Frequency of Genetic Polymorphisms of CYP2C19 in Native Hawaiian, and Asian and Pacific Islander Subgroups: Implications for Personalized Medicine

Pharmacogenetic testing, where prescriptions are tailored to the individual patient based on his/her genetic makeup, increases the ability to predict individual drug response. However, little is known about the prevalence of clinically actionable pharmacogenes in diverse populations. This study seeks to assess the prevalence of select drug-gene alleles that are implicated in the metabolism of commonly prescribed drugs, so-called Very Important Pharmacogenes (VIPs). The results of this study will fill in the gaps of knowledge of VIPs in underrepresented populations and characterize their potential risk for drug adverse events or due to their underlying genetic polymorphisms, especially in patients of Asian, Hawaiian or Marshallese, or Samoan descent. The Ensemble genome browser was used to compare the frequencies of three major single nucleotide polymorphisms (SNPs) in the cytochrome P450 subfamily 2 class 19 (CYP2C19) in European (EUR) with our studied populations. Specially, SNPs of interest included rs4244285 G\u3eA, rs4986893 G\u3eA, and rs12248560 C\u3eT, for CYP2C19*2, *3, and *17, respectively. In this cross-sectional study, chi-square or Fisher’s exact test was used, when appropriate, with P \u3c 0.05 for significance. Biobank DNA samples of 1064 participants were used to calculate genotype and allele frequencies for our population groups. The sample was distributed across six self-reported ethnicities; Filipino (21.61%), Japanese (19.73%), Korean (9.77%), Hawaiian (14.84%), Marshallese (15.13%), and Samoan (18.89%). In each ethnicity from our population, the distributions of allele and genotype frequencies of the CYP2C19 *2 (rs4244285 G\u3eA), *3 (rs4986893 G\u3eA), and *17 (rs12248560 C\u3eT) variants were significantly different from EUR. The overall loss-of-function allele (A) frequencies of *2 (rs4244285 G\u3eA) and *3 (rs4986893 G\u3eA) were significantly higher in our population groups (25%-36% and 2.5%-10%, respectively) than EUR (15%, and 0%, respectively). In contrast, the overall increased function allele (T) frequencies of *17 (rs12248560 C\u3eT) were significantly higher in EUR (22.5%) than in our population (1%-6%). In conclusion, our results are consistent with published reports of Asian populations are enriched with the reduced or loss of function alleles of CYP2C19 compared with EUR.https://scholarscompass.vcu.edu/gradposters/1136/thumbnail.jp

Pharmacogenetic Perspective for Optimal Gout Management

Pharmacogenetics (PGx) is an emerging field of pharmacology focusing on how gene variations affect the patient’s response to treatment. Pharmacogenetics is a promising tool to optimize the selection and dosing of medications, including urate-lowering therapies (ULTs) among patients with gout. The global prevalence of gout is rising, and it disproportionately affects specific racial groups and individuals with select socioeconomic status. Genetic and experimental findings have provided evidence that genetic polymorphisms associated with serum urate pathology are also of pharmacogenetic interest. Patients with gout present with several comorbidities, warranting the use of several acute and long-term medications that increase their pill burden and the risk of adverse drug events. Implementing PGx testing can identify individuals who are more or less likely to benefit from a given treatment, improve medication adherence, and reduce pill burden. The purpose of this non-systematic review was to evaluate the contemporary evidence for PGx use in gout management, especially treatment modalities associated with specific genetic polymorphisms that could impact medication safety and efficacy. Strong evidence suggests that individuals carrying the HLA-B*58:01 allele are at a higher risk of serious and life-threatening skin reactions when taking allopurinol. Additionally, racial disparities in the frequency of HLA-B*58:01 warrant genetic screening in high-risk populations, specifically some Asian subgroups and African Americans. Individuals that are G6PD-deficient can develop hemolytic anemia and methemoglobinemia with pegloticase and probenecid use. Patients with the less active form of the drug-metabolizing CYP2C9 are at higher risk for NSAID-related upper gastrointestinal (GI) bleeding. Emerging evidence of clinically significant drug-gene pairs among various gout therapies is growing. Genes found to modulate the response to allopurinol include AOX, ABCG2, and SLC22A12. Meanwhile, UGT1A1 appears to modulate the response to Febuxostat. While CYP2C9 may modulate the toxicity of benzbromarone, SLC22A12 and ABCB1 were found to modulate the response to both benzbromarone and probenecid. The genes CYP2D6, ABCB1, gene cluster (rs6916345 G>A), and SEPHS1 were recently reported to modulate the safety and efficacy of colchicine. Finally, HCG22 and IL1RN are linked with the response to corticosteroid and anakinra, respectively. This review examines and synthesizes the most current level of evidence for using PGx to maximize gout pharmacotherapy