Genome Sequence Variability Predicts Drug Precautions and Withdrawals from the Market.
Despite substantial premarket efforts, a significant portion of approved drugs has been withdrawn from the market for safety reasons. The deleterious impact of nonsynonymous substitutions predicted by the SIFT algorithm on structure and function of drug-related proteins was evaluated for 2504 personal genomes. Both withdrawn (n = 154) and precautionary (Beers criteria (n = 90), and US FDA pharmacogenomic biomarkers (n = 96)) drugs showed significantly lower genomic deleteriousness scores (P < 0.001) compared to others (n = 752). Furthermore, the rates of drug withdrawals and precautions correlated significantly with the deleteriousness scores of the drugs (P < 0.01); this trend was confirmed for all drugs included in the withdrawal and precaution lists by the United Nations, European Medicines Agency, DrugBank, Beers criteria, and US FDA. Our findings suggest that the person-to-person genome sequence variability is a strong independent predictor of drug withdrawals and precautions. We propose novel measures of drug safety based on personal genome sequence analysis.
Seoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul 110799, Korea.
Kye Hwa
http://orcid.org/0000-0002-7593-7020
KH
Lee
Seoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul 110799, Korea.
Su Youn
SY
Baik
Seoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul 110799, Korea.
Soo Youn
SY
Lee
Seoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul 110799, Korea.
Chan Hee
CH
Park
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America.
Paul J
PJ
Park
Seoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul 110799, Korea.|Biomedical Informatics Training and Education Center (BITEC), Seoul National University Hospital, Seoul 110744, Korea.
Ju Han
JH
Kim
J Am Geriatr Soc. 2015 Nov;63(11):2227-46
26446832
Nature. 2015 Oct 1;526(7571):68-74
26432245
Science. 2012 Feb 17;335(6070):823-8
22344438
JAMA. 2002 May 1;287(17):2215-20
11980521
Nature. 2012 Nov 1;491(7422):56-65
23128226
Nucleic Acids Res. 2016 Jan 4;44(D1):D471-80
26527732
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D668-72
16381955
Genome Res. 2012 Sep;22(9):1748-59
22955986
Nucleic Acids Res. 2002 Sep 1;30(17):3894-900
12202775
Nucleic Acids Res. 2012 Jan;40(Database issue):D790-6
22102587
Arch Intern Med. 1991 Sep;151(9):1825-32
1888249
Bioinformatics. 2013 Jun 15;29(12):1504-10
23620363
Pharmacol Rev. 2011 Jun;63(2):437-59
21436344
JAMA. 2006 May 3;295(17):2072-5
16670415
Genome Res. 2009 Sep;19(9):1553-61
19602639
Genome Biol. 2007;8(11):R232
17976239
Nat Methods. 2010 Apr;7(4):250-1
20354513
Am J Public Health. 2008 Aug;98(8):1366-71
18556607
Bioinformatics. 2009 Jun 15;25(12):i54-62
19478016
Pharmacogenomics. 2006 Sep;7(6):889-908
16981848
Clin Pharmacol Ther. 2011 Jun;89(6):793-7
21490594
Nucleic Acids Res. 2002 Jan 1;30(1):47-9
11752250
Arch Intern Med. 2005 Jun 27;165(12):1363-9
15983284
PLoS Comput Biol. 2010 Dec 02;6(12):e1001025
21152010
N Engl J Med. 2011 Mar 24;364(12):1144-53
21428770
J Am Geriatr Soc. 2012 Apr;60(4):616-31
22376048
Open Med. 2014 Jan 28;8(1):e14-9
25009681
Nucleic Acids Res. 2016 Jan 4;44(D1):D1202-13
26400175
Nat Genet. 2014 Mar;46(3):310-5
24487276
Am J Hum Genet. 2011 Apr 8;88(4):440-9
21457909
Genome Res. 2010 Jan;20(1):110-21
19858363
Nat Protoc. 2009;4(7):1073-81
19561590
JAMA. 1998 Apr 15;279(15):1200-5
9555760
Nat Rev Drug Discov. 2002 Jan;1(1):37-44
12119608
N Engl J Med. 2005 May 26;352(21):2211-21
15917386
Arch Intern Med. 2002 Aug 12-26;162(15):1682-8
12153370
Science. 2004 Oct 22;306(5696):636-40
15499007
Nucleic Acids Res. 2010 Sep;38(16):e164
20601685