Characterization of ADME gene variation in 21 populations by exome sequencing

Daniel H. Hovelson, Zhengyu Xue, Matthew Zawistowski, Margaret G. Ehm, Elizabeth C. Harris, Sophie L. Stocker, Annette S. Gross, In Jin Jang, Ichiro Ieiri, Jong Eun Lee, Lon R. Cardon, Stephanie L. Chissoe, Gonçalo Abecasis, Matthew R. Nelson

研究成果: ジャーナルへの寄稿記事

6 引用 (Scopus)

抄録

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 -13 ) and showed significantly greater levels of population differentiation (P=7.6×10 -11 ). 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.

元の言語英語
ページ(範囲)89-100
ページ数12
ジャーナルPharmacogenetics and Genomics
27
発行部数3
DOI
出版物ステータス出版済み - 1 1 2017

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Exome
Population
Genes
Gene Frequency

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

これを引用

Hovelson, D. H., Xue, Z., Zawistowski, M., Ehm, M. G., Harris, E. C., Stocker, S. L., ... Nelson, M. R. (2017). Characterization of ADME gene variation in 21 populations by exome sequencing. Pharmacogenetics and Genomics, 27(3), 89-100. https://doi.org/10.1097/FPC.0000000000000260

Characterization of ADME gene variation in 21 populations by exome sequencing. / Hovelson, Daniel H.; Xue, Zhengyu; Zawistowski, Matthew; Ehm, Margaret G.; Harris, Elizabeth C.; Stocker, Sophie L.; Gross, Annette S.; Jang, In Jin; Ieiri, Ichiro; Lee, Jong Eun; Cardon, Lon R.; Chissoe, Stephanie L.; Abecasis, Gonçalo; Nelson, Matthew R.

:: Pharmacogenetics and Genomics, 巻 27, 番号 3, 01.01.2017, p. 89-100.

研究成果: ジャーナルへの寄稿記事

Hovelson, DH, Xue, Z, Zawistowski, M, Ehm, MG, Harris, EC, Stocker, SL, Gross, AS, Jang, IJ, Ieiri, I, Lee, JE, Cardon, LR, Chissoe, SL, Abecasis, G & Nelson, MR 2017, 'Characterization of ADME gene variation in 21 populations by exome sequencing', Pharmacogenetics and Genomics, 巻. 27, 番号 3, pp. 89-100. https://doi.org/10.1097/FPC.0000000000000260
Hovelson DH, Xue Z, Zawistowski M, Ehm MG, Harris EC, Stocker SL その他. Characterization of ADME gene variation in 21 populations by exome sequencing. Pharmacogenetics and Genomics. 2017 1 1;27(3):89-100. https://doi.org/10.1097/FPC.0000000000000260
Hovelson, Daniel H. ; Xue, Zhengyu ; Zawistowski, Matthew ; Ehm, Margaret G. ; Harris, Elizabeth C. ; Stocker, Sophie L. ; Gross, Annette S. ; Jang, In Jin ; Ieiri, Ichiro ; Lee, Jong Eun ; Cardon, Lon R. ; Chissoe, Stephanie L. ; Abecasis, Gonçalo ; Nelson, Matthew R. / Characterization of ADME gene variation in 21 populations by exome sequencing. :: Pharmacogenetics and Genomics. 2017 ; 巻 27, 番号 3. pp. 89-100.
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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 -13 ) and showed significantly greater levels of population differentiation (P=7.6×10 -11 ). 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.",
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AU - Xue, Zhengyu

AU - Zawistowski, Matthew

AU - Ehm, Margaret G.

AU - Harris, Elizabeth C.

AU - Stocker, Sophie L.

AU - Gross, Annette S.

AU - Jang, In Jin

AU - Ieiri, Ichiro

AU - Lee, Jong Eun

AU - Cardon, Lon R.

AU - Chissoe, Stephanie L.

AU - Abecasis, Gonçalo

AU - Nelson, Matthew R.

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N2 - 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 -13 ) and showed significantly greater levels of population differentiation (P=7.6×10 -11 ). 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.

AB - 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 -13 ) and showed significantly greater levels of population differentiation (P=7.6×10 -11 ). 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.

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