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Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset.

The study of genetic influences on drug response and efficacy ('pharmacogenetics') has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative meth... Full description

Journal Title: Human molecular genetics April 15, 2014, Vol.23(8), pp.1957-1963
Main Author: Gordon, Adam S
Other Authors: Tabor, Holly K , Johnson, Andrew D , Snively, Beverly M , Assimes, Themistocles L , Auer, Paul L , Ioannidis, John P A , Peters, Ulrike , Robinson, Jennifer G , Sucheston, Lara E , Wang, Danxin , Sotoodehnia, Nona , Rotter, Jerome I , Psaty, Bruce M , Jackson, Rebecca D , Herrington, David M , O'Donnell, Christopher J , Reiner, Alexander P , Rich, Stephen S , Rieder, Mark J , Bamshad, Michael J , Nickerson, Deborah A , Gordon, Adam S
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1460-2083 ; DOI: 10.1093/hmg/ddt588
Link: http://search.proquest.com/docview/1509409388/?pq-origsite=primo
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title: Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset.
format: Article
creator:
  • Gordon, Adam S
  • Tabor, Holly K
  • Johnson, Andrew D
  • Snively, Beverly M
  • Assimes, Themistocles L
  • Auer, Paul L
  • Ioannidis, John P A
  • Peters, Ulrike
  • Robinson, Jennifer G
  • Sucheston, Lara E
  • Wang, Danxin
  • Sotoodehnia, Nona
  • Rotter, Jerome I
  • Psaty, Bruce M
  • Jackson, Rebecca D
  • Herrington, David M
  • O'Donnell, Christopher J
  • Reiner, Alexander P
  • Rich, Stephen S
  • Rieder, Mark J
  • Bamshad, Michael J
  • Nickerson, Deborah A
  • Gordon, Adam S
subjects:
  • Cytochrome P-450 Enzyme System–Genetics
  • Databases, Genetic–Genetics
  • European Continental Ancestry Group–Genetics
  • Exome–Metabolism
  • Humans–Genetics
  • Pharmaceutical Preparations–Genetics
  • Pharmacogenetics–Genetics
  • Polymorphism, Genetic–Genetics
  • Pharmaceutical Preparations
  • Cytochrome P-450 Enzyme System
ispartof: Human molecular genetics, April 15, 2014, Vol.23(8), pp.1957-1963
description: The study of genetic influences on drug response and efficacy ('pharmacogenetics') has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6-11.7% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.
language: eng
source:
identifier: E-ISSN: 1460-2083 ; DOI: 10.1093/hmg/ddt588
fulltext: fulltext
issn:
  • 14602083
  • 1460-2083
url: Link


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titleQuantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset.
creatorGordon, Adam S ; Tabor, Holly K ; Johnson, Andrew D ; Snively, Beverly M ; Assimes, Themistocles L ; Auer, Paul L ; Ioannidis, John P A ; Peters, Ulrike ; Robinson, Jennifer G ; Sucheston, Lara E ; Wang, Danxin ; Sotoodehnia, Nona ; Rotter, Jerome I ; Psaty, Bruce M ; Jackson, Rebecca D ; Herrington, David M ; O'Donnell, Christopher J ; Reiner, Alexander P ; Rich, Stephen S ; Rieder, Mark J ; Bamshad, Michael J ; Nickerson, Deborah A ; Gordon, Adam S
contributorGabriel, Stacey B (correspondence author) ; Altshuler, David M (record owner) ; Abecasis, Gonçalo R ; Allayee, Hooman ; Daly, Mark J ; de Bakker, Paul I W ; Depristo, Mark A ; Donnelly, Peter ; Farlow, Deborah N ; Fennell, Tim ; Garimella, Kiran ; Hazen, Stanley L ; Hu, Youna ; Jordan, Daniel M ; Kathiresan, Sekar ; Kang, Hyun Min ; Kiezun, Adam ; Lettre, Guillaume ; Li, Bingshan ; Li, Mingyao ; Newton-Cheh, Christopher H ; Padmanabhan, Sandosh ; Peloso, Gina ; Pulit, Sara ; Rader, Daniel J ; Reich, David ; Reilly, Muredach P ; Rivas, Manuel A ; Schwartz, Steve ; Scott, Laura ; Siscovick, David S ; Spertus, John A ; Stitziel, Nathaniel O ; Stoletzki, Nina ; Sunyaev, Shamil R ; Voight, Benjamin F ; Willer, Cristen J ; Rich, Stephen S ; Akylbekova, Ermeg ; Atwood, Larry D ; Ballantyne, Christie M ; Barbalic, Maja ; Barr, R Graham ; Benjamin, Emelia J ; Bis, Joshua ; Boerwinkle, Eric ; Bowden, Donald W ; Brody, Jennifer ; Budoff, Matthew ; Burke, Greg ; Buxbaum, Sarah ; Carr, Jeff ; Chen, Donna T ; Chen, Ida Y ; Chen, Wei-Min ; Concannon, Pat ; Crosby, Jacy ; Cupples, L Adrienne ; D'Agostino, Ralph ; Destefano, Anita L ; Dreisbach, Albert ; Dupuis, Josée ; Durda, J Peter ; Ellis, Jaclyn ; Folsom, Aaron R ; Fornage, Myriam ; Fox, Caroline S ; Fox, Ervin ; Funari, Vincent ; Ganesh, Santhi K ; Gardin, Julius ; Goff, David ; Gordon, Ora ; Grody, Wayne ; Gross, Myron ; Guo, Xiuqing ; Hall, Ira M ; Heard-Costa, Nancy L ; Heckbert, Susan R ; Heintz, Nicholas ; Herrington, David M ; Hickson, Demarc ; Huang, Jie ; Hwang, Shih-Jen ; Jacobs, David R ; Jenny, Nancy S ; Johnson, Andrew D ; Johnson, Craig W ; Kawut, Steven ; Kronmal, Richard ; Kurz, Raluca ; Lange, Ethan M ; Lange, Leslie A ; Larson, Martin G ; Lawson, Mark ; Lewis, Cora E ; Levy, Daniel ; Li, Dalin ; Lin, Honghuang ; Liu, Chunyu ; Liu, Jiankang ; Liu, Kiang ; Liu, Xiaoming ; Liu, Yongmei ; Longstreth, William T ; Lumley, Thomas ; Lunetta, Kathryn ; Mackey, Aaron J ; Mackey, Rachel ; Manichaikul, Ani ; Maxwell, Taylor ; Mcknight, Barbara ; Meigs, James B ; Morrison, Alanna C ; Musani, Solomon K ; Mychaleckyj, Josyf C ; Nettleton, Jennifer A ; North, Kari ; O'Donnell, Christopher J ; O'Leary, Daniel ; Ong, Frank ; Palmas, Walter ; Pankow, James S ; Pankratz, Nathan D ; Paul, Shom ; Perez, Marco ; Person, Sharina D ; Polak, Joseph ; Post, Wendy S ; Psaty, Bruce M ; Quinlan, Aaron R ; Raffel, Leslie J ; Ramachandran, Vasan S ; Reiner, Alexander P ; Hutchinson, Fred ; Rice, Kenneth ; Rotter, Jerome I ; Sanders, Jill P ; Schreiner, Pamela ; Seshadri, Sudha ; Shea, Steve ; Sidney, Stephen ; Silverstein, Kevin ; Siscovick, David S ; Smith, Nicholas L ; Sotoodehnia, Nona ; Srinivasan, Asoke ; Taylor, Herman A ; Taylor, Kent ; Thomas, Fridtjof ; Tracy, Russell P ; Tsai, Michael Y ; Volcik, Kelly A ; Wassel, Chrstina L ; Watson, Karol ; Wei, Gina ; White, Wendy ; Wiggins, Kerri L ; Wilk, Jemma B ; Williams, O Dale ; Wilson, Gregory ; Wilson, James G ; Wolf, Phillip ; Zakai, Neil A ; Hardy, John ; Meschia, James F ; Nalls, Michael ; Rich, Stephen S ; Singleton, Andrew ; Worrall, Brad ; Bamshad, Michael J ; Barnes, Kathleen C ; Abdulhamid, Ibrahim ; Accurso, Frank ; Anbar, Ran ; Beaty, Terri ; Bigham, Abigail ; Black, Phillip ; Bleecker, Eugene ; Buckingham, Kati ; Cairns, Anne Marie ; Chen, Wei-Min ; Caplan, Daniel ; Chatfield, Barbara ; Chidekel, Aaron ; Cho, Michael ; Christiani, David C ; Crapo, James D ; Crouch, Julia ; Daley, Denise ; Dang, Anthony ; Dang, Hong ; De Paula, Alicia ; Decelie-Germana, Joan ; Dozor, Allen ; Drumm, Mitch ; Dyson, Maynard ; Emerson, Julia ; Emond, Mary J ; Ferkol, Thomas ; Fink, Robert ; Foster, Cassandra ; Froh, Deborah ; Gao, Li ; Gershan, William ; Gibson, Ronald L ; Godwin, Elizabeth ; Gondor, Magdalen ; Gutierrez, Hector ; Hansel, Nadia N ; Hassoun, Paul M ; Hiatt, Peter ; Hokanson, John E ; Howenstine, Michelle ; Hummer, Laura K ; Kanga, Jamshed ; Kim, Yoonhee ; Knowles, Michael R ; Konstan, Michael ; Lahiri, Thomas ; Laird, Nan ; Lange, Christoph ; Lin, Lin ; Louie, L ; Lynch, David ; Make, Barry ; Martin, Thomas R
ispartofHuman molecular genetics, April 15, 2014, Vol.23(8), pp.1957-1963
identifierE-ISSN: 1460-2083 ; DOI: 10.1093/hmg/ddt588
subjectCytochrome P-450 Enzyme System–Genetics ; Databases, Genetic–Genetics ; European Continental Ancestry Group–Genetics ; Exome–Metabolism ; Humans–Genetics ; Pharmaceutical Preparations–Genetics ; Pharmacogenetics–Genetics ; Polymorphism, Genetic–Genetics ; Pharmaceutical Preparations ; Cytochrome P-450 Enzyme System
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descriptionThe study of genetic influences on drug response and efficacy ('pharmacogenetics') has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6-11.7% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.
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3Snively, Beverly M
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13Psaty, Bruce M
14Jackson, Rebecca D
15Herrington, David M
16O'Donnell, Christopher J
17Reiner, Alexander P
18Rich, Stephen S
19Rieder, Mark J
20Bamshad, Michael J
21Nickerson, Deborah A
titleQuantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset.
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0Cytochrome P-450 Enzyme System–Genetics
1Databases, Genetic–Genetics
2European Continental Ancestry Group–Genetics
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2Abecasis, Gonçalo R
3Allayee, Hooman
4Daly, Mark J
5de Bakker, Paul I W
6Depristo, Mark A
7Donnelly, Peter
8Farlow, Deborah N
9Fennell, Tim
10Garimella, Kiran
11Hazen, Stanley L
12Hu, Youna
13Jordan, Daniel M
14Kathiresan, Sekar
15Kang, Hyun Min
16Kiezun, Adam
17Lettre, Guillaume
18Li, Bingshan
19Li, Mingyao
20Newton-Cheh, Christopher H
21Padmanabhan, Sandosh
22Peloso, Gina
23Pulit, Sara
24Rader, Daniel J
25Reich, David
26Reilly, Muredach P
27Rivas, Manuel A
28Schwartz, Steve
29Scott, Laura
30Siscovick, David S
31Spertus, John A
32Stitziel, Nathaniel O
33Stoletzki, Nina
34Sunyaev, Shamil R
35Voight, Benjamin F
36Willer, Cristen J
37Rich, Stephen S
38Akylbekova, Ermeg
39Atwood, Larry D
40Ballantyne, Christie M
41Barbalic, Maja
42Barr, R Graham
43Benjamin, Emelia J
44Bis, Joshua
45Boerwinkle, Eric
46Bowden, Donald W
47Brody, Jennifer
48Budoff, Matthew
49Burke, Greg
50Buxbaum, Sarah
51Carr, Jeff
52Chen, Donna T
53Chen, Ida Y
54Chen, Wei-Min
55Concannon, Pat
56Crosby, Jacy
57Cupples, L Adrienne
58D'Agostino, Ralph
59Destefano, Anita L
60Dreisbach, Albert
61Dupuis, Josée
62Durda, J Peter
63Ellis, Jaclyn
64Folsom, Aaron R
65Fornage, Myriam
66Fox, Caroline S
67Fox, Ervin
68Funari, Vincent
69Ganesh, Santhi K
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74Gross, Myron
75Guo, Xiuqing
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83Hwang, Shih-Jen
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85Jenny, Nancy S
86Johnson, Andrew D
87Johnson, Craig W
88Kawut, Steven
89Kronmal, Richard
90Kurz, Raluca
91Lange, Ethan M
92Lange, Leslie A
93Larson, Martin G
94Lawson, Mark
95Lewis, Cora E
96Levy, Daniel
97Li, Dalin
98Lin, Honghuang
99Liu, Chunyu
100...
startdate20140415
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citationpf 1957 pt 1963 vol 23 issue 8
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titleQuantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset.
authorGordon, Adam S ; Tabor, Holly K ; Johnson, Andrew D ; Snively, Beverly M ; Assimes, Themistocles L ; Auer, Paul L ; Ioannidis, John P A ; Peters, Ulrike ; Robinson, Jennifer G ; Sucheston, Lara E ; Wang, Danxin ; Sotoodehnia, Nona ; Rotter, Jerome I ; Psaty, Bruce M ; Jackson, Rebecca D ; Herrington,...
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1Databases, Genetic–Genetics
2European Continental Ancestry Group–Genetics
3Exome–Metabolism
4Humans–Genetics
5Pharmaceutical Preparations–Genetics
6Pharmacogenetics–Genetics
7Polymorphism, Genetic–Genetics
8Pharmaceutical Preparations
9Cytochrome P-450...
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0Gordon, Adam S
1Tabor, Holly K
2Johnson, Andrew D
3Snively, Beverly M
4Assimes, Themistocles L
5Auer, Paul L
6Ioannidis, John P A
7Peters, Ulrike
8Robinson, Jennifer G
9Sucheston, Lara E
10Wang, Danxin
11Sotoodehnia, Nona
12Rotter, Jerome I
13Psaty, Bruce M
14Jackson, Rebecca D
15Herrington, David M
16O'Donnell, Christopher J
17Reiner, Alexander P
18Rich, Stephen S
19Rieder, Mark J
20Bamshad, Michael J
21Nickerson, Deborah A
22Gabriel, Stacey B
23Altshuler, David M
24Abecasis, Gonçalo R
25Allayee, Hooman
26Daly, Mark J
27de Bakker, Paul I W
28Depristo, Mark A
29Donnelly, Peter
30Farlow, Deborah N
31Fennell, Tim
32Garimella, Kiran
33Hazen, Stanley L
34Hu, Youna
35Jordan, Daniel M
36Kathiresan, Sekar
37Kang, Hyun Min
38Kiezun, Adam
39Lettre, Guillaume
40Li, Bingshan
41Li, Mingyao
42Newton-Cheh, Christopher H
43Padmanabhan, Sandosh
44Peloso, Gina
45Pulit, Sara
46Rader, Daniel J
47Reich, David
48Reilly, Muredach P
49Rivas, Manuel A
50Schwartz, Steve
51Scott, Laura
52Siscovick, David S
53Spertus, John A
54Stitziel, Nathaniel O
55Stoletzki, Nina
56Sunyaev, Shamil R
57Voight, Benjamin F
58Willer, Cristen J
59Akylbekova, Ermeg
60Atwood, Larry D
61Ballantyne, Christie M
62Barbalic, Maja
63Barr, R Graham
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91Gardin, Julius
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96Guo, Xiuqing
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68Funari, Vincent
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70Gardin, Julius
71Goff, David
72Gordon, Ora
73Grody, Wayne
74Gross, Myron
75Guo, Xiuqing
76Hall, Ira M
77Heard-Costa, Nancy L
78Heckbert, Susan R
79Heintz, Nicholas
80Herrington, David M
81Hickson, DeMarc
82Huang, Jie
83Hwang, Shih-Jen
84Jacobs, David R
85Jenny, Nancy S
86Johnson, Andrew D
87Johnson, Craig W
88Kawut, Steven
89Kronmal, Richard
90Kurz, Raluca
91Lange, Ethan M
92Lange, Leslie A
93Larson, Martin G
94Lawson, Mark
95Lewis, Cora E
96Levy, Daniel
97Li, Dalin
98Lin, Honghuang
99Liu, Chunyu
100...
atitleQuantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset.
jtitleHuman molecular genetics
risdate20140415
volume23
issue8
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date2014-04-15