Adverse drug reactions are often medically devastating, and can lead to severe consequences for patients. Unpredictable drug reactions are a long-standing issue in evaluating the safety of medications.
While many adverse reactions are unique to specific patient populations or circumstances, previous trials often didn’t have insight into the basis of these differences. Understanding the underlying causes of adverse reactions is a crucial step toward preventing or lowering the incidence of drug reaction events.
Multiomics research has expanded the available medical strategies for understanding drug reactions. Recent studies have linked human leukocyte antigen (HLA) alleles to certain adverse drug reaction syndromes. With more insight into these connections, researchers can help prevent adverse reactions in susceptible populations.
About the HLA Complex
The HLA complex is the human version of the major histocompatibility complex (MHC) found in some vertebrate species. The HLA complex facilitates the immune system’s ability to distinguish between the body’s proteins and proteins of foreign or invading organisms.
In humans, the genes in the HLA complex are divided into three regions, called classes I, II, and III. Class I has three gene types, and class II has six.
The HLA proteins from class I are present in cells throughout the body. Those from class II are present in certain cells of the immune system. Both types bind to peptides (antigens) and present them to the immune system.
Class III genes code for protein types with functions different from those of class I and II. This includes immune regulatory molecules like tumor necrosis factors.
What Causes Adverse Drug Reactions?
It’s been suggested that adverse drug reactions occur via the adaptive immune system. However, how the interactions between the immune system and drugs lead to adverse reactions is not fully known. There are a number of theories with respect to the mechanisms of drug interactions with immune receptors.
One theory involves the hapten mechanism. A drug protein-complex stimulates a specific T-cell response to a given drug. It is then presented to the MHC as a new epitope.
A similar theory, the p-i concept, also focuses on drug stimulation of T-cells. However, in this version, a drug can stimulate T cells directly when it binds with the T-cell receptor.
The danger hypothesis has also been proposed; in this version, drug reactions are caused based on whether or not the drug causes cell damage. It may be involved in drug hypersensitivity by providing signal 2, accessory signals that co-stimulate immune response with peptide-MHC complexes.
HLA Expression & Drug Reactions
Ongoing research projects are attempting to unravel the roles of these mechanisms in adverse drug reactions. Currently, it is clear that people who express specific HLAs experience drug hypersensitivity. Accurate HLA typing has made it possible to connect HLA alleles and adverse drug reactions, including drug hypersensitivity.
For example, Stevens-Johnson syndrome (SJS) is a serious skin condition. It can progress to toxic epidermal necrolysis (TEN) if enough of the patient’s skin and mucous membranes are affected. In rare cases, SJS/TEN develops as an adverse reaction to common cold medications.
A 2020 review found six previous studies identifying 81 different HLA genotypes associated with cold medicine-induced SJS/TEN. HLA-A*0206, HLA-A*3303, HLA-B*4403, and HLA-C*0501 were associated with cold medicine induced SJS/TEN.
Because cold medicines are such a common over-the-counter medication, genetic testing may not be possible on a widespread scale. However, for people with a family history of adverse drug reactions, these insights can prevent serious negative side effects.
HLA as a Pharmacogenetic Biomarker
Finding affordable, realistic ways to implement genetic screenings is an important next step for pharmacogenetics. In one example from 2012, the National Institute of Health Sciences in Tokyo, Japan, developed a test for allopurinol-related SJS-TEN.
The assay uses single nucleotide polymorphisms (SNPs) around the HLA region linked with allopurinol-related SJS-TEN in Japanese patients. These SNPs serve as biomarkers for susceptibility to allopurinol-induced SJS-TEN. The team was able to detect various genotypes and find HLA-B*58:01 carriers.
With more tests like this, healthcare providers would be able to screen their patients for drug reaction warning signs. Then, they could opt for a different treatment plan.
The Value of Pharmacogenetic Screening
As we learn more about genes’ impact on drug response, pharmacogenetic screenings become a more viable option for patients. Further research has shown how preventative screenings could reduce the risk of certain populations having negative drug reactions.
Abacavir is a drug commonly used to treat HIV/AIDs, but can cause abacavir hypersensitivity syndrome (AHS). In patients with AHS, severe fever, rash, and vomiting are common—the syndrome can even be fatal.
Research has linked the HLA-B*5701 allele with AHS. In a group of 489 Canadian HIV-positive patients exposed to abacavir, 20 of them had the HLA-B*5701 allele. 18 of those 20 patients developed AHS during the course of treatment.
In a research project conducted several years after this initial study, AHS reactions in clinical trials were reduced to 1% of participants when those with the HLA-B*5701 were excluded. These results show the potential of pharmacogenetic screening conducted prior to administration of certain drugs.
We don’t yet know how much each theory of HLA mechanisms contributes to the development of adverse and hypersensitivity drug interactions. However, it’s clear that HLA is linked to many of these drug reactions.
We’ve yet to realize the full potential of pharmacogenetic screening in terms of HLA mechanisms. Biomarkers that screen for HLA alleles can aid personalized medicine efforts, preventing adverse reactions by guiding alternative drug selection for certain patients.
Pharmacogenetic research can also assist with drug discovery efforts. It’s important to develop new drug options for people at risk of life-threatening reactions.
Psomagen thanks Dr. Stacy Matthews Branch for her contributions to the research and writing of the original version of this article. Dr. Branch is a biomedical consultant, medical writer, 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 Ph.D. from North Carolina State University.
