Uloga polimorfizma gena ABCG2, ABCB1 i SLCO1B1 u nastanku štetnih učinaka rosuvastatina

doctoral thesis

• Title (english): The role of polymorphism genes ABCG2, ABCB1 and SLCO1B1 in predicting the side effects of rosuvastatin
• Author: Ivana Radman
• Mentor: Iveta Šimić (mentor)
• Committee member: Srećko Marušić (predsjednik povjerenstva)
• Committee member: Lea Smirčić-Duvnjak (član povjerenstva)
• Committee member: Nada Božina (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Internal Medicine); Zagreb
• Defense date and country: 2024-10-04, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Pharmacology
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Internal Medicine
• Universal decimal classification (UDC): 615 - Pharmacology. Therapeutics. Toxicology

Abstract

UVOD: Inhibitori 3-hidroksi-metilglutaril-CoA (HMG-CoA) reduktaze, statini, učinkoviti su lijekovi za snižavanje kolesterola u krvi i prevenciji kardiovaskularnih događaja. U brojnim je izvješćima potvrđeno da statini imaju dobar sigurnosni profil, no ipak se u manjeg broja bolesnika javlja neka od nuspojava.

CILJ: Naša studija je imala za cilj procijeniti utjecaj genskih polimorfizama membranskih prijenosnika SLCO1B1, ABCB1 i ABCG2 te metaboličkih enzima CYP2C9 i CYP2C19 na pojavu miotoksičnosti i hepatotoksičnosti povezane s rosuvastatinom.

METODE: U razdoblju od dvije godine u studiju je konsekutivno uključeno 220 bolesnika na terapiji rosuvastatinom od kojih su 95 razvili nuspojave (88 bolesnika mišićne, 6 jetrene i 1 obje), a 125 bolesnika bez nuspojava su poslužili kao kontrola. U multivarijatnom regresijskom modelu analizirane su prediktorske varijable definirane u hipotezi i ciljevima (polimorfizmi gena SLCO1B1, ABCB1, ABCG2, CYP2C9, CYP2C19 te razina interakcije lijek-lijek-gen), a koje su u prethodnim bivarijatnim analizama pokazivale razinu značajnosti P<0,200.

REZULTATI: Naši rezultati povezuju varijante rizičnih gena s nastankom nuspojava rosuvastatina: SLCO1B1 c.521 C>A (OR=2,52; 95% CI=1,42-4,48; P=0,002); ABCG2 c.421C>A (OR=2,68; 95% CI=1,28-5,60; P=0,008) i CYP2C9*2*3 (OR=2,40; 95% CI=1,15-5,00; P=0,019). Naša studija je prva studija koja je pokazala da postoji značajan utjecaj varijantnih genotipova gena
CYP2C9 na pojavu miotoksičnosti rosuvastatina.

ZAKLJUČAK: Polimorfizam gubitka funkcije u genima SLCO1B1 c.521T>C, ABCG2 c.421C>A i CYP2C9*2*3 povezan je s nastankom nuspojava rosuvastatina.

Abstract (english)

INTRODUCTION: 3-hydroxy-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, statins, are effective drugs for blood cholesterol lowering and preventing of cardiovascular events. Numerous reports have confirmed that statins have a good safety profile, but some of the side effects occur in a small number of patients.

OBJECTIVE: Our study aimed to evaluate the influence of gene polymorphisms of membrane transporters SLCO1B1, ABCB1 and ABCG2 and metabolic enzymes CYP2C9 and CYP2C19 on the occurrence of rosuvastatin-related myotoxicity and hepatotoxicity.

METHODS: In a period of two years, 220 patients on rosuvastatin therapy were consecutively included in the study, of which 95 developed side effects (88 muscular, 6 hepatic, and 1 both), and 125 patients without side effects served as controls. In the multivariate regression model, the predictor variables defined by the hypotheses and goals (polymorphisms of the SLCO1B1, ABCB1, ABCG2, CYP2C9, CYP2C19 genes and the drug-drug-gene interaction) were analyzed, which in
previous bivariate analyzes showed a significance level of P<0.200.

RESULTS: Our results associate risk gene variants with the occurrence of rosuvastatin side effects: SLCO1B1 c.521 C>A (OR=2.52; 95% CI=1.42-4.48; P=0.002); ABCG2 c.421C>A (OR=2.68; 95% CI=1.28-5.60; P=0.008) and CYP2C9*2*3 (OR=2.40; 95% CI=1.15- 5.00; P=0.019). Our study is the first study that showed a significant influence of variant genotypes of the CYP2C9 gene on the occurrence of rosuvastatin myotoxicity.

CONCLUSION: Loss-of-function polymorphisms in SLCO1B1 c.521T>C, ABCG2 c.421C>A and CYP2C9*2*3 genes are associated with rosuvastatin side effects.

• Keywords: rosuvastatin; nuspojave; miotoksičnost; hepatotoksičnost; polimorfizam; ABCB1 c.3435C>T; ABCG2 c.421C>A; SLCO1B1 c.521T>C
• Keywords (english): rosuvastatin; side effects; myotoxicity; hepatotoxicity; polymorphism; ABCB1 c.3435C>T; ABCG2 c.421C>A; SLCO1B1 c.521T>C
• Language: croatian
• URN:NBN: urn:nbn:hr:105:359935
• Study programme: Title: Biomedicine and Health Sciences; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstvo (doktor/doktorica znanosti, područje biomedicine i zdravstvo)
• Type of resource: Text
• Extent: 100 str.
• File origin: Born digital
• Access conditions: Open access
• Created on: 2024-10-14 08:04:05