For years, the unpredictability of drug reactions has served as an underlying uncertainty in the safety of medications. This is because many of these reactions are specific to certain individuals and populations and under specific circumstances with an unknown basis. Adverse drug reactions can be very medically devastating, leading to severe consequences including death. The capacity to find a means to predict the risk of adverse reactions for patients can help prevent or drastically lower the incidence of these drug reaction events.
Technological advances in the ability to obtain enormous amounts of genetic information have added to the available strategies for medical treatment. Genetic information is being harnessed to provide ways to identify those who are at risk of adverse reactions to pharmacological agents. Links have been established between the human leukocyte antigen (HLA) alleles and adverse drug reaction syndromes associated with certain drugs. Using this information has afforded the ability to prevent hypersensitivity reactions in those who are susceptible.
Drug-Induced Hypersensitivity Reaction
The HLA complex is the human version of the major histocompatibility complex (MHC). In humans, the genes in this complex are made of three classes (I, II, III). Each class has different HLA genes; class I has three types, class II has six, and class III genes code for other protein types with functions different from those of class I and II. The primary role of the HLA complex is to facilitate the immune system’s ability to distinguish between the body’s proteins and proteins of foreign or invading organisms. The HLA proteins from class I are present on cells throughout the body. Those from class II are present on certain cells of the immune system. Both types bind to peptides (antigens) and present them to the immune system.
The link between adverse drug reactions and the HLA complex suggests that the reactions occur via the adaptive (acquired, specialized) immune system. However, how the interactions between the immune system and drugs lead to adverse reactions are not fully known. There are a number of theories with respect to the mechanisms of drug interactions with immune receptors.
For example, the hapten mechanism describes the role of a drug-protein complex (presented on an MHC complex) in stimulating a specific T-cell response. The p-i concept refers to the ability of a drug to stimulate T cells directly by binding to the T-cell receptor (1,2). The danger hypothesis has also been proposed, and it is thought that it may be involved in drug hypersensitivity by providing signal 2 (accessory signals that co-stimulate immune response with peptide-MHC complexes) (2). Research is ongoing to better understand and determine the roles of these mechanisms.
Drug hypersensitivity occurs in people who express specific HLAs. Therefore, genetic susceptibility plays a major role in idiosyncratic drug reactions. Increased accuracy in HLA typing has made it possible to make convincing connections between the presence of HLA alleles and the occurrence of adverse drug reactions, including drug hypersensitivity. For instance, associations between the HLA-B*38 allele and sulfamethoxazole have been established for members of European populations. Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS-TEN) is an adverse reaction corresponding to this association. This type of information can be used to make predictions regarding the risk or likelihood of a person to develop reactions to a given drug.
Value of Pharmacogenetic Screening
Strong associations have been made between the HLA-B*57:01 allele and T-cell-mediated hypersensitivity to abacavir (an HIV/AIDS drug) in European and African populations. In a study by Berka et al (3), 3.7% of patients treated with abacavir developed adverse drug reactions to the drug. Polymerase chain reaction sequence-specific primer–based genotyping was used to characterize the HLA alleles in these patients. Ninety percent of the patients with the HLA-B*5701 allele treated with abacavir developed adverse drug reactions.
A systematic review and meta-analysis (4) revealed associations between HLA-B*1502 and the anticonvulsant carbamazepine in Han-Chinese, Thai, and Malaysian populations. The mechanism for the adverse reactions in these cases is thought to involve the binding of the drug to the site of antigen binding in HLA. This, in turn, may cause a change in the selection of peptides that can bind to T cells. This is considered yet another possible model for drug-T-cell receptor interaction (5).
HLA as a Pharmacogenetic Biomarker
The application of genetic testing can serve as a means to prevent adverse and hypersensitivity drug reactions. Maekawa et al (6) developed an assay using single nucleotide polymorphisms (SNPs) around the HLA region that is strongly linked with allopurinol-related SJS-TEN in Japanese patients. These SNPs, therefore, served as biomarkers for susceptibility to allopurinol-induced SJS-TEN. The team was able to detect various genotypes and find HLA-B*58:01 carriers.
Another adverse reaction, statin-related myopathy (SRM) has been studied in non-Asian populations. However, a study regarding predictive biomarkers in a Japanese population was conducted (7). A solid association between HLA-DRB1*04:06 and SRM was observed. Although more studies are needed to validate this finding, it suggests that the development of SRM may be related to the identified allele.
Although it is not yet understood if the current theories regarding the mechanisms of HLA and drug interactions all contribute at some level to the development of adverse and hypersensitivity drug reactions, it is clear that HLA has strong links to the pathogenesis of a number of these reactions. With this current information, specific biomarkers that screen for HLA alleles can facilitate personalized medicine efforts to prevent reactions by allowing different drug choices for susceptible individuals. Pharmacogenetic research in this area can also help with drug discovery so that new drugs can be developed that are safe for those with known susceptibilities to health and life-threatening drug reactions.
- Pichler WJ. The p-i Concept: Pharmacological Interaction of Drugs With Immune Receptors. The World Allergy Organization Journal. 2008;1(6):96-102. doi:10.1097/WOX.0b013e3181778282.
- Yun J, Cai F, Lee FJ, Pichler WJ. T-cell-mediated drug hypersensitivity: immune mechanisms and their clinical relevance. Asia Pacific Allergy. 2016;6(2):77-89. doi:10.5415/apallergy.2016.6.2.77.
- Berka N, Gill JM, Liacini A, O’Bryan T, Khan FM. Human leukocyte antigen (HLA)and pharmacogenetics: screening for HLA-B*57:01 among human immunodeficiency virus-positive patients from southern Alberta. Hum Immunol. 2012 Feb;73(2):164-7.
- Tangamornsuksan W, Chaiyakunapruk N, Somkrua R, Lohitnavy M, Tassaneeyakul W. Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol. 2013 Sep;149(9):1025-32.
- Pavlos R, Mallal S, Phillips E. HLA and pharmacogenetics of drughypersensitivity. Pharmacogenomics. 2012 Aug;13(11):1285-306.
- Maekawa K, Nishikawa J, Kaniwa N, Sugiyama E, Koizumi T, Kurose K, Tohkin M,Saito Y. Development of a rapid and inexpensive assay for detecting a surrogate genetic polymorphism of HLA-B*58:01: a partially predictive but useful biomarkerfor allopurinol-related Stevens-Johnson syndrome/toxic epidermal necrolysis inJapanese. Drug Metab Pharmacokinet. 2012;27(4):447-50.
- Sai K, Kajinami K, Akao H, Iwadare M, Sato-Ishida R, Kawai Y, Takeda K,Tanimoto T, Yamano T, Akasaka T, Ishida T, Hirata KI, Saku K, Yagi S, Soeki T,Sata M, Ueno M, Miyazaki S, Shiraki A, Oyama JI, Node K, Sugamura K, Ogawa H, Kurose K, Maekawa K, Matsuzawa Y, Imatoh T, Hasegawa R; JapaneseÂ Pharmacogenomics Data Science Consortium., Saito Y. A possible role for HLA-DRB1*04:06 in
About the Author:
Dr. Stacy Matthews Branch is a biomedical consultant, medical writer for Macrogen, and veterinary medical doctor. She owns Djehuty Biomed Consulting and has published research articles and book chapters in the areas of molecular, developmental, reproductive, forensic, and clinical toxicology. Dr. Matthews Branch received her DVM from Tuskegee University and her PhD from North Carolina State University.
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