Dataset Information

Characterization of ADME gene variation in 21 populations by exome sequencing.

ABSTRACT: OBJECTIVE:Proteins involving absorption, distribution, metabolism, and excretion (ADME) play a critical role in drug pharmacokinetics. The type and frequency of genetic variation in the ADME genes differ among populations. The aim of this study was to systematically investigate common and rare ADME coding variation in diverse ethnic populations by exome sequencing. MATERIALS AND METHODS:Data derived from commercial exome capture arrays and next-generation sequencing were used to characterize coding variation in 298 ADME genes in 251 Northeast Asians and 1181 individuals from the 1000 Genomes Project. RESULTS:Approximately 75% of the ADME coding sequence was captured at high quality across the joint samples harboring more than 8000 variants, with 49% of individuals carrying at least one 'knockout' allele. ADME genes carried 50% more nonsynonymous variation than non-ADME genes (P=8.2×10) and showed significantly greater levels of population differentiation (P=7.6×10). Out of the 2135 variants identified that were predicted to be deleterious, 633 were not on commercially available ADME or general-purpose genotyping arrays. Forty deleterious variants within important ADME genes, with frequencies of at least 2% in at least one population, were identified as candidates for future pharmacogenetic studies. CONCLUSION:Exome sequencing was effective in accurately genotyping most ADME variants important for pharmacogenetic research, in addition to identifying rare or potentially de novo coding variants that may be clinically meaningful. Furthermore, as a class, ADME genes are more variable and less sensitive to purifying selection than non-ADME genes.

SUBMITTER: Hovelson DH

PROVIDER: S-EPMC5287433 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Characterization of ADME gene variation in 21 populations by exome sequencing.

Hovelson Daniel H DH Xue Zhengyu Z Zawistowski Matthew M Ehm Margaret G MG Harris Elizabeth C EC Stocker Sophie L SL Gross Annette S AS Jang In-Jin IJ Ieiri Ichiro I Lee Jong-Eun JE Cardon Lon R LR Chissoe Stephanie L SL Abecasis Gonçalo G Nelson Matthew R MR

Pharmacogenetics and genomics 20170301 3

<h4>Objective</h4>Proteins involving absorption, distribution, metabolism, and excretion (ADME) play a critical role in drug pharmacokinetics. The type and frequency of genetic variation in the ADME genes differ among populations. The aim of this study was to systematically investigate common and rare ADME coding variation in diverse ethnic populations by exome sequencing.<h4>Materials and methods</h4>Data derived from commercial exome capture arrays and next-generation sequencing were used to c ...[more]

PMID: 27984508

Similar Datasets

Project description:In genes related to drug pharmacokinetics, molecular variations determine interindividual variability in the therapeutic efficacy and adverse drug reactions. The assessment of single-nucleotide variants (SNVs) is used with growing frequency in pharmacogenetic practice, and recently, high-throughput genomic analyses obtained through next-generation sequencing (NGS) have been recognized as powerful tools to identify common, rare and novel variants. These genetic profiles remain underexplored in Latin-American populations, including Colombia. In this study, we investigated the variability of 35 genes included in the ADME core panel (absorption, distribution, metabolism, and excretion) by whole-exome sequencing (WES) of 509 unrelated Colombian individuals with no previous reports of adverse drug reactions. Rare variants were filtered according to the minor allele frequencies (MAF) <1% and potential deleterious consequences. The functional impact of novel and rare missense variants was assessed using an optimized framework for pharmacogenetic variants. Bioinformatic analyses included the identification of clinically validated variants described in PharmGKB and ClinVar databases. Ancestry from WES data was inferred using the R package EthSEQ v2.1.4. Allelic frequencies were compared to other populations reported in the public gnomAD database. Our analysis revealed that rare missense pharmacogenetic variants were 2.1 times more frequent than common variants with 121 variants predicted as potentially deleterious. Rare loss of function (LoF) variants were identified in 65.7% of evaluated genes. Regarding variants with clinical pharmacogenetic effect, our study revealed 89 sequence variations in 28 genes represented by missense (62%), synonymous (22.5%), splice site (11.2%), and indels (3.4%). In this group, ABCB1, ABCC2, CY2B6, CYP2D6, DPYD, NAT2, SLC22A1, and UGTB2B7, are the most polymorphic genes. NAT2, CYP2B6 and DPYD metabolizer phenotypes demonstrated the highest variability. Ancestry analysis indicated admixture in 73% of the population. Allelic frequencies exhibit significant differences with other Latin-American populations, highlighting the importance of pharmacogenomic studies in populations of different ethnicities. Altogether, our data revealed that rare variants are an important source of variability in pharmacogenes involved in the pharmacokinetics of drugs and likely account for the unexplained interindividual variability in drug response. These findings provide evidence of the utility of WES for pharmacogenomic testing and into clinical practice.

Project description:Introduction: Investigating variation in genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs are key to characterizing pharmacogenomic (PGx) relationships. ADME gene variation is relatively well characterized in European and Asian populations, but data from African populations are under-studied-which has implications for drug safety and effective use in Africa. Results: We identified significant ADME gene variation in African populations using data from 458 high-coverage whole genome sequences, 412 of which are novel, and from previously available African sequences from the 1,000 Genomes Project. ADME variation was not uniform across African populations, particularly within high impact coding variation. Copy number variation was detected in 116 ADME genes, with equal ratios of duplications/deletions. We identified 930 potential high impact coding variants, of which most are discrete to a single African population cluster. Large frequency differences (i.e., >10%) were seen in common high impact variants between clusters. Several novel variants are predicted to have a significant impact on protein structure, but additional functional work is needed to confirm the outcome of these for PGx use. Most variants of known clinical outcome are rare in Africa compared to European populations, potentially reflecting a clinical PGx research bias to European populations. Discussion: The genetic diversity of ADME genes across sub-Saharan African populations is large. The Southern African population cluster is most distinct from that of far West Africa. PGx strategies based on European variants will be of limited use in African populations. Although established variants are important, PGx must take into account the full range of African variation. This work urges further characterization of variants in African populations including in vitro and in silico studies, and to consider the unique African ADME landscape when developing precision medicine guidelines and tools for African populations.

Project description:It has been well documented that genetic factors can influence predisposition to develop alcoholism. While the underlying genomic changes may be of several types, two of the most common and disease associated are copy number variations (CNVs) and sequence alterations of protein coding regions. The goal of this study was to identify CNVs and single-nucleotide polymorphisms that occur in gene coding regions that may play a role in influencing the risk of an individual developing alcoholism. Toward this end, two mouse strains were used that have been selectively bred based on their differential sensitivity to alcohol: the Inbred long sleep (ILS) and Inbred short sleep (ISS) mouse strains. Differences in initial response to alcohol have been linked to risk for alcoholism, and the ILS/ISS strains are used to investigate the genetics of initial sensitivity to alcohol. Array comparative genomic hybridization (arrayCGH) and exome sequencing were conducted to identify CNVs and gene coding sequence differences, respectively, between ILS and ISS mice. Mouse arrayCGH was performed using catalog Agilent 1 × 244 k mouse arrays. Subsequently, exome sequencing was carried out using an Illumina HiSeq 2000 instrument. ArrayCGH detected 74 CNVs that were strain-specific (38 ILS/36 ISS), including several ISS-specific deletions that contained genes implicated in brain function and neurotransmitter release. Among several interesting coding variations detected by exome sequencing was the gain of a premature stop codon in the alpha-amylase 2B (AMY2B) gene specifically in the ILS strain. In total, exome sequencing detected 2,597 and 1,768 strain-specific exonic gene variants in the ILS and ISS mice, respectively. This study represents the most comprehensive and detailed genomic comparison of ILS and ISS mouse strains to date. The two complementary genome-wide approaches identified strain-specific CNVs and gene coding sequence variations that should provide strong candidates to contribute to the alcohol-related phenotypic differences associated with these strains.

Dataset Information

Characterization of ADME gene variation in 21 populations by exome sequencing.

Publications

Characterization of ADME gene variation in 21 populations by exome sequencing.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets