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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 Apr;20(4):277-81. 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.

  1. CYP2C9:144Arg>Cys
  2. 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
Key PubMed IDs: 10073515, 8873220
Genomic Variant & GenBank ID: 15489579 A>C on NT_030059
mRNA Variant & GenBank ID: 1075 A>C on NM_000771
Protein Variant & GenBank ID: 359Ile>Leu on NP_000762
dbSNP rs#: rs1057910
GoldenPath Position: chr10:96731043 (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*3
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