High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme.

Cytochrome P450 3A4 (CYP3A4) is a key drug-metabolizing enzyme. Loss-of-function variants have been reported as rare events, and the first demonstration of a CYP3A4 protein lacking functional activity is caused by CYP3A4*20 allele. Here we characterized the world distribution and origin of CYP3A4*20 mutation. CYP3A4*20 was determined in more than 4000 individuals representing different populations, and haplotype analysis was performed using CYP3A polymorphisms and microsatellite markers. CYP3A4*20 allele was present in 1.2% of the Spanish population (up to 3.8% in specific regions), and all CYP3A4*20 carriers had a common haplotype. This is compatible with a Spanish founder effect and classifies CYP3A4 as a polymorphic enzyme. This constitutes the first description of a CYP3A4 loss-of-function variant with high frequency in a population. CYP3A4*20 results together with the key role of CYP3A4 in drug metabolism support screening for rare CYP3A4 functional alleles among subjects with adverse drug events in certain populations.This work was supported by projects from the Spanish Ministry of Economy and Competiveness (grant number SAF2012-35779). Government of Extremadura-AEXCID (13/A001), the RIBEF IberoAmerican Network of Pharmacogenetics and SIFF (http: //www.ribef.com). MA-R and VM are predoctoral fellows of 'la Caixa'/ CNIO international PhD programme. LI-P is supported by CIBERER. MC is a predoctoral fellow supported by Severo Ochoa. AAdC is supported by the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 259735. MEGN is supported by the European Union (FSE), Gobierno de Extremadura and Consejeria de Empleo, Empresa e Innovacion Grant PD10199.S