Global distribution of functionally important CYP2C9 alleles and their inferred metabolic consequences

Abstract

Background Genetic variability in the cytochrome P450 CYP2C9 constitutes an important predictor for efficacy and safety of various commonly prescribed drugs, including coumarin anticoagulants, phenytoin and multiple non-steroidal anti-inflammatory drugs (NSAIDs). A global map of CYP2C9 variability and its inferred functional consequences has been lacking. Results Frequencies of eight functionally relevant CYP2C9 alleles (*2, *3, *5, *6, *8, *11, *13 and *14) were analyzed. In total, 108 original articles were identified that included genotype data from a total of 81,662 unrelated individuals across 70 countries and 40 unique ethnic groups. The results revealed that CYP2C9*2 was most abundant in Europe and the Middle East, whereas CYP2C9*3 was the main reason for reduced CYP2C9 activity across South Asia. Our data show extensive variation within superpopulations with up to tenfold differences between geographically adjacent populations in Malaysia, Thailand and Vietnam. Translation of genetic CYP2C9 variability into functional consequences indicates that up to 40% of patients in Southern Europe and the Middle East might benefit from warfarin and phenytoin dose reductions, while 3% of patients in Southern Europe and Israel are recommended to reduce starting doses of NSAIDs. Conclusions This study provides a comprehensive map of the genetic and functional variability of CYP2C9 with high ethnogeographic resolution. The presented data can serve as a useful resource for CYP2C9 allele and phenotype frequencies and might guide the optimization of genotyping strategies, particularly for indigenous and founder populations with distinct genetic profiles.

Role of Cytochrome P450 2C9 in COVID-19 Treatment: Current Status and Future Directions

“…CYP2C9 is a highly polymorphic enzyme, with 62 allelic variants identified and named thus far by the PharmVar Consortium, and the recently identified novel CYP2C9 variant (I213V) [ 63 ]. The most well-studied CYP2C9 alleles are CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910), associated with the reduced metabolism of CYP2C9 substrates in vivo, such as warfarin and phenytoin [ 64 ]. CYP2C9*2 is most prevalent in Middle Eastern populations (up to 18.1%) followed by South European populations (up to 16.5%), whereas CYP2C9*3 is most abundant in Emiratis (21.3%) and South Asian populations (up to 11.9%), followed by South European populations (up to 10.1%) [ 64 ].…”

“…The most well-studied CYP2C9 alleles are CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910), associated with the reduced metabolism of CYP2C9 substrates in vivo, such as warfarin and phenytoin [ 64 ]. CYP2C9*2 is most prevalent in Middle Eastern populations (up to 18.1%) followed by South European populations (up to 16.5%), whereas CYP2C9*3 is most abundant in Emiratis (21.3%) and South Asian populations (up to 11.9%), followed by South European populations (up to 10.1%) [ 64 ]. CYP genetic variances encompass intra-individual, inter-individual, intra-ethnic or inter-ethnic genetic polymorphisms [ 13 ].…”

Allelic Variants in the Warfarin-related Genes VKORC1 and CYP2C9 in a Western Saudi Population

“…13 The frequencies of the VKORC1 and CYP2C9 alleles exhibit significant intra-and inter-ethnic variations. 11 A limited number of studies have been conducted in Saudi Arabia to investigate the frequency of VKORC1(-1639G>A), CYP2C9*2, and CYP2C9*3 alleles in different regions. According to the study by Alzahrani et al (2013), the prevalence of the VKORC1 (-1639G>A), CYP2C9*2, and CYP2C9*3 alleles were 42.4%, 13.3%, and 2.3%, respectively, among the population of the Eastern region of Saudi Arabia.…”

“…10 More than 60 variants in the CYP2C9 gene have been reported. 11 A clinically crucial SNP in the CYP2C9 gene occurs at locations 430 and 1075. A change of cytosine with thymine at position 430 (430C>T, rs1799853) is known as the CYP2C9 *2 allele, while adenine to cytosine substitution at position 1075 (1075A>C, rs1057910) is known as the CYP2C9 *3 allele.…”

“…The frequencies of the VKORC1 and CYP2C9 alleles exhibit significant intra- and inter-ethnic variations. 11 A limited number of studies have been conducted in Saudi Arabia to investigate the frequency of VKORC1 (-1639G>A), CYP2C9 *2, and CYP2C9 *3 alleles in different regions. According to the study by Alzahrani et al .…”