Variant Annotations
PharmGKB variant annotations provide information about variant-drug pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.
Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.
There are 2 annotations for this variant. Register or sign in to see them.
VIP Variant in CYP2A6
The rs28399468 (6600G>T) Arg485Leu variant is found in the CYP2A6*8, *10 and *37 alleles. Please note; several other variants also make up the CYP2A6*8, *10 and *37 alleles, as defined by the CYP-450 nomenclature committee: http://www.cypalleles.ki.se/cyp2a6.htm. See the PharmGKB CYP2A6 haplotype tab for more details.
Associations with drug metabolism
The rs28399468 T allele (when combined with other CYP2A6 alleles) has been associated with reduced tegafur metabolism and decreased response to S-1 treatment (tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate drug combination), as well as poor metabolism and clearance of pilocarpine (see the table below for more details).
| CYP2A6 Allele or Genotype | Details of genotyping | Drug | Association | Reference and study details |
|---|---|---|---|---|
| Genotype *1/*1 | Sequenced for *9 at -48T>G (rs28399433), *10 at 6600G>T (rs28399468), *7 at 6558T>C (rs5031016). *4 gene deletion. Therefore *1 was defined as wildtype with none of the above variants. | S-1 and oxaliplatin | Associated with increased tegafur metabolism and a trend for higher 5 FU plasma concentrations compared to individuals with one or two variant alleles (*4, *7, *9, *10 combined) (p values were not given), but not associated with increased likelihood of diarrhea or neutropenia. | [Article:21326246] Study: Biliary tract cancer patients, (n=48). |
| Individuals with two variant alleles, (combined genotypes): *4/*4, *4/*7, *4/*9, *7/*9, *9/*9 | *4: entire gene deletion, positions genotyped: g.-48T>G (for *9) (rs28399433), g. 6558T>C (rs5031016 Ile471Thr) (for *7, *10), and g. 6600G>T (rs28399468, Arg485Leu ) (for *10) | S-1 | Reduced treatment efficacy compared to individuals with one or two wildtype *1 alleles. Increased risk of disease progression and reduced progression-free survival, as measured by significantly reduced probability of tumor response | [Article:19604090] n= 50 Korean patients with metastatic gastric cancer |
| Individuals with one or two variant alleles, (combined genotypes): *4/*7, *4/*9, *4/*10, *9/*9, *1/*4 | *4 entire gene deletion, positions genotyped: g.-48T>G (rs28399433) (for *9), g.6558T>C (rs5031016 Ile471Thr) (for *7, *10), and g.6600G>T (rs28399468, Arg485Leu ) (for *10). | S-1 and cisplatin | Significantly associated with lower response rate, increased risk of disease progression and reduced overall survival time. | [Article:21364592] n=106, Korean patients, with metastatic gastric cancer |
| Genotype *7/*9 or *4A/*7 or *4A/*9 or *4A/*10 | *4A (entire gene deletion), *7: Ile471Thr (rs5031016), *8: Arg485Leu (rs28399468), *9: g.-48T>G (rs28399433), *10: Ile471Thr (rs5031016) and Arg485Leu (rs28399468) | Pilocarpine | Poor metabolism and low clearance. | [Article:18698229] study 1 n=20, study 2 n=8, healthy Japanese individuals administered with a single dose of pilocarpine hydrochloride. |
The CYP2A6 gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand, therefore the alleles within our variant annotations and haplotypes will differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.
Publications related to rs28399468 at chr19:41349732: 2
| An in vivo pilot study characterizing the new CYP2A6*7, *8, and *10 alleles. Biochemical and biophysical research communications. 2002. Xu C, et al. [Article:11779172@PubMed] | |
| Genetic polymorphisms in human CYP2A6 gene causing impaired nicotine metabolism. British journal of clinical pharmacology. 2002. Yoshida Ryoko, et al. [Article:12445030@PubMed] |
Cross-References
- UCSC Golden Path:
- chr19:41349732
- dbSNP:
- rs28399468
- LS-SNP:
- rs28399468
Platform Availability
- Illumina