Abstract
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.
Highlights
ATP-binding cassette (ABC) transporters are a superfamily of membrane proteins that, in humans, comprise 48 genes
The most studied are polymorphisms in ABCB1, which have been associated with methotrexate clearance (Kim et al 2012a), response to antiretroviral protease inhibitors (Coelho et al 2013), as well as with pharmacokinetics, response, and toxicity of imatinib (Dulucq et al 2008; Ma et al 2017)
To directly compare the evolutionary constraint, we compared the observed number of missense and loss-of-function variants in ABC genes with the expected numbers based on the genetic background variability
Summary
ATP-binding cassette (ABC) transporters are a superfamily of membrane proteins that, in humans, comprise 48 genes. ABC transporters catalyse the translocation of a wide spectrum of endogenous substrates across biological membranes, including amino acids, sugars, nucleosides, vitamins, lipids, bile acids, leukotrienes, prostaglandins, uric acid, antioxidants, as well as a multitude of natural toxins (Liang et al 2015). Genetic variants in ABC transporters contribute to the interindividual variability in the risk of adverse drug reactions and treatment efficacy, and are key modulators of drug resistance. Variants in ABCG2 (encoding BCRP) were reproducibly associated with exposure
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
