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том ХXXI, 2025, № 2
ДРУЖЕСТВО
НА КАРДИОЛОЗИТЕ
В БЪЛГАРИЯ
АВТОРСКИ СТАТИИ
ORIGINAL ARTICLES
PERSONALIZING AMLODIPINE THERAPY IN HYPERTENSION THE ROLE
PERSONALIZING AMLODIPINE THERAPY IN HYPERTENSION THE ROLE
OF GENETIC VARIANTS AND POPULATION-SPECIFIC RESPONSES
OF GENETIC VARIANTS AND POPULATION-SPECIFIC RESPONSES
D. P. Amuk i1, R. I. P a ami2
1Depa men o Pha macy, Facul y o Heal h Sciences, Alma A a Uni e si y
2Facul y o Pha macy, Uni e si y Ahmad Dahlan, Yogyaka a, Indonesia
ПЕРСОНАЛИЗИРАНЕ НА ТЕРАПИЯТА С АМЛОДИПИН ПРИ ХИПЕРТОНИЯ –
ПЕРСОНАЛИЗИРАНЕ НА ТЕРАПИЯТА С АМЛОДИПИН ПРИ ХИПЕРТОНИЯ –
РОЛЯТА НА ГЕНЕТИЧНИТЕ ВАРИАНТИ И СПЕЦИФИЧНИТЕ РЕАКЦИИ
РОЛЯТА НА ГЕНЕТИЧНИТЕ ВАРИАНТИ И СПЕЦИФИЧНИТЕ РЕАКЦИИ
НА НАСЕЛЕНИЕТО
НА НАСЕЛЕНИЕТО
Д. П. Амукти1, Р. И. Прамати2
1Катедра по фармация, Факултет по здравни науки, Университет Алма Ата
2Факултет по фармация, Университет Ахмад Далан, Джокякарта, Индонезия
Abs ac . In oduc ion: Amlodipine is a long-ac ing dihyd opy idine calcium channel blocke used in hype ension managemen .
Despi e i s widesp ead use, he apeu ic esponse a ies signi i can ly among indi iduals, in l uenced by gene ic,
en i onmen al, and physiological ac o s. Pha macogenomics, which s udies gene ic a ia ion a ec ing d ug esponses,
has iden i i ed speci i c gene ic a ian s associa ed wi h amlodipine me abolism and e i cacy. Genes such as CYP3A4,
RYR3, CACNA1C, and CACNA1D a e known o play a ole in amlodipine’s pha macokine ics and pha macodynamics.
This e iew examines hese gene ic a ian s and hei impac on amlodipine e i cacy, wi h a ocus on popula ion-
speci i c esponses. Ma e ial and me hods: This s udy u ilized publicly a ailable pha macogenomic da a om he
Pha mGKB and GTEx Po al o iden i y gene ic a ian s associa ed wi h amlodipine e i cacy. Gene ic a ian s om
CYP3A4, RYR3, CACNA1C, and CACNA1D we e selec ed based on hei associa ion wi h amlodipine esponse.
Popula ion-speci i c a ia ions we e also analyzed o assess di e ences in he apeu ic ou comes ac oss di e se
biogeog aphical g oups. Resul s: Se en single nucleo ide polymo phisms (SNPs) om ou genes we e iden i i ed:
CYP3A4 ( s2246709, s2740574), RYR3 ( s877087), CACNA1C ( s2239050, s2239128), and CACNA1D ( s312481).
SNPs such as s2246709 in CYP3A4 and s877087 in RYR3 we e linked o enhanced amlodipine e i cacy in ce ain
popula ions, while s2740574 showed g ea e esponse in women. Va ian s like s2239050 and s312481 in l uenced
amlodipine esponse in Cen al/Sou h Asian and Eu opean popula ions. Conclusion: Gene ic a ian s, including
CYP3A4 ( s2246709, s2740574), RYR3 ( s877087), CACNA1C ( s2239050, s2239128), and CACNA1D ( s312481),
signi i can ly in l uence amlodipine e i cacy in hype ensi e pa ien s. These i ndings unde sco e he impo ance o gene ic
ac o s in pe sonalizing hype ension ea men and op imizing d ug e i cacy ac oss di e se popula ions. Howe e ,
u he clinical alida ion and mechanis ic s udies a e necessa y o con i m he he apeu ic implica ions o hese gene ic
associa ions. Unde s anding he dis ibu ion o hese a ian s ac oss popula ions may aid in ailo ing amlodipine he apy
based on e hnic and geog aphical ac o s, ensu ing a mo e p ecise and e ec i e ea men app oach.
Key wo ds: hype ension, amlodipine, pha macogenomics, gene ic a ian s, CYP3A4, RYR3, CACNA1C, CACNA1D, single
nucleo ide polymo phisms, d ug e i cacy, popula ion-speci i c esponse, calcium channel blocke , p ecision medicine
Аdd ess
o co espondence Danang P ase yaning Amuk i, e-mail: [email p o ec ed]
Резюме.Въведение: Амлодипин е дългодействащ дихидропиридинов блокер на калциевите канали, използван за лече-
ние на хипертония. Въпреки широката му употреба терапевтичният отговор варира значително при отделните
индивиди, тъй като се влияе от генетични, екологични и физиологични фактори. Фармакогеномиката, която
изучава генетичните вариации, влияещи върху лекарствените реакции, е идентифицирала специфични гене-
тични варианти, свързани с метаболизма и ефикасността на амлодипин. Известно е, че гени като CYP3A4,
RYR3, CACNA1C и CACNA1D играят роля във фармакокинетиката и фармакодинамиката на амлодипин. В този
материал се разглеждат тези генетични варианти и тяхното въздействие върху ефикасността на амлодипин,
като се акцентира върху специфичните за популацията реакции. Материал и методи: В това проучване бяха
This is an open access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (CC BY 4.0), which pe mi s un es ic ed
use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal au ho and sou ce a e c edi ed.
doi: 10.3897/bgca dio.31.e145941
73
Pe sonalizing amlodipine he apy in hype ension...
I
Hype ension is a leading global heal h conce n, a -
ec ing o e 1.3 billion people wo ldwide and con ibu -
ing signi i can ly o ca dio ascula diseases, s oke, and
enal ailu e [1, 2]. Eff ec i e managemen o hype en-
sion is c i ical o educing mo bidi y and mo ali y a es
[3]. Among he a ious an ihype ensi e agen s, am-
lodipine, a long-ac ing dihyd opy idine calcium channel
blocke (CCB), is widely p esc ibed due o i s p o en
effi cacy, ole abili y, and abili y o educe blood p es-
su e ac oss di e se pa ien popula ions [4]. Howe e ,
despi e i s b oad clinical use, signi i can in e indi idu-
al a iabili y exis s in esponse o amlodipine he apy,
which poses challenges o pe sonalized hype ension
managemen [5, 6].
This a iabili y in he apeu ic esponse is in l uenced
by mul iple ac o s, including age, sex, como bidi ies,
and en i onmen al condi ions. In ecen yea s, gene ic
ac o s ha e eme ged as c ucial de e minan s o d ug
effi cacy and sa e y [7]. Pha macogenomics, he s udy
o how genes aff ec an indi idual’s esponse o d ugs,
has p o ided insigh s in o he mechanisms unde lying
a iable esponses o an ihype ensi e he apies. Spe-
ci i c gene ic a ian s in key genes, such as CYP3A4,
RYR3, CACNA1C, and CACNA1D, ha e been iden i-
i ed as playing a ole in he me abolism, anspo , and
pha macodynamic ac ion o amlodipine [8, 9]. Popula-
ion-speci i c diff e ences u he complica e he pha ma-
cogenomics o amlodipine. Gene ic a ia ions can a y
signi i can ly ac oss biogeog aphical g oups, in l uenc-
ing he d ug’s effi cacy and isk o ad e se eff ec s. Fo
example, ce ain alleles a e mo e p e alen in A ican,
Eu opean, o Asian popula ions, which may explain he
obse ed diff e ences in clinical ou comes [10, 11]. Un-
de s anding hese associa ions is essen ial o de el-
oping a ge ed he apeu ic s a egies o op imize blood
p essu e con ol in di e se popula ions [12].
This e iew aims o explo e he impac o gene -
ic a ian s on amlodipine effi cacy in hype ensi e pa-
ien s, wi h a ocus on popula ion-speci i c esponses.
By analyzing pha macogenomic da a and biogeo-
g aphical a ia ions, we seek o p o ide a comp ehen-
si e unde s anding o he ole o gene ics in an ihype -
ensi e he apy. Such insigh s will pa e he way o
p ecision medicine app oaches, ensu ing ha pa ien s
ecei e he mos eff ec i e and pe sonalized ea men
o hype ension.
M
S udy Design
This s udy adop s a bioin o ma ics-based app oach o
in es iga e he associa ion be ween gene ic a ian s and
he effi cacy o amlodipine in hype ensi e pa ien s. Da a
was ex ac ed om publicly a ailable pha macogenom-
ic da abases, including Pha mGKB and G ex Po al, o
iden i y ele an gene ic a ian s, hei unc ional signi i -
cance, and popula ion-speci i c dis ibu ions [13, 14].
Pha mGKB Da abase
Pha mGKB (Pha macogenomics Knowledge
Base) was u ilized o ex ac pha macogenomic in o -
използвани публично достъпни фармакогеномни данни от порталите Pha mGKB и GTEx, за да се идентифи-
цират генетични варианти, свързани с ефикасността на амлодипин. Специфичните за популацията вариации
също бяха анализирани, за да се оценят разликите в терапевтичните резултати в различните биогеографски
групи. Резултати: Бяха установени седем единични нуклеотидни полиморфизма (SNP) от четири гена: CYP3A4
( s2246709, s2740574), RYR3 ( s877087), CACNA1C ( s2239050, s2239128) и CACNA1D ( s312481). SNP като
s2246709 в CYP3A4 и s877087 в RYR3 са свързани с повишена ефикасност на амлодипин в определени попу-
лации, докато s2740574 показва по-голям отговор при жените. Варианти като s2239050 и s312481 са повлия-
ли на отговора на амлодипин при популации от Централна/Южна Азия и Европа. Заключение: Генетичните
варианти, включително CYP3A4 ( s2246709, s2740574), RYR3 ( s877087), CACNA1C ( s2239050, s2239128) и
CACNA1D ( s312481), оказват значително влияние върху ефикасността на амлодипин при пациенти с хиперто-
ния. Тези констатации подчертават значението на генетичните фактори за персонализиране на терапията при
хипертония и за оптимизиране на ефикасността на лекарствата при различни популации. Въпреки това са необ-
ходими допълнителни клинични валидирания и механистични проучвания, за да се потвърдят терапевтичните
последици от тези генетични асоциации. Разбирането на разпределението на тези варианти сред популациите
може да помогне за адаптиране на терапията с амлодипин въз основа на етнически и географски фактори, като
се гарантира по-прецизен и ефективен подход към лечението.
Ключови думи:хипертония, амлодипин, фармакогеномика, генетични варианти, CYP3A4, RYR3, CACNA1C, CACNA1D, еди-
нични нуклеотидни полиморфизми, лекарствена ефикасност, специфичен за популацията отговор, блокер на
калциевите канали, прецизна медицина
Адрес
за кореспонденция:Дананг Прасетянинг Амукти, e-mail: [email p o ec ed]
D. P. Amuk i, R. I. P a ami
74
ma ion ela ed o amlodipine. Pha macogenomic asso-
cia ions we e iden i i ed based on d ug effi cacy, gene -
ic a ian anno a ions, and ela ed clinical ou comes.
Sea ch e ms: “Amlodipine”, “Hype ension”, “Gene ic
a ian s”, “Popula ion esponses”. Fil e s Focused on
effi cacy ou comes and clinically ele an pha macog-
enomic e idence.1516
GTEx Po al
The GTEx (Geno ype-Tissue Exp ession) Po al
was used o analyze he exp ession le els o he genes
associa ed wi h amlodipine effi cacy ac oss diff e en is-
sues. Compa a i e analysis o exp ession le els was
conduc ed o assess issue-speci i c gene ac i i y and
i s po en ial ole in d ug esponse [17, 18].
Da a Analysis
Va ian Selec ion: Gene ic a ian s we e i l e ed
based on hei associa ion wi h amlodipine effi cacy
(P- alue < 0.05). Va ian s we e p io i ized based on
hei unc ional anno a ions (eg, coding egions, eg-
ula o y impac ) [19, 20]. Popula ion-Speci i c Analysis:
F equency da a o he selec ed a ian s we e ex ac -
ed om Pha mGKB and c oss- e e enced wi h bio-
geog aphical g oups (eg, A ican, Asian, Eu opean) o
e alua e diff e ences in gene ic a ian dis ibu ions15.
Da a Visualiza ion: Resul s we e p esen ed using a-
bles, hea maps, and ba cha s o illus a e a ian
dis ibu ions, unc ional impac s, and gene exp ession
pa e ns ac oss popula ions and issues.
R
The sea ch o genes ela ed o amlodipine e-
sponse in he Pha mGKB da abase esul ed in 30 ele-
an genes. A e elimina ion based on p- alues g ea e
han 0.05, and selec ion based on d ug effi cacy ca e-
go ies, only genes ha showed signi i can po en ial in
he apeu ic esponse we e e ained.
Iden i i ca ion o gene ic a ian s associa ed
wi h esponse o amlodipine in hype ension
This selec ion p ocess esul ed in 7 SNPs o igi-
na ing om 4 genes in Table 1 and 2. These genes
we e hen aken and u he analyzed o e alua e hei
ole in in l uencing he eff ec i eness o amlodipine
he apy in hype ensi e pa ien s. This u he analysis
is expec ed o e eal deep gene ic ela ionships and
imp o e unde s anding o mo e pe sonalized he apy
o hype ension.
Fig. 1. Resea ch me hod l owcha
C ea ed in h ps://BioRende .com
Table 1. Gene ic a ian s associa ed wi h esponse o amlodipine in hype ension
Genes Va ian s P-Value Cases
CYP3A4 s2246709 0.01 145
RYR3 s877087 0.04 1940
CYP3A4 s2740574 0.02 61
CACNA1C s2239050 0.024 200
CACNA1C s2239050 0.05 53
CACNA1C s2239128 0.04 53
CACNA1D s312481 0.024 200
75
Pe sonalizing amlodipine he apy in hype ension...
Analysis o CYP3A4, RYR3, CACNA1D,
CACNA1 gene exp ession in issues
and i s ela ionship wi h he eff ec i eness
o amlodipine in hype ension
Amlodipine is a widely used calcium channel block-
e and is eff ec i e in managing hype ension. Howe -
e , in e indi idual a iabili y in d ug esponse is in l u-
enced by gene ic ac o s. This analysis explo es he
issue-speci i c exp ession o CYP3A4, RYR3, CAC-
NA1D, and CACNA1 genes, ocusing on hei unc ion-
al oles in pha macokine ics. and pha macodynamics
o amlodipine (Fig. 2).
The CYP3A4 gene is mainly exp essed in he li e
and small in es ine, which plays an impo an ole in am-
lodipine me abolism [21]. High hepa ic exp ession acil-
i a es he bio ans o ma ion o amlodipine o i s inac i e
me aboli es. Va iabili y in CYP3A4 exp ession can al e
d ug plasma le els, aff ec ing he apeu ic ou comes. Fo
Table 2. Associa ion o Gene Va ian s wi h Amlodipine Effi cacy in Diff e en E hnic G oups and Pheno ype Ca ego ies
D ugs Va ian s Associa ion Biogeog aphical G oups Pheno ype
Ca ego ies
Amlodipine s2246709
Geno ypes AG + GG a e associa ed wi h inc eased
esponse o amlodipine in people wi h hype ension
as compa ed o geno ype AA.
A ican Ame ican/A o-Ca ibbean Effi cacy
Amlodipine s877087
The TT geno ype is associa ed wi h inc eased isk
o Hea Failu e when ea ed wi h amlodipine in
people wi h Hype ension.
Mul iple g oups, 64.7% Whi e, 32.1%
Black, 0.3% Ame ican Indian/Alaskan
na i e, 0.9% Asian/Paci i c Islande ,
2.1% o he , 11.5% Hispanic
Effi cacy
Amlodipine s2740574
Geno ypes CT + TT a e associa ed wi h inc eased
esponse o amlodipine in women wi h hype ension
as compa ed o geno ype CC.
A ican Ame ican/A o-Ca ibbean Effi cacy
Amlodipine s2239050
Geno ype GG is associa ed wi h inc eased clinical
bene i o amlodipine in people wi h Hype ension
as compa ed o geno ypes CC + CG.
Cen al/Sou h Asian Effi cacy
Amlodipine s2239050
Geno ype GG is associa ed wi h inc eased
esponse o amlodipine and elodipine in people
wi h hype ension as compa ed o geno ype CG.
Eu opean Effi cacy
Amlodipine s2239128
Allele C is associa ed wi h inc eased esponse
o amlodipine and elodipine in people wi h
Hype ension as compa ed o allele T.
Eu opean Effi cacy
Amlodipine s312481
Geno ype GG is associa ed wi h inc eased clinical
bene i o amlodipine in people wi h hype ension as
compa ed o geno ypes AA + AG.
Cen al/Sou h Asian Effi cacy
Fig. 2. CYP3A4 gene exp ession in human body issues
D. P. Amuk i, R. I. P a ami
76
example, lowe CYP3A4 ac i i y may esul in a lon-
ge d ug hal -li e and inc eased effi cacy o side eff ec s.
RYR3 Gene Exp ession and Calcium Signaling [22].
The RYR3 gene encodes a yanodine ecep o ha
plays a key ole in he elease o in acellula calcium
om he sa coplasmic e iculum [23, 24]. This pa hway
is a key componen in he egula ion o smoo h muscle
con ac ion, including ascula smoo h muscle, which is
he p ima y a ge o amlodipine [25]. Exp ession anal-
ysis esul s showed ha he highes exp ession o he
RYR3 gene was ound in he u e us, ollowed by o h-
e smoo h muscle issues. This high exp ession in he
u e us e l ec s he physiological need o egula ion o
muscle con ac ion o ep oduc i e unc ion, which e-
qui es coo dina ed in acellula calcium elease [26].
Rele ance o Vascula Smoo h Muscle: Al hough he
highes exp ession is ound in he u e us, RYR3 is also
exp essed in ascula smoo h muscle. In he con ex
o hype ension, RYR3 exp ession in ascula smoo h
muscle is o pa icula impo ance because modula ion
o his calcium pa hway aff ec s ascula one and blood
p essu e [27]. Eff ec s on Response o Amlodipine. High
Exp ession: Inc eased exp ession o RYR3 in ascula
smoo h muscle may inc ease sensi i i y o amlodipine,
because yanodine ecep o s p omo e calcium elease
ha is he a ge o L- ype calcium channel blockade.
This may enhance he asodila o y eff ec . Low Exp es-
sion: Con e sely, i RYR3 exp ession is educed, he e-
sponse o amlodipine may be weakened, educing he
d ug’s eff ec i eness in lowe ing blood p essu e [28].
Fig. 3. RYR3 gene exp ession in human body issues
Fig. 4. CACNA1D gene exp ession in human body issues
77
Pe sonalizing amlodipine he apy in hype ension...
The CACNA1D gene encodes he alpha-1 subuni
o he L- ype calcium channel, which is he p ima y a -
ge o amlodipine [29]. This channel plays an impo an
ole in egula ing he en y o calcium ions in o cells,
which aff ec s smoo h muscle con ac ion and cellula
elec ophysiological unc ion [30]. Exp ession analysis
showed ha he highes exp ession o CACNA1D was
ound in he ce ix, accompanied by signi i can exp es-
sion le els in ca dio ascula issues, such as he hea
and blood essels [31, 32]. Exp ession in he Ce ix:
High exp ession o CACNA1D in he ce ix is likely e-
la ed o he need o egula ion o ce ical smoo h mus-
cle con ac ions, especially in he con ex o ep oduc-
i e unc ions such as labo . The ole o L- ype calcium
channels in his issue is o media e coo dina ed cal-
cium esponses o physiological s imuli. Exp ession in
Ca dio ascula Tissues: In blood essels and he hea ,
CACNA1D exp ession de e mines he eff ec i eness o
L- ype calcium channel blockade by amlodipine. These
channels con ibu e di ec ly o he egula ion o as-
cula esis ance and blood p essu e. Rela ionship o
Amlodipine Effi cacy CACNA1D exp ession in ca dio-
ascula issues is an impo an ac o in de e mining
he clinical esponse o amlodipine: High Exp ession
in Blood Vessels Inc eases sensi i i y o calcium chan-
nel blockade, he eby enhancing he asodila o y eff ec
and lowe ing blood p essu e. Low Exp ession in Blood
Vessels May esul in a weake esponse o amlodip-
ine, educing he d ug’s eff ec i eness in lowe ing blood
p essu e [33].
The CACNA1 gene encodes an addi ional sub-
uni o he L- ype calcium channel, which suppo s
he s abili y and unc ion o he channel, including in
esponse o amlodipine [34]. Analysis showed he
highes exp ession o his gene in he colon, e l ec ing
i s impo an ole in he egula ion o gas oin es inal
smoo h muscle mo ili y. Al hough exp ession in he co-
lon is no di ec ly ela ed o blood p essu e egula ion,
CACNA1 exp ession in ca dio ascula issues, such as
blood essels, suppo s he effi cacy o amlodipine by
enhancing he unc ion o calcium channels in educing
ascula esis ance. Op imal exp ession le els may in-
c ease sensi i i y o amlodipine, while low exp ession
may educe d ug effi cacy. In addi ion, exp ession in he
colon may p o ide insigh in o po en ial gas oin es inal
side eff ec s o amlodipine use [35].
D
Amlodipine wo ks by inhibi ing L- ype calcium
channels, which a e egula ed by genes such as
CACNA1D and me abolized by he enzyme CYP3A4.
This mechanism dec eases pe iphe al ascula esis-
ance, leading o lowe blood p essu e. Howe e , he
esponse o amlodipine a ies signi i can ly be ween
indi iduals, which is la gely due o gene ic diff e enc-
es. Se e al gene ic a ian s ha e been iden i i ed as
de e minan s o esponse o amlodipine, including
s2246709, s877087, s2740574, and s2239050, wi h
diff e en eff ec s on effi cacy and po en ial side eff ec s.
Se e al gene ic a ian s ha e been iden i i ed o in l u-
ence indi idual esponses o amlodipine in hype en-
si e pa ien s. The AG + GG geno ype a s2246709 in
A ican-Ame ican/A o-Ca ibbeans showed a be e hy-
pe ensi e esponse han he AA geno ype, indica ing
an in l uence o his a ia ion on calcium channel ex-
p ession o unc ion. In [36] con as , he TT geno ype
a s877087 ound in di e se popula ions was associ-
a ed wi h an inc eased isk o hea ailu e in hype -
ensi e pa ien s ecei ing amlodipine, e l ec ing a po-
en ial speci i c gene ic side eff ec ha equi es clinical
a en ion. In A ican-Ame ican/A o-Ca ibbean women,
Fig. 5. CACNA1 gene exp ession in human body issues
D. P. Amuk i, R. I. P a ami
78
he CT + TT geno ype a s2740574 con e ed a mo e
op imal hype ensi e esponse han he CC geno ype,
mos likely h ough modula ion o CYP3A4 me aboliz-
ing enzyme ac i i y [37].
O he gene ic a ia ions, such as he GG geno ype
a s2239050, a e associa ed wi h inc eased clinical
bene i o amlodipine in Cen al/Sou h Asian and Eu o-
pean popula ions, sugges ing ha hese a ia ions may
enhance d ug effi cacy h ough mechanisms aff ec ing
calcium channel anspo o in e ac ions. In Eu ope-
ans, he C allele a s2239128 inc eases he esponse
o amlodipine and elodipine compa ed o he T allele,
likely due o diff e ences in calcium channel affi ni y [38].
In addi ion, he GG geno ype a s312481, which is
common in Cen al/Sou h Asians, is associa ed wi h
g ea e clinical bene i compa ed o he AA + AG gen-
o ypes, sugges ing a link o blood p essu e egula ion
[39]. These a ia ions highligh he impo ance o con-
side ing gene ic ac o s in pe sonalizing hype ension
he apy wi h amlodipine [40, 41].
In e ms o pha macodynamics, CACNA1C and
CACNA1D egula e he L- ype calcium channels,
which a e he p ima y a ge s o amlodipine. SNPs
such as s2239050 (GG geno ype) in Cen al/Sou h
Asian and Eu opean popula ions ha e been associ-
a ed wi h inc eased d ug effi cacy, possibly due o en-
hanced calcium channel inhibi ion [31, 32]. Simila ly,
he C allele a s2239128 is linked o g ea e esponse
o amlodipine and elodipine in Eu opean popula ions,
sugges ing an eff ec on channel binding affi ni y. Mo e-
o e , a ia ions in RYR3 may con ibu e o ad e se
eff ec s in ce ain indi iduals. The TT geno ype a
s877087 has been associa ed wi h an inc eased isk
o hea ailu e in hype ensi e pa ien s ecei ing am-
lodipine, po en ially due o al e ed calcium signaling,
which aff ec s ca diac con ac ili y. This sugges s ha
pha macogenomic sc eening could help iden i y pa-
ien s a isk o ca dio ascula side eff ec s when p e-
sc ibed amlodipine [39].
The diff e en dis ibu ion o gene ic a ian s
ac oss popula ions sugges s ha s a egies o pe -
sonalizing amlodipine he apy should be ailo ed
based on e hnic and geog aphic ac o s. Fo exam-
ple, SNPs associa ed wi h inc eased esponse o
amlodipine a e mo e common in Asian popula ions,
which may p o ide a basis o conside ing dose ad-
jus men s o mo e app op ia e an ihype ensi e he -
apy choices o hese popula ions. Al hough asso-
cia ions be ween gene ic a ian s and esponse o
amlodipine ha e been iden i i ed, u he alida ion
h ough clinical s udies is needed o con i m hei
he apeu ic implica ions. Pa ien -based pha macoki-
ne ic and pha macodynamic s udies would be help ul
in con i ming he speci i c ole o he iden i i ed SNPs
in d ug me abolism and effi cacy.
C
Gene ic a ian s o CYP3A4 ( s2246709,
s2740574), RYR3 ( s877087), CACNA1C ( s2239050,
s2239128), and CACNA1D ( s312481) play a ole
in de e mining he eff ec i eness o amlodipine in hy-
pe ensi e pa ien s. These i ndings emphasize he
impo ance o pha macogenomics in pe sonalizing
he apy, allowing ea men op imiza ion based on pop-
ula ion-speci i c gene ic a ia ions o inc ease eff ec i e-
ness and educe side eff ec s.
Acknowledgemen s
Wi h hea el g a i ude, I would like o dedica e his wo k o
someone e y special in my li e Ria Indah P a ami. You un-
wa e ing suppo , pa ience, and encou agemen ha e been
he s eady o ce behind e e y s ep o his jou ney. Th ough
long nigh s, challenges, and momen s o doub , you p es-
ence eminded me why pe se e ance ma e s. To you, my u-
u e pa ne in li e, hank you o belie ing in me when I ques-
ioned mysel , and o eminding me ha science and lo e
can g ow hand in hand. This pape is no jus an academic
miles one i is also a ibu e o he s eng h we build oge he .
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