Pharmacogenomics in Precision Medicine: From a Perspective of Ethnic Differences

290 Pages·2020·5.331 MB·English

by  Weimin Cai, Zhaoqian Liu, Liyan Miao, Xiaoqiang Xiang

Weimin Cai
Zhaoqian Liu
Liyan Miao
Xiaoqiang Xiang  Editors
Pharmacogenomics
in Precision
Medicine
From a Perspective of Ethnic Differences
Pharmacogenomics in Precision Medicine
(cid:129) (cid:129) (cid:129)
Weimin Cai Zhaoqian Liu Liyan Miao
Xiaoqiang Xiang
Editors
Pharmacogenomics
in Precision Medicine
From a Perspective of Ethnic Differences
Editors
WeiminCai ZhaoqianLiu
SchoolofPharmacy XiangyaHospital
FudanUniversity CentralSouthUniversity
Shanghai,Shanghai,China Changsha,Hunan,China
LiyanMiao XiaoqiangXiang
SchoolofPharmacy SchoolofPharmacy
SuzhouUniversity FudanUniversity
Suzhou,Jiangsu,China Shanghai,Shanghai,China
ISBN978-981-15-3894-0 ISBN978-981-15-3895-7 (eBook)
https://doi.org/10.1007/978-981-15-3895-7
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Preface
This book focuses on the pharmacogenomics and precision medicine which is to
maximize the likelihood of therapeutic efficacy and to minimize the risk of drug
toxicityforanindividualpatient.
This book introduces the principles of pharmacogenomics and precision medi-
cine,followedbythepharmacogenomicsaspectsofmajortherapeuticareassuchas
cardiovascular disease, cancer, organ transplantation, psychiatry, infection, and
thrombotic disease. It also includes related areas of genotyping technology and
therapeutic drug monitoring in pharmacogenomics; gut microbiota; ethical, legal,
andregulatoryissues;cost-effectivenessofpharmacogenomics-guideddrugtherapy;
applicationofpharmacogenomics indrugdiscoveryand development; andclinical
implementationofpharmacogenomicsforpersonalizedprecisionmedicine.
The ethnic difference of drug effect has become one of the important factors
influencing drug uses, medication management, clinical trial, and development of
new drugs. Therefore, we have paid much attention from a perspective of ethnic
differences to pharmacokinetics and pharmacodynamics caused by genetic poly-
morphism in a purpose of rational use and development of existing and new
medications.
ThecontributorsofPharmacogenomicsinPrecisionMedicinecomefromateam
of experts, including professors from academic institutions and practitioners from
hospitals.Thisbookwillgiveanin-depthoverviewofthecurrentstateofpharmaco-
genomics in drug therapy for all health care professionals and graduate students in
theearofprecisionmedicine.
Shanghai,China WeiminCai
January2020 ZhaoqianLiu
LiyanMiao
XiaoqiangXiang
v
Contents
1 IntroductionandPrinciplesofPharmacogenomicsinPrecision
Medicine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
WeiminCaiandZitengWang
2 PharmacogenomicsinCardiovascularDiseases. . . . . . . . . . . . . . . . 21
XiaoqiangXiangandZhipingJin
3 PharmacogenomicsofAntitumorChemotherapeuticAgents. . . . . . 39
ZhaoqianLiu,ChenxueMao,XiangpingLi,andJiyeYin
4 PharmacogenomicsofAntitumorTargetedAgentand
Immunotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
ZhaoqianLiu,ChenxueMao,andJiyeYin
5 PharmacogenomicsofImmunosuppressants. . . . . . . . . . . . . . . . . . 83
Xiao-yanQiu,ZhuoWu,Qin-xiaXu,Chang-chengSheng,
andZhengJiao
6 PharmacogenomicsofPsychiatricDrugs. . . . . . . . . . . . . . . . . . . . . 107
ShengyingQin,JingsongMa,CongHuai,andWeiZhou
7 PharmacogenomicsofAnti-InfectiveAgents. . . . . . . . . . . . . . . . . . 123
XianminMeng,QianZhang,andPingDong
8 PharmacogenomicsofAntithromboticDrugs. . . . . . . . . . . . . . . . . 137
LiyanMiao,ChengXie,XiaoliangDing,andWenhaoQu
9 PharmacogenomicsinTherapeuticDrugMonitoring. . . . . . . . . . . 155
BingChen,HeFengChen,JiaQianLu,andBeimingXu
10 Pharmacomicrobiomics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
WeihuaHuangandWeiZhang
11 GenotypingTechnologiesinPharmacogenomics. . . . . . . . . . . . . . . 201
BingjieZou,NanSheng,LiyingFeng,andGuohuaZhou
vii
viii Contents
12 TheEthical,Legal,andRegulatoryIssuesAssociatedwith
Pharmacogenomics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
LiyanMiao,JingjingZhang,LingYi,andShenjiaHuang
13 Cost-EffectivenessofPharmacogenomics-GuidedDrug
Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
ZhijiaTangandWeiminCai
14 ApplicationofPharmacogenomicsinDrugDiscoveryand
Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
XiaoqiangXiangandYawenYuan
15 BarriersandSolutionsinClinicalImplementationof
PharmacogenomicsforPersonalizedMedicine. . . . . . . . . . . . . . . . 277
ZhaoqianLiu,XiLi,andBotingZhou
Chapter 1
Introduction and Principles
of Pharmacogenomics in Precision Medicine
WeiminCaiandZitengWang
Abstract The individual and ethnic differences of drug effects are very important
issues in clinical drug therapy. They may be caused by genetic variations which
mainly come from polymorphisms of genes encoding metabolic enzymes, trans-
porters and drug targets that affect the in vivo pharmacokinetic and pharmacody-
namicsofdrugs.WiththedevelopmentandhugesuccessesofHGPproject,oneof
itsmajorapplicationsisemergeofanewresearchareaofpharmacogenomics,which
isusedinstandardizationandindividualizationofdrugtherapy.Inordertofulfillits
goal,precisionmedicineisthekeytosolvetheproblem.
Keywords Pharmacogenomics·Precisionmedicine·Polymorphism·Biomarkers
1.1 Introduction
The individual and ethnic differences of drug effects are very important issues in
clinical drug therapy. Besides seemingly obvious factors such as body weight,
height, gender, age, drug quality, organ function, disease progress complication,
and food/drug interaction, genetics also plays an important role in such area. The
differenceofdrugeffectscausedbygeneticvariationmainlycomesfrompolymor-
phismofcodinggenesofdrugmetabolizingenzymes,transportersanddrugtargets,
whichwillinfluencetheirpharmacokineticsandpharmacodynamics.Therefore,they
consist of main research field of pharmacogenomics. Furthermore, Precision Med-
icineInitiativedrawsmoreattentionofstudyandapplicationofpharmacogenomics.
This chapter will introduce principles of genetic basis, pharmacogenomics, and
precisionmedicine.
W.Cai(*)·Z.Wang
DepartmentofClinicalPharmacy,FudanUniversity,SchoolofPharmacy,Shanghai,People’s
RepublicofChina
e-mail:[email protected]
©SpringerNatureSingaporePteLtd.2020 1
W.Caietal.(eds.),PharmacogenomicsinPrecisionMedicine,
https://doi.org/10.1007/978-981-15-3895-7_1
2 W.CaiandZ.Wang
1.1.1 Genetic Concepts of Pharmacogenomics
1.1.1.1 Gene
Gene is the basic element of heritage information. It usually indicates a specific
product (e.g., protein or RNA molecule) of function located in a single nucleotide
sequence.
Human genes usuallyconsistoftwomajorregions. One iscalledcodingregion
(5%ofgenome),includingexonsandintrons.Anotherisflankingsequence,located
inupstreamordownstreamofcodingregion,whichhasregulatingeffect,consisting
ofpromoter,enhancer,andterminator(Fig.1.1).
There are 23 pairs of chromosomes in human genome, including 22 pairs of
autosomal and one pairs of sex chromosomes. In 1953, British scientists, James
D. Watson and Francis H.C. Crick, proposed an earliest model of structure of
deoxyribonucleicacid(DNA)accordingtoX-raydiffractionmapandrelatedmate-
rials. It was published in Nature magazine and draws enormous attention from the
world [1]. At the present time, human genome contains about 300 millions of
Fig.1.1 Structureofatypicalhumangene.(Modifiedfromtheoriginalfileathttps://commons.
wikimedia.org/wiki/File:0321_DNA_Macrostructure.jpg)
1 IntroductionandPrinciplesofPharmacogenomicsinPrecisionMedicine 3
nucleotidesand27,000genes.Theycontrolindividualdevelopment,growth,repro-
duction,andmetabolismandplayanimportantroleindiseaseprogress.
Gene has three basic characters. First one is self-replication of gene, which is
existed as codon in DNA in order to ensure continuity and stability of genetic
informationincelldivision;secondoneisgeneexpression,whichconvertsgenetic
informationstoredinDNAsequencesviatranscriptionandtranslationtoRNAand
protein molecules with biological function; third one is gene mutation, which is
smallchangeinsinglenucleotidesequenceandnumbertopavethewayofbiological
evolutionandgeneticpolymorphism.
1.1.1.2 GeneticPolymorphism
Genetic polymorphism means that there are two or more discontinuous mutations
and genotypes at the same time and often in a biological population. Genetic
polymorphism is very common especially in human, whose construction, expres-
sion,andfunctionofgenehavebeenextensivelystudied.
Accordingtogenevariationinhuman,geneticpolymorphismisusuallyconsisted
of three categories [2]. (1) DNA fragment length polymorphism (FLP), which is
deletion,repetition,orinsertionofasinglebaseandresultsinchangesinrestriction
endonucleaselociandDNAfragmentlength.Itisalsocalledasrestrictionfragment
length polymorphism (RFLP). (2) The polymorphism of DNA repeat sequence
(RSP),inparticularlyshorttandemrepeats,issmallsatelliteDNAandmicrosatellite
DNA.RSPismainlymanifestedinthevariationofthenumberofcopiesofrepetitive
sequences. (3) Single nucleotide polymorphism (SNP) is scattered difference of
single nucleotide, including the deletion and insertion of a single base, but more
frequently the substitution of a single base, which often appears in CG sequence.
SNPisawell-studiedpolymorphismatthepresenttime.
Human genome has about three billion base pairs, in which there are approxi-
mately27,000geneswhichcanbepassedfromparenttooffspring.Smalldifferences
in gene can result in big variation in phenotypes, such as body height, skin color,
fingerprint, blood type, and even personality. Variation in specific gene will influ-
encehumansusceptibilitytodiseaseandreactiontodrugs(suchaspharmacokinet-
ics,pharmacodynamics,andadversereaction)[3].Occurrenceofpolymorphismisa
resultofmultigenealleles.Itisusuallyconsideredaspolymorphismiffrequencyof
genemutationismorethan1%,otherwiseasnaturalmutation.
Studyofgeneticpolymorphismwillpavethewayforclinicalmedicine,genetics,
preventivemedicine,andclinicalpharmacy.Forexample,functionalimpairmentor
completelossofdrugmetabolizingenzymesandtransportersbySNPwillresultin
disposition changes of related drugs in vivo. There are variations of number,
construction, and function of receptors in certain percentage of individuals, which
could affect target protein affinity and finally pharmacological activity of drugs.
Some protein and related gene, which determine drug activity, will also influence
pathophysiologyofdiseases.Therefore,personalizeduseofmedicationcanbemetif
pharmacotherapy is based on genetic polymorphism. Take hypertension drug