title: High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme.
abstract: 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.
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Apellániz-Ruiz
authors.affiliation: 1] Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain [2] ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Inglada-Pérez
authors.affiliation: CICAB Clinical Research Centre at Extremadura University Hospital and Medical School, Badajoz, Spain.
authors.forename: M E G
authors.initials: ME
authors.lastname: Naranjo
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Sánchez
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Mancikova
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Currás-Freixes
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: A A
authors.initials: AA
authors.lastname: de Cubas
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Comino-Méndez
authors.affiliation: Research Group on Molecular and Cellular Screening Processes, Laboratory of Microorganisms and Biomolecules, Centre of Biotechnology of Sfax, Sfax, Tunisia.
authors.forename: S
authors.initials: S
authors.lastname: Triki
authors.affiliation: Research Group on Molecular and Cellular Screening Processes, Laboratory of Microorganisms and Biomolecules, Centre of Biotechnology of Sfax, Sfax, Tunisia.
authors.forename: A
authors.initials: A
authors.lastname: Rebai
authors.affiliation: Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: M
authors.initials: M
authors.lastname: Rasool
authors.affiliation: Pontificia Universidad Católica Argentina and Genos Laboratory, Buenos Aires, Argentina.
authors.forename: G
authors.initials: G
authors.lastname: Moya
authors.affiliation: Faculty of Medicine CNC-Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: M
authors.initials: M
authors.lastname: Grazina
authors.affiliation: Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, Padova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Opocher
authors.affiliation: 1] Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain [2] ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Cascón
authors.affiliation: Programa de Genética Humana, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: P
authors.initials: P
authors.lastname: Taboada-Echalar
authors.affiliation: Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Ingelman-Sundberg
authors.affiliation: 1] Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia [2] Fundación Pública de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, Santiago de Compostela, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Carracedo
authors.affiliation: 1] Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain [2] ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Robledo
authors.affiliation: CICAB Clinical Research Centre at Extremadura University Hospital and Medical School, Badajoz, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Llerena
authors.affiliation: 1] Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain [2] ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Rodríguez-Antona
mesh_terms: D000483:Alleles; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics; D005006:Ethnicity / Q000235:genetics*; D018703:Founder Effect; D005787:Gene Frequency / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human