Nomenclature for alleles of the human carboxylesterase 1 gene

The carboxylesterase 1 gene (CES1) in humans encodes a hydrolase, which is implicated in the metabolism of several commonly used drugs 1. This gene is located on chromosome 16 with a highly homologous pseudogene, CES1P1, in its proximity. A duplicated segment of CES1 replaces most of CES1P1 in some individuals, thus leading to the formation of a hybrid gene, which has its 5′ end, exon 1, and a portion of intron 1 from CES1P1 and the rest from CES12. This hybrid gene has been referred to as CES1A2 to distinguish it from the original copy of CES1, which is also known as CES1A12,3. There are two structural haplotypes of CES1, probably reflecting a double overcrossing event 2. Each of them carries one copy of CES1A1 in addition to one copy of either CES1P1 or CES1A2. Hence, the presence of CES1A2 in some individuals defines a structural haplotype different from the haplotype carrying CES1P1. Several haplotypes of CES1A2 have been identified on the basis of single nucleotide variations in its promoter including one major haplotype and several minor haplotypes 4. One of the minor CES1A2 haplotypes has two overlapping Sp1 sites that confers significantly higher transcriptional activity compared with the major haplotype of CES1A24,5. A previous study reported two variants of CES1A1 in which exon 1, with or without its flanking sequences, has been replaced by the corresponding CES1P1 segments 6,7. These were named CES1A1c and CES1A1b, respectively, to distinguish them from the CES1 reference sequence, which was called CES1A1a. In recent studies, CES1A2 has been referred to as CES1P1VAR8,9, whereas CES1A1c and CES1A1b or a closely related CES1A1b variant were denoted CES1VAR and CES1SVAR, respectively 10. The designations CES1VAR and CES1SVAR have the advantage that they are based on the name approved by the HUGO Gene Nomenclature Committee, CES1, thus avoiding the use of CES1A1. However, since these two CES1 variants were deposited in GenBank under the names CES1A1b and CES1A1c, a search for CES1SVAR and CES1VAR in this database comes up without results. Further, we believe that the new nomenclature for CES1A2 raises concerns as it assumes that CES1A2 and CES1P1 are representatives of the same gene, an assumption that may lead to misconceptions. Indeed, several studies have genotyped the CES1P1 variant −816A>C without discriminating the A at this polymorphic site from the A at the corresponding position in CES1A29,11,12. This approach is questionable as the A at position −816 in CES1A2 appears to be nonpolymorphic and resides on a haplotype different from the haplotype, which carries CES1P16. For example, it may lead to an overestimation of the frequency of the CES1P1 −816A allele in populations with a high frequency of CES1A2 such as Asian populations 2. The lack of distinction between the A allele at position −816 in CES1P1 and the corresponding but nonpolymorphic A in CES1A2 may also be of concern from a functional point of view. One such concern is that the CES1A2 haplotype with the overlapping Sp1 sites and high transcriptional activity has the potential to produce large quantities of functional enzyme 4,5, whereas CES1P1 has no such potential 2. Moreover, evidence has been provided that CES1A2 influences the pharmacokinetics of irinotecan 6, although the impact of having CES1A2 generally appears to be low 8,13. The formation of hybrids consisting of a gene and a related pseudogene has been reported for other genes than CES1. This includes the hybrids of the gene encoding cytochrome P450 2D6 (CYP2D6) and pseudogene CYP2D7, that is, the so-called CYP2D7/D6 hybrids 14,15. These are categorized as CYP2D6 variants and not as variants of pseudogene CYP2D716.