Investigation into Ethnicity and Drug-Gene Interactions

Drugs rely heavily on bodily processes and pharmacokinetic parameters to enact their desired effect. One major pharmacokinetic parameter utilized is metabolism, which is the breakdown of molecules into smaller, more easily excreted ones. Some drugs use metabolism to become active within the body and most drugs go through some form of metabolism prior to being excreted from the body. Genetics plays a significant role in determining how effective metabolism is on a person to person basis. Individuals may have genetic mutations decreasing, increasing, or not affecting metabolism. While race or ethnicity is not defined by genetic makeup, some ethnicities are predisposed to certain genetic variances.

Many medical texts expressing the need for genetic testing often state those of Han Chinese descent as a group to be tested for significant genetic variances. The problem that arises, due to modern-day travel and migration, is that an individual might not know their line of descent down to the region, which makes genetic testing all the more important. Mutations in 6 different genes have been identified to occur more in people of Asian descent, which include CYP2C19, CYP2D6, VKORC1, HLA-B, NUDT15, and UGT1A1.1,2 CYP2C19 alleles for intermediate and poor metabolizers affect Asians 2.1x more and lead to decreased antiplatelet activity of clopidogrel.1 CYP2C19 poor metabolizers have the potential for suboptimal response to tricyclic antidepressants, possible QT prolongation with selective serotonin reuptake inhibitors (SSRIs), and possible toxicities like hepatotoxicity and neurologic dysfunction with voriconazole.1 Asians are 1.2x more likely to have the intermediate metabolizer allele for CYP2D6 and are more likely to have a poor metabolizer allele.1 CYP2D6 mutations affect tamoxifen levels leading to lower drug concentrations and possible cancer recurrence.1 Asians are 2.1x more likely to have the rs9923231 variant of VKORC1.1 With the rs9923231 variant, standard doses of warfarin may cause supratherapeutic effects, thus lower doses are recommended in this genetic carrier.1 Asians are 6.7x more likely to have the HLA-B*58:01 allele, which carries an increased risk for severe reactions to allopurinol such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).1 They are also 172x more likely to have the HLA-B*15:02 allele, increasing the risk for SJS and TEN from the medications: carbamazepine, oxcarbazepine, and phenytoin.1 The intermediate and poor metabolizer alleles for NUDT15 are 620x more likely in East Asians.1 Having this allele causes an increased risk of myelosuppression with thiopurines.1 Finally, the poor metabolizer alleles of UGT1A1 (*6, *28, *36, *37) are more common in Asian descent.2 For these alleles, there is an increased risk for atazanavir and atazanavir/ritonavir toxicity while *6 and *28 alleles can cause an increased risk of toxicity from irinotecan and FOLFIRI chemotherapy.2

Radouani et al. reviewed many studies identifying various genetic mutations found in patients across Africa. Notable variances were found in CYP2C9 (*2, *3, *5, *6 *8, *11), VKORC1 (rs9923231), CYP2C19, CYP2D6, and CYP2B6.3 CYP2C9 alleles *2 and *3 have the most evidence supporting their effects on metabolism.4,5 CYP2C9*2 is a decreased function allele, while *3 is a no function allele and the article specifically investigated how warfarin was impacted by these alleles.3-5 Patients with these alleles may experience an increased risk of supratherapeutic treatment with warfarin.3-5 The rs9923231 variant of VKORC1 was found to have increased incidence in some African regions.3 The rs9923231 variant has its own allele genotyping and depending on the genotype, patients may need an increased or decreased dose of warfarin to be in therapeutic range.3-5 When investigating clopidogrel, the article found mutations in CYP2C19 in regions of Africa that affected the desired antiplatelet activity.3-5 CYP2D6 mutations were found in some African populations that increased codeine metabolism leading to increased morphine concentrations and therapeutic overdoses.3 When investigating CYP2B6, patients in some African regions, like Congolese, had higher frequencies of alleles that possibly affect the metabolism rates of the antiretroviral efavirenz.3-5 Of the Congolese individuals, 17% had the rapid metabolizer genotype *GG, 55% had the intermediate metabolizer genotype of *GT, and 28% had the poor metabolizer genotype of *TT.3 Clinical guideline recommendations suggest rapid metabolizer genotype receive standard dosing with expected slightly lower trough concentrations.6 Intermediate and poor metabolizers initiated on a decreased dose have an increased likelihood of experiencing higher trough concentrations leading to adverse CNS effects which may lead to discontinuation of therapy.6

When investigating United States Hispanic patients and their genetic variances, CYP3A5*3 had the most common frequency while CYP2C9*3 and CYP2C19*4 had increased prevalence.7 CYP3A5*3 is an allele of no function, meaning patients with this allele may experience decreased metabolism of tacrolimus and may need a reduced dose to be in therapeutic range.4,5,7 CYP2C9*3 is an allele of no function, which may cause decreased metabolism and clearance of medications like ibuprofen, meloxicam, celecoxib, warfarin, phenytoin, and others.4,5,7 Patients with this allele who are on warfarin or phenytoin may be at increased risk for toxicity.4,5 CYP2C19*4 is a no function allele, possibly decreasing metabolism for clopidogrel leading to toxicities and subtherapeutic outcomes. CYP2C19*4 is associated with toxicities of citalopram due to decreased metabolism of the drug.4,5,7

Genetic recombination and exposure to some environmental factors increase the chances for mutations to occur. Due to this, different areas of the world may have specific mutations with increased frequencies. Whether a person is born in a distinct region of a continent or they have ancestral ties to that region, they may be at an increased risk for having specific genetic mutations. Genetic testing can be extremely beneficial for those of Asian, African, or Hispanic ethnicities especially. These ethnicities have increased frequencies of alleles that could result in toxicities or drug concentrations outside of therapeutic range. Thus, genetic testing will reduce the risk of harm and allow providers to select a more optimal medication to treat the patient. Genetic testing is becoming a more common practice in medical care due to its ability to help providers make safer choices for treatment. While there may be some concern for costs associated with genetic testing, most can be covered by insurance with a provider’s recommendation. Testing services will drop in price with the continuing advancement of technology and standardization in healthcare practices.

1. Lo C, Nguyen S, Yang C, Witt L, Wen A, Liao TV, Nguyen J, Lin B, Altman R, Palaniappan L. Pharmacogenomics in Asian subpopulations and impacts on commonly prescribed medications. Clin Transl Sci. 2020 Sep;13(5):861-70.
2. Shimoyama S. Pharmacogenetics of irinotecan: an ethnicity-based prediction of irinotecan adverse events. World J Gastrointest Surg. 2010 Jan 27;2(1):14-21.
3. Radouani F, Zass L, Hamdi Y, da Rocha J, Sallam R, Abdelhak S, Ahmed S, Azzouzi M, Benamri I, Benkahla A, Bouhaouala-Zahar B, Chaouch M, Jmel H, Kefi R, Ksouri A, Kumuthini J, Masilela P, Masimirembwa C, Othman H, Panji S, Romdhane L, Samtal C, Sibira R, Ghedira K, Fadlelmola F, Kamal Kassim S, Mulder N. A review of clinical pharmacogenetics studies in African populations. Per Med. 2020 Mar;17(2):155-70.
4. Whirl-Carrillo M, Huddart R, Gong L, Sangkuhl K, Thorn CF, Whaley R, Klein TE. An evidence-based framework for evaluating pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2021 Sep;110(3):563-72.
5. Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, Altman RB, Klein TE. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012 Oct;92(4):414-7.
6. Desta Z, Gammal RS, Gong L, Whirl-Carrillo M, Gaur AH, Sukasem C, Hockings J, Myers A, Swart M, Tyndale RF, Masimirembwa C, Iwuchukwu OF, Chirwa S, Lennox J, Gaedigk A, Klein TE, Haas DW. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and efavirenz-containing antiretroviral therapy. Clin Pharmacol Ther. 2019 Oct;106(4):726-733.
7. Claudio-Campos K, Duconge J, Cadilla CL, Ruaño G. Pharmacogenetics of drug-metabolizing enzymes in US Hispanics. Drug Metab Pers Ther. 2015 Jun 1;30(2):87-105.