Important Variant Information for CYP2C9

Citation: Cytochrome P450 2C9-CYP2C9. Van Booven D, Marsh S, McLeod H, Carrillo MW, Sangkuhl K, Klein TE, Altman RB. Pharmacogenet Genomics. 2010 Feb 11. Epub ahead of print. PMID: 20150829

PharmGKB VIP Submitted by: Derek Van Booven (CREATE), Sharon Marsh, Howard McLeod (CREATE), Michelle Whirl Carrillo (PharmGKB), Katrin Sangkuhl (PharmGKB)
PharmGKB Submission date: January 16th, 2007
PharmGKB VIP Updated: November 18, 2009
PharmGKB VIP Reviewed: November 18, 2009

There are Two Important Variants for CYP2C9.

CYP2C9:144Arg>Cys
CYP2C9:359Ile>Leu

1. CYP2C9: 144Arg>Cys

Gene HGNC Name:

CYP2C9

Variant Summary:

This variant in exon 3 is the defining allele for the CYP2C9*2 haplotype. Other variant positions delineate between haplotypes in the *2 series (see http://www.imm.ki.se/CYPalleles for defining website), but a T allele at this position defines a CYP2C9*2 haplotype. For further information about the CYP2C9*2 haplotype see Key Haplotypes CYP2C9*2.

According to most in-vitro data, substrate affinity is not affected substantially by the *2 haplotype, but the maximum rate of metabolism (Vmax) is reduced to approximately 50% of that for CYP2C9*1 (wild-type) [PMID: 11927841; 15637526; 14597963; 11337938].
Individuals homozygous for this variant have been found to have much lower clearance values for S-acenocoumarol, S-warfarin, phenytoin, tolbutamide, ibuprofen, nateglinide, fluvastatin, phenprocoumon when compared to individuals homozygous for R (Arg) [PMID: 15637526; 16863464]. Homozygotes for this variant also have a lower clearance as compared to individuals homozygous for R (Arg) (68-90%) for the following drugs: phenytoin, tolbutamide, ibuprofen, nateglinide, fluvastatin, phenprocoumon [PMID: 15637526]. The R144C variant has been genotyped in various populations. The variant exists in about 10-20% of the Caucasian population, and is rare in the tested Asian and African-American populations [PMID: 19151603; 15469410].

Population	N subjects	Allele Frequency of "T"	PMID
Chinese (Shanghai)	394	0.001	12803577
Korean	574	0.000	11298075
Japanese	147	0.000	16111713
Japanese	140	0.000	9631918
Japanese	64	0.000	16424822
Vietnamese (Kinh)	157	0.000	15795654
Iranian	200	0.128	17201743
Turkish	499	0.106	10510154
Ashekenazi Jew	100	0.085	16111713
Yemenite Jew	99	0.051	16111713
Moroccan Jew	100	0.095	16111713
Libyan Jew	89	0.152	16111713
Egyptian	247	0.120	12047484
Ethiopian	150	0.040	11678789
African-American	66	0.000	16424822
Caucasian	115	0.143	16424822
Russian	290	0.105	12879168
Croatian	200	0.165	12950145
French Caucasians	151	0.150	12803577
German	118	0.140	12445031
Swedish	430	0.107	9920790
Spanish	157	0.143	11372590
Italian	157	0.110	11678789

Key PubMed IDs:

9241660, 8004131

Genomic Variant & GenBank ID:

15450573 C>T on NT_030059

mRNA Variant & GenBank ID:

430 C>T on NM_000771

Protein Variant & GenBank ID:

144Arg>Cys on NP_000762

dbSNP rs#:

rs1799853

GoldenPath Position:

Chr10:96692037 (hg18)

Key Drugs/Substrates:

NSAIDs (16118328), COX-2 inhibitors (12893985), tolbutamide (15637526), glipizide (15637526), fluvastatin (15637526), warfarin (8004131), phenytoin (11434505)

Key Phenotypes/Diseases:

N/A

Phenotype Data Sets:

WUSTL warfarin dosing data, group A, Hot flashes in tamoxifen patients, CYP2C9 variants and flurbiprofen metabolism, CYP2C9 variants and naproxen metabolism, CYP2C9 variants and piroxicam metabolism, Effects of dapsone on CYP2C9 variants and flurbiprofen metabolism, Effects of dapsone on CYP2C9 variants and naproxen metabolism, Lipid measurement in tamoxifen study-set 2, Meperidine N-demethylation by human CYP450 isoforms, Patient responses to tamoxifen, Thyroid binding globulin in tamoxifen patients

Key Haplotypes:

CYP2C9*2

2. CYP2C9: 359Ile>Leu

Gene HGNC Name:

CYP2C9

Variant Summary:

The variant at this position is the defining allele for the CYP2C9*3 haplotype. Other variant positions delineate between haplotypes in the *3 series (see http://www.imm.ki.se/CYPalleles for defining website), but a C allele at this position defines a CYP2C9*3 haplotype. For further information about the CYP2C9*3 haplotype see Key Haplotypes CYP2C9*3.

The catalytic activity of the *3 haplotype is significantly reduced for most CYP2C9 substrates because of both an increase in Km and a reduction in Vmax [PMID: 11927841; 15637526; 14597963].
Leu/Leu homozygotes have lower metabolic activity for CYP2C9 substrates in general, including tolbutamide and phenytoin [PMID: 10761997]. However, much of the supporting data are from in-vitro studies and homozygous individuals are rare [PMID: 19082874]. In other studies, it has been found that heterozygotes have about half the clearance as wild-type, for the following drugs: S-warfarin, tolbutamide, fluvastatin, glimepiride, tenoxicam, candesartan, celecoxib, phenytoin [PMID: 15637526].
The clearance of S-ibuprofen is reduced in CYP2C9*3/*3 homozygotes compared with wild-type homogozygotes [PMID: 15289789]. In in-vivo studies, the CYP2C9*3 haplotype in heterozygote subjects has been associated with a lower clearance and longer half-life of flurbiprofen [PMID: 12698304].

Population	N subjects	Allele Frequency of "C"	PMID
Chinese (Shanghai)	394	0.036	12803577
Korean	574	0.011	11298075
Japanese	147	0.007	16111713
Japanese	140	0.054	9631918
Japanese	64	0.016	16424822
Vietnamese (Kinh)	157	0.022	15795654
Iranian	200	0.000	17201743
Turkish	499	0.100	10510154
Ashekenazi Jew	100	0.080	16111713
Yemenite Jew	99	0.081	16111713
Moroccan Jew	100	0.115	16111713
Libyan Jew	89	0.174	16111713
Egyptian	247	0.060	12047484
Ethiopian	150	0.020	11678789
African-American	66	0.008	16424822
Caucasian	115	0.109	16424822
Russian	290	0.067	12879168
Croatian	200	0.095	12950145
French Caucasians	151	0.080	12803577
German	118	0.050	12445031
Swedish	430	0.074	9920790
Spanish	157	0.162	11372590
Italian	157	0.090	11678789