High frequency and founder effect of the CYP3A420 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme

• Published in: The pharmacogenomics journal Vol. 15; no. 3; pp. 288 - 292
• Main Authors: Apellániz-Ruiz, M, Inglada-Pérez, L, Naranjo, M E G, Sánchez, L, Mancikova, V, Currás-Freixes, M, de Cubas, A A, Comino-Méndez, I, Triki, S, Rebai, A, Rasool, M, Moya, G, Grazina, M, Opocher, G, Cascón, A, Taboada-Echalar, P, Ingelman-Sundberg, M, Carracedo, A, Robledo, M, Llerena, A, Rodríguez-Antona, C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2015; Nature Publishing Group
• Subjects: 631/208/727; Alleles; Analysis; Biomedical and Life Sciences; Biomedicine; CYP3A4 protein; Cytochrome P-450; Cytochrome P-450 CYP3A - genetics; Cytochrome P450; Drug metabolism; Drug-Related Side Effects and Adverse Reactions - genetics; Enzymes; Ethnic Groups - genetics; Founder Effect; Gene Expression; Gene Frequency - genetics; Genetic markers; Haplotypes; Haplotypes - genetics; Human Genetics; Humans; Microsatellites; Oncology; original-article; Pharmacogenetics; Pharmacotherapy; Physiological aspects; Polymorphism, Single Nucleotide - genetics; Population genetics; Psychopharmacology; Spain
• ISSN: 1470-269X; 1473-1150; 1473-1150
• DOI: 10.1038/tpj.2014.67

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.