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Subject: HLA Testing and Disease Associations/Drug Hypersensitivity Reactions
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The proteins encoded by HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and essential in self versus nonself immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune diseases. In addition, linkage disequilibrium extends across multiple HLA and non-HLA genes in the MHC. The identification of disease-specific susceptibility (risk) and protective markers can be used in immunogenetic profiling, risk assessment, and therapeutic decisions. Known HLA predisposition genes and their association with autoimmunity, infectious diseases, and drug sensitivities/side effects are constantly being refined; new associations are constantly emerging in light of expanded knowledge of the HLA genetic map.
The evolving use of various HLA typing methods has introduced confusion to the interpretation of disease associations. For example, many early studies, using serologic typing methods, identified an association with DR4 for RA. Because DR4 has many different alleles, some of which are RA associated while some are not, the associations were generally weaker than when precise alleles were subsequently investigated. Later studies using DNA-based methods have consistently shown that, in Caucasians, the alleles DRB1*04:01, *04:04, *04:05, and *04:08 are highly associated with RA. Another example is ankylosing spondylitis (AS) and HLA-B27. HLA-B27 is estimated to contribute only 16–50% of the total genetic risk. The strongest association with AS is with HLA-B*27:05 among the Japanese and HLA-B*27:04 in the Chinese. There are less frequent associations with the alleles HLA-B*27:01, *27:02, *27:03, *27:04, *27:07, *27:08, and *27:10.
Variations at individual amino acid sites have also shown promising results in understanding disease associations. In RA, for example, investigators were able to demonstrate that many of the HLA associations with RA are best explained by differences in the specific amino acids that occur at positions 11, 71, and 74 in HLA-DRB1; position 9 in HLA-B; and position 9 in HLA-DPB1, which are all located in peptide-binding grooves. These amino acid differences account for many of the MHC associations to RA risk. These sites may modulate differential binding to key antigens involved in autoimmunity.
Ethnic differences must also be taken into account. The frequency of a particular allele in one population can be very different from that in another population. For example, DR4 was shown not to be associated with RA in Israeli Jews because their most common DR4 allele, DRB1*04:02, is not associated with the disease. For the same reason, in disease association studies, the control group with which the patient group is compared must be ethnically matched for the results to be valid. Variations between patient populations are also responsible for some differences among studies.
A sizable fraction of HLA alleles are in linkage disequilibrium (LD), the nonrandom association of alleles at two or more loci. This is very important when interpreting association studies. For example, the ancestral 8.1 haplotype spans the MHC region and includes A*01:01-C*07:01-B*08:01-DRB1*03:01-DRB3*01:01-DQA1*05:01-DQB1*02:01. Because all of these alleles can be associated and can occur together, it is therefore difficult to interpret which locus is primarily responsible for the disease risk in such cases.
One limitation of population studies is that the results cannot be easily transferred to an individual patient. The alleles that have been shown to be associated with diseases are susceptibility alleles and are identical to genes that are present among normal individuals, albeit with a lower frequency. One can use the calculation of relative risk (RR) to determine the probability that the disease will occur among individuals positive for the allele when compared with individuals negative for the allele. RR is the ratio of the probability of the event occurring in the exposed group versus a nonexposed group.
How do HLA antigens confer disease susceptibility? Data regarding the relationship of HLA antigens to disease susceptibility remain at the level of associations, not disease mechanisms. Nevertheless, HLA associations that are reproducible and robust provide important clues about the development of certain rheumatic diseases. A variety of models have been postulated to explain these associations functionally. These include the importance of HLA polymorphisms in:
Shaping the T-cell repertoire during development
Shaping the peripheral T-cell repertoire
Determining which antigenic peptides are bound and, therefore, presented to the immune system for recognition
Generating molecular mimicry between self antigens and either the HLA molecule itself or peptides that it recognizes
Affecting HLA protein presentation of either foreign or self-antigenic peptides to autoreactive T cells
Influencing how infection, exogenous agents, or “molecular mimicry” may reactivate silenced T cells in autoimmune diseases
Affecting immune suppression and cancer development in important ways through the loss of HLA gene expression because of viral infection, somatic mutations, or other causes
Influencing antigen processing and presentation
Identification of the mechanistic basis of these disease associations may lead to novel and specific treatments, as well as preventive strategies.
Listed below are some of the current known disease associations based on various publications:
Ankylosing spondylitis: HLA-B*27 (especially HLA-B*27:05)
Celiac disease: HLA-DQA1*05-DQB1*02:01, DQA1*03-DQB1*03:02
Acute anterior uveitis: HLA-B*27 (especially HLA-B*27:05).
Behçet disease: HLA-B*51, RR is only 6–10.
Birdshot chorioretinopathy: HLA-A*29 (especially with HLA-A*29:02).
Idiopathic membranous glomerulonephritis insulin-dependent (type 1) diabetes mellitus:
Narcolepsy: HLA-DQB1*06:02 allele on the DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype. Individuals homozygous for HLA-DQB1*06:02 have a higher risk of acquiring narcolepsy than individuals heterozygous for this allele. Heterozygous with HLA-DQB1*03:01, HLA-DQB1*05:01, and -DQB1*06:01 are thought to be protective.
HLA-DRB1*04:01/04:04/04:05/04:08, -DRB1*01:01 Caucasian; HLA-DRB1*04:05 Japanese; HLA-DRB1*14:02 American Indian
HLA and drug sensitivities/side effects:
The reverse transcriptase inhibitor, abacavir and HLA-B*57:01, the gout prophylactic, allopurinol and HLA-B*58:01, and the antiepileptic, carbamazepine and HLA-B*15:02