Important Haplotype Information for CYP2C19
Submitted by: Jason Robarge, Rebecca Fletcher, Anne Nguyen (COBRA), Caroline F. Thorn (PharmGKB)
Reviewed by: Under Review
Submitted date: September 30, 2006
There are Two Important Haplotypes for CYP2C19.
| Gene HGNC Name: | CYP2C19 |
|---|---|
| Haplotype Name | CYP2C19*2 |
| Haplotype Summary: | The principal polymorphism responsible for the mephenytoin poor metabolizer (PM) phenotype is CYP2C19*2 [PMID: 8195181]. CYP2C19*2 is also known historically as CYP2C19m1. This allele was first detected in White and Asian PMs of mephenytoin [PMID: 8195181]. The *2 allele also contributes to the PM phenotype for omeprazole [PMID: 9014204] and other CYP2C19 substrates. The haplotype is defined by the SNP CYP2C19:681G>A and 3-4 additional SNPs make up the haplotype for CYP2C19*2 and subdivide it into CYP2C9*2A and CYP2C19*2B. *2A differs from *2B at amino acid 92 (CYP2C19:276G>C; E92D). The haplotype shows different distribution in different racial and ethnic groups (as shown in the frequency table below), with Asian populations having higher frequencies of the *2 allele than White, Black or African American, and Hispanic or Latino populations. Of particular note are the Pacific Islander populations of Papua New Guinea and Vanuatu where very high frequencies of *2 alleles are observed and may be of significance for the prophylaxis of malaria with the CYP2C19 substrate drug proguanil [PMID: 14583683; 10591538]. |
| Key PubMed IDs: | 8195181; 9014204; 14583683; 10591538 |
| Key Drugs/Substrates: | lansoprazole; omeprazole; pantoprazole; rabeprazole; phenytoin; mephenytoin; phenobarbitone; amitriptyline; carisoprodol; citalopram; clomipramine; cyclophosphamide; hexobarbital; imipramine; indomethacin; mephobarbital; moclobemide; nelfinavir; nilutamide; primidone; progesterone; proguanil; propranolol; teniposide; warfarin |
| Key Phenotypes/Diseases: | Phenotypes: Mephenytoin poor metabolizer (OMIM: 124020); Omeprazole poor metabolizer (OMIM: 124020); Proguanil poor metabolizer (OMIM: 124020) |
| Key Variants defining SNP in bold |
CYP2C19:681G>A (rs4244285), CYP2C19:99C>T (rs17885098), CYP2C19:990C>T (rs3758580), CYP2C19:991A>G (rs3758581), CYP2C19:276G>C (*2B) |
| Gene HGNC Name: | CYP2C19 |
|---|---|
| Haplotype Name | CYP2C19*3 |
| Haplotype Summary: | The CYP2C19*3 haplotype is the second most studied haplotype of CYP2C19. It is comprised of 3 variant positions with the defining SNP being CYP2C19:636G>A which results in a Trp/Ter change at amino acid 212 and truncation of the protein. CYP2C19*3 was also known historically as CYP2C19m2 [PMID: 7969038]. In Asian populations CYP2C19*2 plus CYP2C19*3 account for 99% of PM phenotypes [PMID: 9435198], however the CYP2C19*3 allele is much less frequent in White, Black or African American, and Hispanic or Latino populations (as shown in the frequency table below). The Pacific Islander populations of Papua New Guinea and Vanuatu, as well as having a high frequency of CYP2C19*2 alleles, also have an uncommonly high frequency of CYP2C19*3 alleles which may be of significance for the prophylaxis of malaria with the CYP2C19 substrate drug proguanil [PMID: 14583683; 10591538]. |
| Key PubMed IDs: | 7969038; 7586932; 9435198; 14583683; 10591538 |
| Key Drugs/Substrates: | lansoprazole; omeprazole; pantoprazole; rabeprazole; phenytoin; mephenytoin; phenobarbitone; amitriptyline; carisoprodol; citalopram; clomipramine; cyclophosphamide; hexobarbital; imipramine; indomethacin; mephobarbital; moclobemide; nelfinavir; nilutamide; primidone; progesterone; proguanil; propranolol; teniposide; warfarin |
| Key Phenotypes/Diseases: | Phenotypes: Mephenytoin poor metabolizer (OMIM: 124020); Omeprazole poor metabolizer (OMIM: 124020); Proguanil poor metabolizer (OMIM: 124020) |
| Key Variants defining SNP in bold |
CYP2C19:636G>A (rs4986893), CYP2C19:991A>G (rs3758581), CYP2C19: 1251A>C (rs17886522) |
Frequency Table
| Population Reported | Population OMB | drug | disease | % *1 Allele | % *2 Allele | % *3 Allele | number of chromosomes | number of samples | PMID | notes |
|---|---|---|---|---|---|---|---|---|---|---|
| French Caucasian | White | mephenytoin | NA | 13% | 0.3% | 344 | 172 | 9732415 | Ibeanu et al, 1998 | |
| Belgian | White | 90.9% | 9.1% | 0% | 242 |
121 |
14616425 | Allabi et al, 2003 | ||
| Beninese | Black or African American | 87.0% | 13.0% | 0% | 238 |
119 |
14616425 |
Allabi et al, 2003 |
||
| Mexican American | Hispanic or Latino | 90.2% | 9.7% | 0.1% | 692 |
346 |
16815315 |
Luo et al, 2006 |
||
| African American | Black or African American |
81.0% | 18.2% | 0.8% | 472 |
236 |
16815315 | Luo et al, 2006 | ||
| Caucasian |
White | 86.4% | 12.7% | 0.9% | 546 |
273 |
16815315 | Luo et al, 2006 | ||
| East Asian (Chinese, Japanese, Korean) | Asian | 61.5% | 28.9% | 9.6% | 322 |
161 |
16815315 | Luo et al, 2006 | ||
| Southeast Asian (Filipino, Vietnamese, Cambodian) | Asian | 63.1% | 31.2% | 5.7% | 160 |
80 |
16815315 | Luo et al, 2006 | ||
| Canadian Native Indian | American Indian or Alaska Native | 80.9% |
19.1% | 0% | 230 |
115 |
9797794 |
Nowak et al, 1998 |
||
| Chinese | Asian | 64% |
29% | 7% | 138 |
69 |
9797794 | Nowak et al, 1998 | ||
| Japanese | Asian | 61.8% |
27.4% | 10.8% | 434 |
217 |
8807668 | Takakubo at el, 1996 |
||
| Inuit | American Indian or Alaska Native |
88% | 12% | 0% | 180 |
90 |
8873219 | Jurima-Romet et al, 1997 |
||
| White | White | 86.7% | 13% | 0.3% | 346 |
173 |
9797794; 9435198 | Frequencies taken from PMID 9797794 without verification against original report | ||
| Han Chinese | Asian | mephenytoin | 55.9% | 36.6% | 7.4% | 202 | 101 | 9103550 | Xiao et al, 1997 | |
| Bai Chinese | Asian | mephenytoin | 68.8% | 25.7% | 5.2% | 404 | 202 | 9103550 | Xiao et al, 1997 | |
| Sepik, Papua New Guinea | Native Hawaiian or Other Pacific Islander | proguanil | 39% | 45% | 16% | 802 | 401 | 14583683 | Masta et al, 2003 |
Disclaimer: Percentages may not add up to 100% due to presence of other * alleles not listed in this table