Are Drug Allergies Genetic?
Drug allergies are an immune-mediated type of adverse drug reactions. Though these reactions are unpredictable for the most part, genetic polymorphisms of certain genes can predispose patients to allergy. These genetically predisposed individuals show familial and ethnic clustering. This means that people belonging to a population showing certain genetic markers are at risk of developing this type of allergic reactions to drugs.
For example, the association of alleles HLA-B*57:01 with abacavir and HLA-B*15:02 with carbamazepine are most well-documented. In 2008, the US FDA issued an alert recommending genetic testing for the HLA-B*5701 allele in all patients before starting the treatment with abacavir.
Similarly, according to the FDA, testing for HLA-B*1502 allele should be done for all patients with ancestry in populations with increased frequency of this allele. The FDA label states that patients who are found positive for this test should not be administered carbamazepine unless the benefits outweigh the risks.
This is why you don't see doctors asking for a family history of any drug allergy. Rather you will be asked questions like
- What was the time frame of the reaction?
- Has the medication been used in the past?
- Has this reaction occured before?
- How long ago was the reaction?
The most appropriate way to know if you are allergic to a drug would be to undergo drug allergy tests because several factors play a role to make you allergic which are impossible to determine otherwise. In fact, if you were allergic to penicillins or another drug more than 10 years ago (more or less), you do not have to be allergic now. Apparently, the allergy goes away in some years. Right way to know about it would be to for a test.
Does this mean drug allergies are hereditary?
This does not mean that drug allergies run in families. There is no reason to say that if a parent shows an allergic reaction to a drug then the children or any one of them will develop this allergy. Having a genetic association means that if a person has inherited one or more genetic alterations, this person has been put at a greater risk. However, these genetic alterations do not account for the entire risk and many patients who show these markers (for example, HLA-B*57:01 allele responsible for causing an allergic reaction to abacavir) do not develop the allergic reaction. These reactions are probably a summative effect of multiple susceptibility factors including environmental factors.
How are drug allergies associated with genetics?
To understand how drug allergies are related to the genetic makeup of individuals, we must first look deep into the mechanism of these drug hypersensitivity reactions.
There are two types of adverse reactions to drugs, type A and type B. Adverse drug reactions (ADRs) that can be explained by pharmacological property of the drug-like its mechanism of action or dosage are called type A ADRs. These reactions can be predicted.
ADRs that cannot be explained by the drug features and whose occurrence cannot be predicted are called type B ADRs. The term "drug allergy" or "drug hypersensitivity reactions" applies to type B adverse reactions mediated through immunological mechanisms.
Drug hypersensitivity reactions are further classified into four types by Gell and Coombs:
True type I or immediate ADRs mediated by IgE
Allergy to aspirin, beta-lactum antibiotics (such as penicillins), NSAIDs comes under this type of ADRs. Numerous genetic association have been discovered for reactions to these drugs. Although HLA gene products are not directly involved in IgE signalling, both production and specificity of IgE appear to correlate with certain HLA genes. However, the importance and utility of testing for those genotypes has not been established yet.
Type II mediated by IgG or IgM antibodies (Cytotoxic) and Type III mediated by IgG and complement or Fc receptor (Immune Complex)
These reactions are less commonly observed. Penicillins are known to form haptens on blood cells which are subsequently targeted by IgG and IgM antibodies causing thrombocytopenia or hemolytic anaemia. There is currently no data on the genetic association to type II and type III reactions.
Type IV or delayed hypersensitivity reaction mediated by cellular immune mechanisms such as the recruitment and activation of T cells
Type IV reaction may lead to symptomatic or asymptomatic manifestations including agranulocytosis (DIA), hepatitis (DILI), pneumonitis, fever, lymphadenopathy and myositis.
These reactions are strongly linked with HLA genes. Examples include abacavir and HLA-B*15:02 causing DRESS, carbamazepine and HLA-B*31:01 causing SJS/TEN, and flucloxacillin and HLA-B*57:01 causing DILI. Other genes associated with type IV reactions include TAP1/2, MICA/MICB and HFE.
HLA alleles are most polymorphic of the human genome leading to a broad range of genetic diversity. Different ethnic populations express a range of common alleles and this has resulted in several forms of drug allergies primarily affecting specific geographical regions. For example, in carbamazepine induced Steven-Johnson syndrome that is strongly associated with HLA-B*15:02, it is expressed at high levels in Chinese populations, but absent from the Caucasian population.
How a drug can cause an allergic reaction?
Going to basics of immunology, for any foreign substance to cause an allergic reaction - it must be able to stimulate an immune response. This immune response is meant to get our body rid of the foreign substance which could be harmful. Sometimes, body misunderstands other substances as foreign when this "substance" can stimulate an immune response. Drug products can act as a foreign substance called "antigens" and stimulate our immune response.
These drug-derived antigens are presented by HLA class I or II molecules present on the surface of antigen-presenting cells who then present it to CD8+ or CD4+ T cells. The job of these T-cells is to recognize the antigen and stimulate an immune response. The presentation of drug antigen on HLA to a corresponding T-cell receptor constitutes the first signal in T-cell activation and may occur via one of three mechanisms proposed so far:
- Hapten mechanism
- Pharmacological interaction, or
- Altered self-peptide repertoire
Explaining these mechanisms would be out of the scope of this article. It is enough to understand that these mechanisms may be complementary and all relevant in a single patient for a single drug which explains the heterogeneity of these drug-allergy reactions.
It is also important to note that, there are several self-regulating checkpoints against unwanted drug reactions. The interaction between HLA proteins and drug antigen does not necessarily guarantee an allergic reaction. This is probably why many patients presenting HLA risk alleles do not develop an allergic reaction when exposed to the culprit drug.
Drugs with high molecular weight are more capable of causing an allergic reaction. Drugs given through topical route are more capable than those given by IV or IM followed by those taken orally.
Common Drug Allergies
Penicillin is the most frequent drug allergy affecting approximately 10% of the patients. For these patients, carbapenems ( such as imipenem) are prescribed as an alternative after taking prophylactic skin tests for carbapenems. 90% of patients who claim to have penicillin allergy show a negative penicillin skin test response.
The most common allergic reaction to cephalosporins is drug fever and maculopapular rashes. Positive skin test to penicillin is associated with a higher risk of allergic reactions to cephalosporins (about 2%).
Sulfonamides are associated with delayed cutaneous maculopapular eruptions, Steven-Johnson syndrome and TEN.
4. Local anaesthetics (such as novocaine, lidocaine)
These reactions are extremely rare and usually a result of other ingredients in the medications such as preservatives or epinephrine.
5. NSAIDs and Aspirin
NSAIDs and aspirin can cause urticaria, angioedema and anaphylaxis in allergic patients.
Many factors can contribute to drug allergies, including genetics. The degree to which genetics contributes is not entirely understood and varies by drug as well as the type of adverse drug reaction.
Abacavir is a drug used for HIV. Abacavir hypersensitivity occurs in 9% of patients receiving abacavir treatment. It is characterized by life-threatening manifestations involving multi-systems. The drug hypersensitiviity reaction is strongly associated with HLA polymorphism HLA-B*57:01. Genetic testing to this allele have been recommended and found useful in preventing abacavir allergy.
Allopurinol is used in the treatment of gout to decrease problematic high levels of uric acid in the blood. Association of HLA-B*5801 with allopurinol-induced SCARs have been detected in Han Chinese, Japanese, Thais, Koreans, and Caucasians.
Carbamazepine is an anticonvulsant drug used in the treatment of epilepsy. Its administration is associated with a high prevalence of hypersensitivity reactions including Steven-Johnsons syndrome and toxic epidermal necrolysis. The most significant genetic association of the HLA-B*1502 had been detected with Carbamazepine in 8% of Han Chinese population but only 1 to 2% of white persons, explaining the lower incidence of carbamazepine-induced Steven-Johnson syndrome in whites compared with Han Chinese.
What do drug allergies look like?
Drug allergies manifest either within 1-6 hours following drug intake in case of immediate reactions. These include mild to life-threatening symptoms of anaphylaxis. Some reactions develop several hours to days later, primarily as exanthematous eruptions.
Around 68% of allergic drug reactions are skin manifestations. Others can be systemic reactions. The most severe reactions to drugs are stevens-johnson syndrome and toxic epidermal necrolysis. Other common types of allergic drug reactions may include:
- IgE mediated - Combination of urticaria, angioedema. vomiting, diarrhoea, cough, wheeze, low blood pressure and/or syncope 1 to 6 hours after starting a medication; usually requires previous exposure to the drug.
- Serum sickness-like reaction: Rash, fever, joint pains, lymphadenopathy 1 or 3 weeks after starting a medication; could occur earlier if previous exposure was there.
- Allergic contact dermatitis - Dermatitis in area of cutaneous contact that evolves over days; requires previous exposure.
- Delayed drug exanthem- Fine macules and papules that occur days after the initiation of medication and resolves a few days after the med is discontinued; doesn't involve a reaction to other organs or system.
- Steven Johnson syndrome- Fever, mucosal involvement, cutaneous target and bullous lesions; possible involvement of kidney, lungs, and liver. It develops 4-28 hours start of use.
- Anaemia, cytopenia, thrombocytopenia
This is not a comprehensive list. Depending on the drug an allergy may look like anything else also.
Many factors can contribute to drug allergies, including genetics. The degree to which genetics contributes is not entirely understood and varies by drug as well as the type of adverse drug reaction. HLA typing had been recommended for two drugs so far for whom genetic association was found to be most strong. The genetic tests have been proven to be safe, fast, and a cheap screening tool.
- Elissa M. A., Khan D. A. Diagnosing and managing drug allergy. (2018) Canadian Medical Association Journal. 190 (17):532-538.
- Gibson A., Ogese M., Pirmohamed M. Genetic and nongenetic factors that may predispose individuals to allergic drug reactions. (2018). 18(4):325–332.
- Ma Q., Anthony Lu Y.H. Pharmacogenetics, Pharmacogenomics, and Individualized Medicine. (2011) Pharmacol Rev 63:437–459.
- Thong B. Y. H., Tan T.C. Epidemiology and risk factors for drug allergy. (2010) British Journal of Clinical Pharmacology. 71 (5): 684-700.
This content is for informational purposes only and does not substitute for formal and individualized diagnosis, prognosis, treatment, prescription, and/or dietary advice from a licensed medical professional. Do not stop or alter your current course of treatment. If pregnant or nursing, consult with a qualified provider on an individual basis. Seek immediate help if you are experiencing a medical emergency.
Questions & Answers
© 2019 Sherry Haynes