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

The Pharmacogenomics Journal volume 15, pages 288–292 (2015)Cite this article

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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.

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Acknowledgements

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 Consejería de Empleo, Empresa e Innovación Grant PD10199.

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Authors and Affiliations

  1. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    M Apellániz-Ruiz, L Inglada-Pérez, L Sánchez, V Mancikova, M Currás-Freixes, A A de Cubas, I Comino-Méndez, A Cascón, M Robledo & C Rodríguez-Antona

  2. ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain

    L Inglada-Pérez, A Cascón, M Robledo & C Rodríguez-Antona

  3. CICAB Clinical Research Centre at Extremadura University Hospital and Medical School, Badajoz, Spain

    M E G Naranjo & A Llerena

  4. Research Group on Molecular and Cellular Screening Processes, Laboratory of Microorganisms and Biomolecules, Centre of Biotechnology of Sfax, Sfax, Tunisia,

    S Triki & A Rebai

  5. Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia

    M Rasool & A Carracedo

  6. Pontificia Universidad Católica Argentina and Genos Laboratory, Buenos Aires, Argentina

    G Moya

  7. Faculty of Medicine CNC-Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal,

    M Grazina

  8. Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, Padova, Italy

    G Opocher

  9. Programa de Genética Humana, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile

    P Taboada-Echalar

  10. Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden

    M Ingelman-Sundberg

  11. Fundación Pública de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, Santiago de Compostela, Spain

    A Carracedo

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  1. M Apellániz-Ruiz
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  17. M Ingelman-Sundberg
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  19. M Robledo
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  20. A Llerena
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  21. C Rodríguez-Antona
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Correspondence to C Rodríguez-Antona.

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Apellániz-Ruiz, M., Inglada-Pérez, L., Naranjo, M. et al. High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme. Pharmacogenomics J 15, 288–292 (2015). https://doi.org/10.1038/tpj.2014.67

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