Cyp2d6 allelic characterization on type 1 Gaucher disease patients

Abstract

Cytochrome p450 is the main drug metabolic pathway mostly by CYPIIIA3 and CYPIID6 enzymes. CYPIID6 is the responsible for the clearance from 20% of most common drugs as paracetamol or codeine and presented four different phenotypes: normal metabolizer (NM), intermediate metabolizer (IM), poor metabolizer (PM) or ultra-rapid metabolizer (UM). CYP2D6 (MIM*608902) is a highly polymorphic gene that encodes CYPIID6. The different metabolizer capabilities are caused by different alleles on CYP2D6 due to entire gene deletions or duplications or 19 SNPs. This is the pathway to metabolize one of Gaucher disease (GD) treatments, which dose administration is regulated according to the metabolizer phenotype being this an administration limitation. With this background we consider interesting stablish the metabolizer and allelic frequency from CYP2D6 on our GD population. Because of this, we select 109 type 1 GD patients genetically confirmed and we used the xTAG®CYP2D6 kit to identify the CYP2D6 gene alleles. As a result 87 patients were classified as normal, 14 as intermediate, 6 as poor and 2 as ultra-rapid metabolizers. The allelic frequencies were 5.5% for duplication and 4.5% for deletion. The most common allele was wild type and the second one was the null allele *4. Alleles *6 and *9 presented a higher frequency than expected. There was no relationship between the patients’ gender or GBA1 genotype and the allelic or phenotypic frequencies on CYPIID6 enzyme and CYP2D6 gene. To sum up, our Spanish GD series shows an unexpected distribution of alleles that encodes for enzyme with a reduced or absent activity than the results previously reported in Spanish population. This is important due to the pharmacological interactions and the impact of unexpected secondary effect that can be higher on this population. This project has been partially supported by a grant from FEETEG and is submitted to its publication.