total DR2 frequency of 87%. Serology revealed only 74% of 126 subjects to be DR2 positive. This inconsistency within the SSP/DNA data might be due to technical shortcomings, the quality of typing reagents or the use of primers on a population with high consanguinity rate. White et al. (1999) postulated different migration patterns in Oman as the frequencies of HLA antigens differed significantly between the population of Oman and those of Saudi Arabia and Kuwait. Such a high frequency of HLA-DR2 as well as DQ1 in Oman might play a role in disease distribution.

Saudi Arabia

In a study comparing the HLA-DR phenotypes among 109 Saudi Arabian males with Caucasian subjects, Ollier et al. (1985) found that the HLA-DR7 allele was seen in a very high frequency among the Saudi subjects. This was confirmed by a study by Sheth et al. (1985), who discovered that the DR7 antigen showed the highest gene frequency (19.5%) compared to other populations.

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