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

作者：Apellaniz Ruiz M; Inglada Perez L; Naranjo M E G; Sanchez L; Mancikova V; Curras Freixes M; de Cubas A A; Comino Mendez I; Triki S; Rebai A; Rasool M; Moya G; Grazina M; Opocher G; Cascon A; Taboada Echalar P; Ingelman Sundberg M; Carracedo A; Robledo M; Llerena A; Rodriguez Antona C^*

来源：The Pharmacogenomics Journal, 2015, 15(3): 288-292.

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.

• 出版日期2015-6