Four novel defective alleles and comprehensive haplotype analysis of CYP2C9 in Japanese.

Article Details

Citation

Maekawa K, Fukushima-Uesaka H, Tohkin M, Hasegawa R, Kajio H, Kuzuya N, Yasuda K, Kawamoto M, Kamatani N, Suzuki K, Yanagawa T, Saito Y, Sawada J

Four novel defective alleles and comprehensive haplotype analysis of CYP2C9 in Japanese.

Pharmacogenet Genomics. 2006 Jul;16(7):497-514.

PubMed ID
16788382 [ View in PubMed
]
Abstract

Genetic variations in cytochrome P450 2C9 (CYP2C9) are known to contribute to interindividual and interethnic variability in response to clinical drugs such as warfarin. In the present study, CYP2C9 from 263 Japanese subjects was resequenced, resulting in the discovery of 62 variations including 32 novel ones. In addition to the two known non-synonymous single nucleotide polymorphisms (SNPs), Ile359Leu (*3; allele frequency=0.030) and Leu90Pro (*13; 0.002), seven novel non-synonymous SNPs, Leu17Ile (0.002), Lys118ArgfsX9 (*25; 0.002), Thr130Arg (*26; 0.002), Arg150Leu (*27; 0.004), Gln214Leu (*28; 0.002), Pro279Thr (*29; 0.002) and Ala477Thr (*30; 0.002), were found. Functional characterization of novel alleles using a mammalian cell expression system in vitro revealed that *25 was a null allele and that *26, *28 and *30 were defective alleles. The *26 product showed a 90% decrease in the Vmax value but little change in the Km value towards diclofenac. Both *28 and *30 products showed two-fold higher Km values and three-fold lower Vmax values than the *1 allele, suggesting the importance of Gln214 and Ala477 for substrate recognition. Linkage disequilibrium and haplotype analyses were performed using the detected variations. Only five haplotypes (frequency >0.02) accounted for most (>87%) of the inferred haplotypes, and they were closely associated with the haplotypes of CYP2C19 in Japanese. Although the haplotype structure of CYP2C9 was rather simple in Japanese, the haplotype distribution was quite different from those previously reported in Caucasians and Africans. Taken together, novel defective alleles and detailed haplotype structures would be useful for determining metabolic phenotypes of CYP2C9 substrate drugs in Japanese and probably Asians.

DrugBank Data that Cites this Article

Pharmaco-genomics
DrugInteracting Gene/EnzymeAllele nameGenotypesDefining change(s)Type(s)DescriptionDetails
PhenytoinCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*25Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
PhenytoinCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*26Not Available
  • 389C>G
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
PhenytoinCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*28Not Available
  • 641A>T
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
PhenytoinCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*30Not Available
  • 1429G>A
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
CelecoxibCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*25Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
CelecoxibCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*26Not Available
  • 389C>G
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
CelecoxibCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*28Not Available
  • 641A>T
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
CelecoxibCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*30Not Available
  • 1429G>A
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
WarfarinCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*25Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
WarfarinCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*26Not Available
  • 389C>G
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
WarfarinCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*28Not Available
  • 641A>T
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
WarfarinCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*30Not Available
  • 1429G>A
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
ClopidogrelCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*25Not AvailableEffect InferredPoor drug metabolizer, lower dose requirements, higher risk for drug-drug interactionsDetails
ClopidogrelCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*26Not Available
  • 389C>G
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for drug-drug interactionsDetails
ClopidogrelCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*28Not Available
  • 641A>T
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for drug-drug interactionsDetails
ClopidogrelCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*30Not Available
  • 1429G>A
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for drug-drug interactionsDetails
Acetylsalicylic acidCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*25Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
Acetylsalicylic acidCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*26Not Available
  • 389C>G
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
Acetylsalicylic acidCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*28Not Available
  • 641A>T
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
Acetylsalicylic acidCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*30Not Available
  • 1429G>A
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
GlipizideCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*25Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
GlipizideCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*26Not Available
  • 389C>G
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
GlipizideCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*28Not Available
  • 641A>T
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
GlipizideCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*30Not Available
  • 1429G>A
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
TolbutamideCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*25Not AvailableEffect InferredPoor drug metabolizer, lower dose requirementsDetails
TolbutamideCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*26Not Available
  • 389C>G
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
TolbutamideCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*28Not Available
  • 641A>T
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
TolbutamideCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*30Not Available
  • 1429G>A
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
AcenocoumarolCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*25Not AvailableEffect InferredPoor drug metabolizer, associated with lower dose requirement.Details
AcenocoumarolCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*26Not Available
  • 389C>G
Effect InferredPoor drug metabolizer, associated with lower dose requirement.Details
AcenocoumarolCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*28Not Available
  • 641A>T
Effect InferredPoor drug metabolizer, associated with lower dose requirement.Details
AcenocoumarolCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*30Not Available
  • 1429G>A
Effect InferredPoor drug metabolizer, associated with lower dose requirement.Details
PhenprocoumonCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*25Not AvailableADR InferredAssociated with delayed stabilization. If carrier of rs9934438 as well, increased risk of severe overanticoagulation.Details
PhenprocoumonCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*26Not Available
  • 389C>G
ADR InferredAssociated with delayed stabilization. If carrier of rs9934438 as well, increased risk of severe overanticoagulation.Details
PhenprocoumonCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*28Not Available
  • 641A>T
ADR InferredAssociated with delayed stabilization. If carrier of rs9934438 as well, increased risk of severe overanticoagulation.Details
PhenprocoumonCytochrome P450 2C9
Gene symbol: CYP2C9
UniProt: P11712
CYP2C9*30Not Available
  • 1429G>A
ADR InferredAssociated with delayed stabilization. If carrier of rs9934438 as well, increased risk of severe overanticoagulation.Details