Povezanost polimorfizma ABCG2 c.421C>A (rs2231142) s nuspojavama atorvastatina

master's thesis

• Title (english): Association of ABCG2 c.421C>A (rs2231142) polymorphism with atorvastatin adverse reactions
• Author: Marina Galešić
• Mentor: Tamara Božina (mentor)
• Mentor: Karmela Barišić (mentor)
• Committee member: Tamara Božina (predsjednik povjerenstva)
• Committee member: Karmela Barišić (član povjerenstva)
• Committee member: Lidija Bach-Rojecky (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medical biochemistry and haematology); Zagreb
• Defense date and country: 2023-07-14, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Medical Biochemistry

Abstract

Statini su jedni od najpropisivanijih lijekova današnjice, često kao dio kronične politerapije u
kardiovaskularnih pacijenata. Usprkos opravdanom statusu statina kao sigurnih lijekova, neželjene
učinke terapije nužno je prevenirati kako bi se osigurala adherencija, posebice kod terapija u cilju
prevencije kardiovaskularnih događaja. Atorvastatin, supstrat ABCG2 prijenosnika, podložan je
varijabilnoj farmakokinetici u onih s njegovom izmijenjenom ekspresijom. Varijanta p.Q141K
(c.421C>A, rs2231142) povezana je sa smanjenom ekspresijom proteina. To vodi do povećane
koncentracije njegovih supstrata uslijed povećane apsorpcije i nemogućnosti izlučivanja izvan
stanica na čijim je membranama ABCG2 prijenosnik. Polimorfizam ovog farmakogena mogao bi
objasniti o dozi ovisne nuspojave atorvastatina povezane s muskuloskeletnim sustavom i akutne
manifestacije jetrenih oštećenja te ostalo rijeđe uočene nuspojave. CPIC smjernice za propisivanje
statina tiču se SLCO1B1 gena, prvog gena čija je važnost u farmakokinetici ove skupine lijekova
prepoznata. Do danas, utjecaj polimorfizama ABCG2 gena ustanovljen je u slučaju doziranja
rosuvastatina i alopurinola gdje se preporučuju niže, odnosno više doze u onih s uočenim
varijantnim alelom A.
U ovom je diplomskom radu provedena case-control studija s ciljem evaluacije asocijacije
neželjenih učinaka i polimorfizama gena ABCG2. Genotipizacija ABCG2 c.421C>A ukupno 223
ispitanika koji su primali atorvastatin kao dio terapije različitih kardiovaskularnih i metaboličkih
bolesti učinjena je metodom TaqMan® DME. Ispitanici su dihotomizirani (slučajevi vs kontrole) s
obzirom na to jesu li iskusili nuspojave nakon primjene atorvastatina. Pokazana je statistički
značajna povezanost ABCG2 c.421C>A polimorfizma s prijavljivanim nuspojavama (p=0,0416).
Nove spoznaje na području farmakogenomike pomažu u procjeni rizika i koristi kod propisivanja
atorvastatina, što vodi korak bliže personaliziranoj medicini.

Abstract (english)

Statins are among the most prescribed drugs today, often as part of chronic polytherapy in
cardiovascular patients. Despite the justified status of statins as safe drugs, it is necessary to
prevent their side effects in order to ensure adherence, especially in therapies aimed at preventing
cardiovascular events. Atorvastatin, a substrate of the ABCG2 transporter, is subject to variable
pharmacokinetics in individuals with altered expression of this transporter. The p.Q141K variant
(c.421C>A, rs2231142) is associated with reduced protein expression. This leads to increased
concentrations of its substrates due to increased absorption and the inability to be excreted outside
of cells where the ABCG2 acts as an efflux pump. The polymorphism of this pharmacogene could
explain the dose-dependent side effects of atorvastatin associated with the musculoskeletal system,
acute manifestations of liver damage, and other less common side effects. CPIC guidelines for
statin prescribing relate to the SLCO1B1 gene, the first gene whose importance in the
pharmacokinetics of this drug class has been recognized. To date, the influence of ABCG2 gene
polymorphisms has been established in the case of rosuvastatin and allopurinol dosing, where
lower and higher doses are recommended in individuals with the observed variant allele A,
respectively.
In this thesis, a case-control study was conducted to evaluate the association between adverse
effects and ABCG2 gene polymorphisms. Genotyping of ABCG2 c.421C>A was performed using
the TaqMan® DME method on a total of 223 participants receiving atorvastatin as part of therapy
for various cardiovascular and metabolic diseases. The participants were dichotomized (cases vs.
controls) based on whether they experienced side effects after taking atorvastatin or not. A
statistically significant association between the ABCG2 c.421C>A polymorphism and reported
side effects was demonstrated. Novel findings in the field of pharmacogenomics assist in assessing
the risk and benefits of prescribing atorvastatin, bringing us ones step further towards personalized
medicine.

• Keywords: atorvastatin; ABCG2; neželjeni učinci; polimorfizmi; genotipizacija; personalizirana medicina
• Keywords (english): atorvastatin; ABCG2; adverse effects; polymorphisms; genotyping; personalized medicine
• Language: croatian
• URN:NBN: urn:nbn:hr:163:386631
• Study programme: Title: Medical biochemistry; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: magistar/magistra medicinske biokemije (magistar/magistra medicinske biokemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2023-11-17 14:27:16