Comprehensive overview of the pharmacogenetic diversity in Ashkenazi Jews

Zhou, Yitian; Lauschke, Volker M.

doi:10.1136/jmedgenet-2018-105429

Cited by 23 publications

(16 citation statements)

References 49 publications

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“…Indeed, rare single nucleotide variants (SNVs) and copy number variations (CNVs) have recently been shown to be highly prevalent in multiple classes of ADME genes, including phase 1 and phase 2 enzymes, as well as various drug transporters [26], [27], [28], [29], [30], [31], [32], [33], and careful estimates suggest that such rare variants might account for up to 20–40% of the functional variability in pharmacogenes [34]. These estimates are corroborated by structural mapping approaches, showing that rare variants can be found in functionally important residues in CYPs [35] as well as SLC [33] and SLCO [32] transporters.…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenomic network analysis of the gene-drug interaction landscape underlying drug disposition

Zhou

Lauschke

2020

Computational and Structural Biotechnology Journal

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Section: Discussionmentioning

confidence: 99%

Pharmacogenomic network analysis of the gene-drug interaction landscape underlying drug disposition

Zhou

Lauschke

2020

Computational and Structural Biotechnology Journal

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“…Furthermore, around 80% of pharmacogenetic variants were found to be population-specific (Fujikura, Ingelman-Sundberg, & Lauschke, 2015; Kozyra, Ingelman-Sundberg, & Lauschke, 2017; Zhang & Lauschke, 2018). Population-specific variations were of particular importance in populations with pronounced founder effects and repeated bottlenecks, such as Ashkenazi Jews, where their aggregated frequency exceeded 20% (Zhou & Lauschke, 2018). Combined, these studies demonstrate that the pharmacogenetic landscape is complex and that pharmacogenes harbor a plethora of rare variants that are not considered in conventional association studies with potential importance for inter-individual differences in drug disposition and response.…”

Section: Pharmacogenomics and Next-generation Sequencingmentioning

confidence: 99%

Novel genetic and epigenetic factors of importance for inter-individual differences in drug disposition, response and toxicity

Lauschke

Zhou

Ingelman‐Sundberg

2019

Pharmacology & Therapeutics

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Individuals differ substantially in their response to pharmacological treatment. Personalized medicine aspires to embrace these inter-individual differences and customize therapy by taking a wealth of patient-specific data into account. Pharmacogenomic constitutes a cornerstone of personalized medicine that provides therapeutic guidance based on the genomic profile of a given patient. Pharmacogenomics already has applications in the clinics, particularly in oncology, whereas future development in this area is needed in order to establish pharmacogenomic biomarkers as useful clinical tools. In this review we present an updated overview of current and emerging pharmacogenomic biomarkers in different therapeutic areas and critically discuss their potential to transform clinical care. Furthermore, we discuss opportunities of technological, methodological and institutional advances to improve biomarker discovery. We also summarize recent progress in our understanding of epigenetic effects on drug disposition and response, including a discussion of the only few pharmacogenomic biomarkers implemented into routine care. We anticipate, in part due to exciting rapid developments in Next Generation Sequencing technologies, machine learning methods and national biobanks, that the field will make great advances in the upcoming years towards unlocking the full potential of genomic data.

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“…Importantly, while many studies have provided critical data about the clinical importance of ABC polymorphisms (Bosch et al 2005;Fukushima-Uesaka et al 2007;Honjo et al 2002;Leschziner et al 2006;Pramanik et al 2014;Saito et al 2002;Słomka et al 2015), information about their population frequencies is limited and mostly derived from relatively small, heterogeneous cohorts. Furthermore, most studies only interrogated a few selected candidate variants and did not map the entire landscape of rare genetic variability that is characteristic for pharmacogenes (Bush et al 2016;Fujikura et al 2015;Gordon et al 2014;Ingelman-Sundberg et al 2018;Kozyra et al 2017;Wright et al 2018;Zhou and Lauschke 2018). Importantly, the increasing prevalence of Next-Generation Sequencing (NGS) projects on a population scale allows for the first time to systematically parse the inter-individual and inter-population variability in ABC transporter superfamily.…”

Section: Introductionmentioning

confidence: 99%

Ethnogeographic and inter-individual variability of human ABC transporters

2020

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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.

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Comprehensive overview of the pharmacogenetic diversity in Ashkenazi Jews

Cited by 23 publications

References 49 publications

Pharmacogenomic network analysis of the gene-drug interaction landscape underlying drug disposition

Pharmacogenomic network analysis of the gene-drug interaction landscape underlying drug disposition

Novel genetic and epigenetic factors of importance for inter-individual differences in drug disposition, response and toxicity

Ethnogeographic and inter-individual variability of human ABC transporters

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