Targeted ultra-deep sequencing of a South African Bantu-speaking cohort to comprehensively map and characterize common and novel variants in 65 pharmacologically-related genes.
Journal
Pharmacogenetics and genomics
ISSN: 1744-6880
Titre abrégé: Pharmacogenet Genomics
Pays: United States
ID NLM: 101231005
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
pubmed:
5
6
2019
medline:
25
4
2020
entrez:
5
6
2019
Statut:
ppublish
Résumé
African populations are characterised by high genetic diversity, which provides opportunities for discovering and elucidating novel variants of clinical importance, especially those affecting therapeutic outcome. Significantly more knowledge is however needed before such populations can take full advantage of the advances in precision medicine. Coupled with the need to concisely map and better understand the pharmacological implications of genetic diversity in populations of sub-Sharan African ancestry, the aim of this study was to identify and characterize known and novel variants present within 65 important absorption, distribution, metabolism and excretion genes. Targeted ultra-deep next-generation sequencing was used to screen a cohort of 40 South African individuals of Bantu ancestry. We identified a total of 1662 variants of which 129 are novel. Moreover, out of the 1662 variants 22 represent potential loss-of-function variants. A high level of allele frequency differentiation was observed for variants identified in this study when compared with other populations. Notably, on the basis of prior studies, many appear to be pharmacologically important in the pharmacokinetics of a broad range of drugs, including antiretrovirals, chemotherapeutic drugs, antiepileptics, antidepressants, and anticoagulants. An in-depth analysis was undertaken to interrogate the pharmacogenetic implications of this genetic diversity. Despite the new insights gained from this study, the work illustrates that a more comprehensive understanding of population-specific differences is needed to facilitate the development of pharmacogenetic-based interventions for optimal drug therapy in patients of African ancestry.
Sections du résumé
BACKGROUND
African populations are characterised by high genetic diversity, which provides opportunities for discovering and elucidating novel variants of clinical importance, especially those affecting therapeutic outcome. Significantly more knowledge is however needed before such populations can take full advantage of the advances in precision medicine. Coupled with the need to concisely map and better understand the pharmacological implications of genetic diversity in populations of sub-Sharan African ancestry, the aim of this study was to identify and characterize known and novel variants present within 65 important absorption, distribution, metabolism and excretion genes.
PATIENTS AND METHODS
Targeted ultra-deep next-generation sequencing was used to screen a cohort of 40 South African individuals of Bantu ancestry.
RESULTS
We identified a total of 1662 variants of which 129 are novel. Moreover, out of the 1662 variants 22 represent potential loss-of-function variants. A high level of allele frequency differentiation was observed for variants identified in this study when compared with other populations. Notably, on the basis of prior studies, many appear to be pharmacologically important in the pharmacokinetics of a broad range of drugs, including antiretrovirals, chemotherapeutic drugs, antiepileptics, antidepressants, and anticoagulants. An in-depth analysis was undertaken to interrogate the pharmacogenetic implications of this genetic diversity.
CONCLUSION
Despite the new insights gained from this study, the work illustrates that a more comprehensive understanding of population-specific differences is needed to facilitate the development of pharmacogenetic-based interventions for optimal drug therapy in patients of African ancestry.
Identifiants
pubmed: 31162291
doi: 10.1097/FPC.0000000000000380
pmc: PMC6675649
mid: NIHMS1528518
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
167-178Subventions
Organisme : NHGRI NIH HHS
ID : U54 HG006938
Pays : United States
Références
Medicine (Baltimore). 2016 May;95(19):e3437
pubmed: 27175644
Science. 2012 Oct 19;338(6105):374-9
pubmed: 22997136
Nature. 2010 Sep 2;467(7311):52-8
pubmed: 20811451
Br J Clin Pharmacol. 2008 Apr;65(4):558-64
pubmed: 18070221
Pharmacogenomics. 2012 Apr;13(5):555-70
pubmed: 22462748
Pharmacogenomics J. 2011 Oct;11(5):359-67
pubmed: 20531370
Hum Genomics. 2011 May;5(4):265-82
pubmed: 21712189
Mol Biol Evol. 2009 Jul;26(7):1581-9
pubmed: 19369595
Clin Pharmacol Ther. 2010 Apr;87(4):459-64
pubmed: 20072124
PLoS One. 2014 Jan 31;9(1):e86919
pubmed: 24497997
PLoS One. 2013 Jul 05;8(7):e67946
pubmed: 23861838
Eur J Clin Pharmacol. 2010 Jan;66(1):107-8
pubmed: 19936726
Pharmacol Ther. 2005 Jun;106(3):357-87
pubmed: 15922018
Pharmacogenet Genomics. 2014 Aug;24(8):409-25
pubmed: 24892773
BMC Genet. 2014 May 01;15:52
pubmed: 24884825
Bull World Health Organ. 2011 Nov 1;89(11):838-45
pubmed: 22084530
Immunology. 2011 Oct;134(2):116-22
pubmed: 21896007
Acta Trop. 2016 May;157:54-8
pubmed: 26836270
Clin Pharmacol Ther. 2013 Dec;94(6):640-5
pubmed: 23988873
Trends Pharmacol Sci. 2016 Feb;37(2):85-86
pubmed: 26705087
Clin Kidney J. 2015 Aug;8(4):420-5
pubmed: 26251709
Pharmacogenomics. 2011 Jul;12(7):953-63
pubmed: 21635147
Nature. 2015 Jan 15;517(7534):327-32
pubmed: 25470054
Nature. 2010 Oct 28;467(7319):1061-73
pubmed: 20981092
Nature. 2015 Oct 1;526(7571):75-81
pubmed: 26432246
Br J Clin Pharmacol. 2015 Oct;80(4):818-26
pubmed: 25475751
Clin Pharmacol Ther. 2013 Sep;94(3):317-23
pubmed: 23698643
Dis Markers. 2012;32(1):43-50
pubmed: 22297601
PLoS One. 2011;6(12):e27810
pubmed: 22162992
Science. 2017 May 5;356(6337):543-546
pubmed: 28473590
Pharmacogenet Genomics. 2012 Feb;22(2):159-65
pubmed: 22027650
Drug Saf. 2016 Feb;39(2):159-69
pubmed: 26547719
Gigascience. 2015 Feb 25;4:7
pubmed: 25722852
Genet Med. 2017 Jan;19(1):20-29
pubmed: 27101133
Lancet Infect Dis. 2009 Dec;9(12):760-74
pubmed: 19926036
Pathol Biol (Paris). 2012 Oct;60(5):324-30
pubmed: 21856096
Front Genet. 2012 Nov 05;3:236
pubmed: 23133441
J Acquir Immune Defic Syndr. 2008 Mar 1;47(3):298-303
pubmed: 18398970
Hum Mol Genet. 2011 Oct 15;20(R2):R214-20
pubmed: 21908518
Malar J. 2017 Jan 13;16(1):26
pubmed: 28086874
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
Pharmacogenet Genomics. 2006 Mar;16(3):191-8
pubmed: 16495778
J Acquir Immune Defic Syndr. 2013 Feb 1;62(2):e55-7
pubmed: 23328091
Nature. 2010 Feb 18;463(7283):943-7
pubmed: 20164927
Pharmacogenet Genomics. 2011 Mar;21(3):130-5
pubmed: 21228733
Pharmacogenomics J. 2014 Apr;14(2):160-70
pubmed: 23588107
Pharmacogenet Genomics. 2013 Aug;23(8):415-27
pubmed: 23778320
Clin Infect Dis. 2009 Jun 1;48(11):e108-16
pubmed: 19400747
Clin Pharmacol Ther. 2015 Aug;98(2):127-34
pubmed: 25974703
J Infect Dis. 2007 Aug 15;196 Suppl 1:S63-75
pubmed: 17624828
JAMA. 2009 Oct 7;302(13):1429-36
pubmed: 19809024
BMC Genomics. 2013 Sep 23;14:644
pubmed: 24059264
Int J Mycobacteriol. 2016 Mar;5(1):14-20
pubmed: 26927985
Eur J Hum Genet. 2008 Jul;16(7):780-3
pubmed: 18382479
Clin Pharmacol Ther. 2011 Oct;90(4):625-9
pubmed: 21900891
Antimicrob Agents Chemother. 2011 Sep;55(9):4122-7
pubmed: 21709081
Eur J Clin Pharmacol. 2008 Apr;64(4):357-65
pubmed: 18057928
Bioinformatics. 2011 Aug 1;27(15):2156-8
pubmed: 21653522
Drug Metab Rev. 2013 May;45(2):253-75
pubmed: 23590174
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
Nat Genet. 2009 Jun;41(6):657-65
pubmed: 19465909
AIDS Res Hum Retroviruses. 2017 Jan;33(1):33-40
pubmed: 27478997
Br J Clin Pharmacol. 2011 Jul;72(1):51-62
pubmed: 21320152
J Hum Genet. 2009 May;54(5):261-5
pubmed: 19282874
AIDS. 2016 Feb 20;30(4):609-18
pubmed: 26558723
Pharmacogenet Genomics. 2015 Dec;25(12):584-94
pubmed: 26340336
Nucleic Acids Res. 2009 Jan;37(Database issue):D755-61
pubmed: 18996895
Clin Infect Dis. 2012 Dec;55(11):1558-67
pubmed: 22955427
AIDS Res Ther. 2010 Aug 19;7:32
pubmed: 20723261
PLoS Genet. 2015 Jul 17;11(7):e1005363
pubmed: 26186335
Eur J Clin Pharmacol. 2013 May;69(5):1091-101
pubmed: 23150149
CPT Pharmacometrics Syst Pharmacol. 2013 Aug 28;2:e69
pubmed: 23985967
J Infect Dis. 2006 Dec 1;194(11):1481-91
pubmed: 17083032
Curr Pharmacogenomics Person Med. 2011 Sep;9(3):191-207
pubmed: 22563365
J Clin Oncol. 2005 Dec 20;23(36):9312-8
pubmed: 16361630
Elife. 2016 Jun 21;5:
pubmed: 27324836
Clin Pharmacol Ther. 2018 May;103(5):770-777
pubmed: 29385237
Pharmacogenetics. 1999 Jun;9(3):317-26
pubmed: 10471063