Important Variant Information for CYP2C9

Submitted by: Derek Van Booven (CREATE), Michelle Whirl Carrillo (PharmGKB)
Reviewed by: Reviewed
Submitted date: January 16th, 2007

There are Two Important Variants for CYP2C9.

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

1. CYP2C9: 144Arg>Cys

Gene HGNC Name:

CYP2C9

Variant Summary:

The variant at this position 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 is diagnostic for a CYP2C9*2 haplotype.

The 144Arg>Cys variant has been genotyped in various populations. It occurs with fairly low frequency, existing in about 10-20% of the Caucasian population and extremely rare in the tested Asian and African-American populations. This variant has been shown to correlate significantly with warfarin dose [15900281, 16513444]. Several promoter-region and intronic SNPs have been shown to be in linkage disequilibrium with this variant [15900281], but they have not been shown to influence warfarin dose. Subjects carrying this variant have been shown to require lower levels of warfarin and have more bleeding events [15900281, 11127854, 12414349]. It has also been found that homozygotes for this variant have much lower clearance values for S-acenocoumarol and S-warfarin as compared to individuals homozygous for Arg [15637526]. This variant has little affect in Asian populations since it is so rare, and it has been shown repeatedly that the VKORC1 haplotype is predominantly relevant to warfarin dose [16513444, 17161452]. Other influencing factors on warfarin dose include age and weight [16424822].
The 144Arg>Cys variant has also been associated with sulphaphenazole inhibition, but in at least one study did not correlate with diclofenac hydroxylation in vitro [8809086]. Homozygotes for this variant have lower clearances as compared to individuals homozygous for Arg (68-90%) for the following drugs: phenytoin, tolbutamide, ibuprofen, nateglinide, fluvastatin, phenprocoumon [15637526]. In other studies, the clearance in heterozygotes has been shown to be 58% for losartan, and higher than wild type homozygotes for diclofenac and celecoxib [15637526].

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 is diagnostic for a CYP2C9*3 haplotype.

The 359Ile>Leu variant has been genotyped in various populations. It appears to be least common in the tested Asian and African-American populations. This variant has been shown to correlate significantly with warfarin dose [15900281, 16513444]. Several promoter-region and intronic SNPs have been shown to be in linkage disequilibrium with this variant [15900281], but they have not been shown to influence warfarin dose. Subjects carrying this variant have been shown to require lower levels of warfarin and have more bleeding events [15116052, 15900281, 11127854, 12414349]. However, in at least one study, this genotype could not explain lower warfarin requirements for Chinese and Malay on warfarin - though in the same study it was found to be the most significant factor for Indians, even as compared to VKORC1 haplotype [16513444]. Yet it has been shown repeatedly that the VKORC1 haplotype is predominantly relevant to warfarin dose [16513444, 16513444] especially in Asian populations [16424822].

Homozygosity for this variant has been shown to coincide with lower metabolic activities for CYP2C9 substrates in general, including tolbutamide and phenytoin. However, much of the supporting data are from in vitro studies and homozygous individuals are rare [9662807]. In other studies, it has been found that heterozygotes have about half the clearance for the following drugs: S-warfarin, tolbutamide, fluvastatin, glimepiride, tenoxicam, candesartan, celecoxib, phenytoin [15637526].

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:

Key Haplotypes:

CYP2C9*3

The PGRN is financially supported by grants from NIGMS, NHLBI, NHGRI, NIEHS, NCI, and NLM within the NIH, HHS. PharmGKB is managed at Stanford University. This work is supported by the NIH/NIGMS Pharmacogenetics Research Network and Database (U01GM61374). ©2001-2008 PharmGKB.