Published: 8 June 2018

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Pharmacogenomics – Helps Reduce Rash Decisions

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Prescriber Update 39(2): 25-27
June 2018

Introduction

Pharmacogenomics is the study of how genes influence an individual’s response to medicines.

Human leukocyte antigen (HLA) alleles

Severe cutaneous adverse reactions (SCAR) are rare but potentially lethal. SCAR is an umbrella term that includes Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS).

Variant human leukocyte antigen (HLA) alleles put some individuals at higher risk of developing SCAR. (An allele is variant form of a given gene that is located at a specific position on a specific chromosome.) The prevalence of these HLA variant alleles varies widely between individuals but may be related to their geographical origin¹. Three medicines have a well-established genetic HLA association (Table 1).

Table 1: Abacavir, allopurinol and carbamazepine, their associated human leukocyte antigen alleles and at-risk populations

Medicine	HLA type(s)	At-risk populations (HLA frequency, where known)
Abacavir2,3	HLA-B*57:01	All populations (UK prevalence 4.5%)
Allopurinol4,5	HLA-B*58:01	Han Chinese, Korean, Thai (5-20%) European (1-2%)
Carbamazepine6-8	HLA-B*15:02	Han Chinese, South-East Asian
	HLA-A*31:01	European, Japanese

Other HLA-drug associations have also been reported, including dapsone, phenytoin, sulfamethoxazole, lamotrigine, nevirapine and methzolamide.

Polymorphisms of drug metabolising enzymes

Genetic polymorphisms of drug cytochrome P450 drug metabolising status or other enzymes involved in metabolism can have an effect on drug metabolism and lead to toxicity or lack of response.

Examples of polymorphic drug metabolising enzymes include:

• CYP2D6: important for codeine, tamoxifen, some antipsychotics⁹
• CYP2C9: important for phenytoin¹, warfarin (the Clinical Pharmacogenetics Implementation Consortium recommends the algorithm at www.warfarindosing.org to predict optimal starting doses of warfarin¹⁰)
• thiopurine methyltransferase (TPMT): azathioprine, mercaptopurine
• UDP-glucuronosyltransferase 1-1 (UGT1A1): irinotecan.

Clinical implications

The risk of adverse reactions to medicines can be reduced by screening patients and avoiding prescribing medicines to those with these HLA types or enzyme polymorphisms.

There are differences internationally in the use of these tests. For example, all patients requiring medicines such as allopurinol are screened at some centres in Thailand. In other countries, testing is only performed for patients belonging to certain population groups. For example, the American College of Rheumatology recommends genetic screening before prescribing allopurinol in Koreans with stage 3 or worse chronic kidney disease, and all those of Han Chinese and Thai descent regardless of kidney function¹¹. HLA testing before starting abacavir is universal.

New Zealand reports

Table 2 shows all reports received by the Centre for Adverse Reactions Monitoring (CARM) of SCAR associated with carbamazepine and allopurinol up to 31 December 2017. To date, none of the reports have included information on whether genetic testing had been performed. There are no reports for abacavir.

Table 2: All reports of severe cutaneous adverse reactionsa for carbamazepine and allopurinol received by the Centre for Adverse Reactions Monitoring to 31 December 2017

	Allopurinol	Carbamazepine	Total
Total Reports	46	39	85
Deaths	5	1	6
Reported ethnicityb
European	15	20	35
Māori	10	5	15
Pacific	3	4	7
Other	13	7	20
Unknown	5	3	8

Includes reports for Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS).

Ethnicity is a cultural affiliation and does not necessarily reflect ancestry¹².

Please continue to report any adverse reactions to medicines to CARM (http://nzphvc.otago.ac.nz/report/).

Current and future work

Pharmacogenomics is likely to become more widespread in the future. In New Zealand, UDRUGS (Understanding Adverse Drug Reactions Using Genomic Sequencing) has been established with two major goals: to establish a DNA bank linked to clinical information of patients who have experienced severe adverse drug reactions or exhibited aberrant response to pharmacological treatment, and to explore the range of variations in known pharmacogenes that may contribute to the observed phenotypes¹³.

References

1. Su S-C, Hung S-I, Fan W-L, et al. 2016. Severe cutaneous adverse reactions: The pharmacogenomics from research to clinical implementation. International Journal of Molecular Sciences 17(11): 1890.
2. Mallal S, Phillips E, Carosi G, et al. 2008. HLA-B*5701 screening for hypersensitivity to abacavir. The New England Journal of Medicine 358(6): 568–79.
3. Orkin C, Sadqu ST, Rice L, et al. 2010. Prospective epidemiological study of the prevalence of human leukocyte antigen (HLA)-B*5701 in HIV-1-infected UK subjects. HIV Med 11(3): 187–92. DOI: 10.1111/j.1468-1293.2009.00762.x (accessed 16 May 2018).
4. Somkrua R, Eickman EE, Saokaew S, et al. 2011. Association of HLA-B* 5801 allele and allopurinol-induced Stevens Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. BMC Medical Genetics 12(1): 118.
5. Ko T-M, Tsai C-Y, Chen S-Y, et al. 2015. Use of HLA-B* 58: 01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study. BMJ 351: h4848.
6. Chen P, Lin J-J, Lu C-S, et al. 2011. Carbamazepine-induced toxic effects and HLA-B* 1502 screening in Taiwan. New England Journal of Medicine 364(12): 1126–33.
7. McCormack M, Alfirevic A, Bourgeois S, et al. 2011. HLA-A* 3101 and carbamazepine-induced hypersensitivity reactions in Europeans. New England Journal of Medicine 364(12): 1134–43.
8. Ozeki T, Mushiroda T, Yowang A, et al. 2010. Genome-wide association study identifies HLA-A* 3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population. Human Molecular Genetics 20(5): 1034–41.
9. Drozda K, Müller D, Bishop J. 2014. Pharmacogenic testing for neuropsychiatric drugs: current status of drug labeling, guidelines for using genetic information, and test options. Pharmacotherapy 34(2): 166–84. URL: www.ncbi.nlm.nih.gov/pmc/articles/PMC3939793/ (accessed 16 May 2018).
10. Johnson JA, Gong L, Whirl‐Carrillo M, et al. 2011. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clinical Pharmacology & Therapeutics 90(4): 625–9.
11. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012. American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care & Research 64(10): 1431–46.
12. Stats NZ. 2018. Ethnicity. URL: www.stats.govt.nz/topics/ethnicity (accessed 15 May 2018).
13. Maggo SD, Chua EW, Chin P, Cree S, Pearson J, Doogue M, et al. 2017. A New Zealand platform to enable genetic investigation of adverse drug reactions. New Zealand Medical Journal 130(1466): 62–9.