Updated PharmVar CYP1A2 Nomenclature
From Andrea Gaedigk and Pablo Zubiaur on behalf of the CYP1A2 PharmVar expert panel
PharmVar now provides expert panel curated nomenclature for CYP1A2. Before Dec 16, 2024, PharmVar displayed the legacy content of the former Human Cytochrome P450 Nomenclature Database which was updated for the last time in 2007. This communication highlights the PharmVar expert panel’s recent key efforts including data curation and new data acquisition to provide a more comprehensive catalog of CYP1A2 allelic variation.
Although the CYP1A2 gene is abundantly expressed in the human liver, it is not currently classified as a clinically actionable pharmacogene by FDA, CPIC, DPWG or PharmGKB*. The inconsistency in associations between star alleles or the failure to detect certain associations, might be partly attributed to previous inadequate definitions of haplotypes.
To address shortcomings of the legacy CYP1A2 nomenclature (e.g., incomplete characterization, exons not sequenced, uncertainty of whether all variants of a haplotype were included in star allele definitions, use of different reference sequences over time, existence of many haplotypes that remained undefined, lack of variant phase information, etc.), a thorough review of all pre-existing haplotypes was performed. The panel also carefully reviewed the literature to update the 5’ and 3’ limits and regions to consistently define haplotypes moving forward. In addition, whole genome sequence data of the 1000 Genome Project were utilized to confirm existing star allele definitions and add numerous new star alleles to provide a more complete catalog of allelic CYP1A2 variation. Of note, the well-known variant -163C>A (rs762551; c.-9-154C>A) is among several which have previously been described as “upstream” but are in intron 1 due to the presence of an untranslated first exon. -163C>A has been extensively studied and associated with increased expression. Since the commonly tested variants -3860G>A (rs2069514) and -2467delT (rs35694136) were found to be almost completely linked with -163C>A, it was not deemed practical nor necessary extend the upstream region to -3860G>A, i.e., beyond the noncoding first exon and intron 1.
Following are highlights of the updated PharmVar CYP1A2 nomenclature:
· All haplotypes with -163C>A and no amino acid changes are now listed under a new star number, CYP1A2*30; these alleles may be functionally different compared to CYP1A2*1 alleles in smokers. The former CYP1A2*1F has been reassigned as *30.001.
· The CYP1A2*1C, D, E, G, H, J, K, V, and W legacy star alleles did not meet the most basic PharmVar allele definition criteria and were retired.
· Due to limiting the upstream region (removing -3860G>A, -2467delT and several others), some haplotypes were merged as they no longer differ. For example, *1F, *1L, *1M and *1Q were merged and are now *30.001.
· Twenty-six new star alleles were identified in the 1000 Genomes Project dataset and assigned as *22 through *47. Among these, *24 and *27 are predicted to be nonfunctional due to the presence of a premature stop codon (p.W84X) and a frameshift (p.V35fs), respectively. It remains unknown whether any of the amino acid changes in the remaining novel star alleles alter function.
· Eighteen of the novel star alleles have -163C>A and at least one variant that causes an amino acid change; not testing for the latter misclassifies these alleles as *30.001 (formerly *1F), potentially overestimating their activity.
· CYP1A2*4, *9, *10, *13 and *14 were revised to include -163C>A based on published data or 1000 Genomes Project data.
· Additional information can be found in the “Read Me” and “Change Log” documents which are available through the CYP1A2 PharmVar gene page.
CYP1A2 was the last gene to transition from the Human Cytochrome P450 Nomenclature site to the PharmVar database. This accomplishment marks a significant milestone in our efforts to provide high-quality haplotype-based nomenclature for pharmacogenetic variation. The updated catalog of CYP1A2 star alleles in PharmVar offers a comprehensive inventory and serves as an essential resource paving the way for future research and advancing genotype-based individualized drug therapy.
* CYP1A2 is not included on FDA’s Table of Pharmacogenetic Associations and is listed with rucaparib on the Table of Pharmacogenomic Biomarkers in Drug Labeling where the label states it does not affect drug concentration. CYP1A2 is not listed on CPIC’s gene-drug pair list, DPWG states there are no interaction with evaluated drugs, and PharmGKB has level 3 and 4 clinical annotations on variants in this gene.