Population Differences in Major Functional Polymorphisms of Pharmacokinetics/pharmacodynamics-related Genes in Eastern Asians and Europeans: Implications in the Clinical Trials for Novel Drug Development

Abstract

Drug lag, recently discussed extensively in Japan, can be divided into two phases: clinical development time and application review time. The former factor is still an important problem that might be improved by promoting multi-regional clinical trials and considering the results from other similar populations with Japanese, such as Koreans and Chinese. In this review, we compare the allelic or genotype frequencies of 30 relatively common functional alleles mainly between Eastern Asians and Europeans as well as among 3 major populations in Eastern Asian countries, Japan, Korea, and China, in 12 pharmacokinetics (PK)/pharmacodynamics (PD)-related genes; CYP2C9 (*2 and *3), CYP2C19 (*2, *3 and *17), 13 CYP2D6 haplotypes including *4, *5 and *10, CYP3A5 (*3), UGT1A1 (*28 and *6), NAT2 (*5, *6 and *7), GSTM1 and GSTT1 null genotypes, SLCO1B1 521T>C, ABCG2 421C>A, and HLA-A*31:01 and HLA-B*58:01. In this review, differences in allele frequencies (AFs) or genotype frequencies (GFs) less than 0.1 (in the cases of highest AF (GF) ≥0.1) or less than 0.05 (in the cases of lowest AF (GF) <0.1) were regarded as similar. Between Eastern Asians and Europeans, AFs (or GFs) are regarded as being different for many alleles such as CYP2C9 (*2), CYP2C19 (*2, *3 and *17), CYP2D6 (*4 and *10), CYP3A5 (*3), UGT1A1 (*28 and *6), NAT2 (*5*7), GSTT1 null and ABCG2 421C>A. Among the 3 Eastern Asian populations, however, only AFs of CYP2C19*3, CYP2D6*10, HLA-A*31:01 and HLA-B*58:01 are regarded as dissimilar. For CYP2C19*3, the total functional impact on CYP2C19 could be small if the frequencies of the two null alleles CYP2C19*2 and *3 are combined. Regarding CYP2D6*10, frequency difference over 0.1 is observed only between Japanese and Chinese (0.147). Although environmental factors should be considered for PK/PD differences, we could propose that among Japan, Korea, and China, genetic differences are very small for the analyzed common PK-related gene polymorphisms. On the other hand, AFs of the two HLA alleles important for cutaneous adverse drug reactions are diverse even among Eastern Asians and thus should be taken into account.

Genetic contribution of CYP2C9, CYP2C19, and APOE variants in acenocoumarol response

“…The minor *3 allele frequency has been described in the African population (1.8%) and the major allele in the Southern European (8.6%) population (Kurose et al, 2012). Both the CYP2C9*2 and *3 allele frequencies were similar to that reported by Llerena et al, (2004) in a Mexican-American population (9 and 5%, respectively).…”

“…The CYP2C19*2 allele had a frequency of 7.9%, similar (P > 0.08) to Mexican-American, West Asian, and Southern and Eastern European populations (Luo et al, 2006;Kurose et al, 2012). The CYP2C19*2 allele frequency was statistically different from Western and Northern European; Southern, South-Eastern, and Southern Asian; Caucasian; and African populations (P ≤ 0.042), whose frequencies range from 14 to 29.8% (Kurose et al, 2012).…”

“…The CYP2C19*2 allele frequency was statistically different from Western and Northern European; Southern, South-Eastern, and Southern Asian; Caucasian; and African populations (P ≤ 0.042), whose frequencies range from 14 to 29.8% (Kurose et al, 2012).…”

“…Correlation analysis of the clinical variables contrasted with dose of acenocoumarol. (Kurose et al, 2012). The minor/major *2 allele frequency is described in the Eastern Asian (<0.1%) and Southern European (14.3%) populations, respectively (Kurose et al, 2012).…”

Whole exome sequencing detects variants of genes that mediate response to anticancer drugs

“…Polymorphisms within the amino acid sequences of the majority of phase I and phase II drug-metabolizing enzymes (DMEs), as well as transporters, contribute to the clinical efficacy of drugs (Kurose et al, 2012). Genomewide association studies focusing on the response to drugs, which include analyses of candidate genes encoding DMEs, reveal the endogenous effects of genetic variations that affect drug metabolism and drug responses (Low et al, 2014;Sim et al, 2013).…”