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 7 annotations for this variant. Register or sign in to see them.
VIP Variant in CYP2A6
The rs28399433 (g.-48T>G) variant is found in the CYP2A6*9A, *9B, *13, *15, alleles. Please note; several other variants also make up the CYP2A6*9A, *9B, *13 and *15 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.
All of the following studies genotyped for rs28399433, but may have defined individuals with the G allele as having the CYP2A6*9, *13 or *15 allele:
In the metabolism of caffeine, *9 is associated with reduced metabolism of paraxanthine into 17U, when grouped with intermediate or poor metabolizer alleles, compared to extensive metabolizers [Article:20155256].
rs28399433 genotypes G/T or GG are associated with a trend for reduced CYP2A6 mRNA and protein expression, and reduced rate of 5 FU formation from the prodrug tegafur (not statistically significant), compared to genotype TT [Article:21521021]. A similar association is seen in patients with one or two variant alleles *4, *7, *9, *10 treated with S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine, potassium oxonate combined) and oxaliplatin, who have decreased tegafur metabolism and a trend for lower 5 FU plasma concentrations compared to *1/*1 individuals [Articles:21326246, 19921195]. Individuals with two CYP2A6 variant alleles (*4, *7, *9, *10) have reduced treatment efficacy of S-1 compared to individuals with one or two wildtype *1 alleles [Articles:19604090, 21364592].
A trend for higher EFV plasma concentrations in rs28399433 T/G (CYP2A6*1/*9) heterozygotes compared to TT homozygotes does not reach significance after correcting for multiple comparisons in a small study of 45 individuals [Article:19659438]. Two loss-of-function alleles (*2, *4A-F, *5, *34) or two reduced function alleles (*1H, *1J, *7, *9, *10, *12, *13, *15, *17, *19) or one of each, are associated with reduced efavirenz (EFV) metabolism compared to those without variant alleles (in individuals with CYP2B6 reference alleles) [Article:19238117].
Genotypes *7/*9 or *4A/*9 were associated with poor metabolism and low clearance of pilocarpine [Article:18698229].
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.
