Ethnogeographic and inter-individual variability of human ABC transporters

ATP-binding cassette (ABC) transporters constitute a superfamily of 48 structurally similar membrane transporters that mediate the ATP-dependent cellular export of a plethora of endogenous and xenobiotic substances. Importantly, genetic variants in ABC genes that affect gene function have clinically...

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Autores principales: Xiao, Qingyang, Zhou, Yitian, Lauschke, Volker M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170817/
https://www.ncbi.nlm.nih.gov/pubmed/32206879
http://dx.doi.org/10.1007/s00439-020-02150-6
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author Xiao, Qingyang
Zhou, Yitian
Lauschke, Volker M.
author_facet Xiao, Qingyang
Zhou, Yitian
Lauschke, Volker M.
author_sort Xiao, Qingyang
collection PubMed
description ATP-binding cassette (ABC) transporters constitute a superfamily of 48 structurally similar membrane transporters that mediate the ATP-dependent cellular export of a plethora of endogenous and xenobiotic substances. Importantly, genetic variants in ABC genes that affect gene function have clinically important effects on drug disposition and can be predictors of the risk of adverse drug reactions and efficacy of chemotherapeutics, calcium channel blockers, and protease inhibitors. Furthermore, loss-of-function of ABC transporters is associated with a variety of congenital disorders. Despite their clinical importance, information about the frequencies and global distribution of functionally relevant ABC variants is limited and little is known about the overall genetic complexity of this important gene family. Here, we systematically mapped the genetic landscape of the entire human ABC superfamily using Next-Generation Sequencing data from 138,632 individuals across seven major populations. Overall, we identified 62,793 exonic variants, 98.5% of which were rare. By integrating five computational prediction algorithms with structural mapping approaches using experimentally determined crystal structures, we found that the functional ABC variability is extensive and highly population-specific. Every individual harbored between 9.3 and 13.9 deleterious ABC variants, 76% of which were found only in a single population. Carrier rates of pathogenic variants in ABC transporter genes associated with autosomal recessive congenital diseases, such as cystic fibrosis or pseudoxanthoma elasticum, closely mirrored the corresponding population-specific disease prevalence, thus providing a novel resource for rare disease epidemiology. Combined, we provide the most comprehensive, systematic, and consolidated overview of ethnogeographic ABC transporter variability with important implications for personalized medicine, clinical genetics, and precision public health. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00439-020-02150-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-71708172020-04-27 Ethnogeographic and inter-individual variability of human ABC transporters Xiao, Qingyang Zhou, Yitian Lauschke, Volker M. Hum Genet Original Investigation ATP-binding cassette (ABC) transporters constitute a superfamily of 48 structurally similar membrane transporters that mediate the ATP-dependent cellular export of a plethora of endogenous and xenobiotic substances. Importantly, genetic variants in ABC genes that affect gene function have clinically important effects on drug disposition and can be predictors of the risk of adverse drug reactions and efficacy of chemotherapeutics, calcium channel blockers, and protease inhibitors. Furthermore, loss-of-function of ABC transporters is associated with a variety of congenital disorders. Despite their clinical importance, information about the frequencies and global distribution of functionally relevant ABC variants is limited and little is known about the overall genetic complexity of this important gene family. Here, we systematically mapped the genetic landscape of the entire human ABC superfamily using Next-Generation Sequencing data from 138,632 individuals across seven major populations. Overall, we identified 62,793 exonic variants, 98.5% of which were rare. By integrating five computational prediction algorithms with structural mapping approaches using experimentally determined crystal structures, we found that the functional ABC variability is extensive and highly population-specific. Every individual harbored between 9.3 and 13.9 deleterious ABC variants, 76% of which were found only in a single population. Carrier rates of pathogenic variants in ABC transporter genes associated with autosomal recessive congenital diseases, such as cystic fibrosis or pseudoxanthoma elasticum, closely mirrored the corresponding population-specific disease prevalence, thus providing a novel resource for rare disease epidemiology. Combined, we provide the most comprehensive, systematic, and consolidated overview of ethnogeographic ABC transporter variability with important implications for personalized medicine, clinical genetics, and precision public health. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00439-020-02150-6) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2020-03-23 2020 /pmc/articles/PMC7170817/ /pubmed/32206879 http://dx.doi.org/10.1007/s00439-020-02150-6 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Original Investigation
Xiao, Qingyang
Zhou, Yitian
Lauschke, Volker M.
Ethnogeographic and inter-individual variability of human ABC transporters
title Ethnogeographic and inter-individual variability of human ABC transporters
title_full Ethnogeographic and inter-individual variability of human ABC transporters
title_fullStr Ethnogeographic and inter-individual variability of human ABC transporters
title_full_unstemmed Ethnogeographic and inter-individual variability of human ABC transporters
title_short Ethnogeographic and inter-individual variability of human ABC transporters
title_sort ethnogeographic and inter-individual variability of human abc transporters
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170817/
https://www.ncbi.nlm.nih.gov/pubmed/32206879
http://dx.doi.org/10.1007/s00439-020-02150-6
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