Utjecaj polimorfizama CYP2C19 i haplotipa CYP2C na kliničke ishode terapije klopidogrelom

master's thesis

• Title (english): Impact of CYP2C19 polymorphisms and CYP2C haplotype on the clinical outcomes of clopidogrel therapy
• Author: Karla Peruško
• Mentor: Dunja Rogić (mentor)
• Mentor: Lana Ganoci (mentor)
• Committee member: Dunja Rogić (predsjednik povjerenstva)
• Committee member: Lana Ganoci (član povjerenstva)
• Committee member: Iva Mucalo (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medical biochemistry and haematology); Zagreb
• Defense date and country: 2024-06-06, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Medical Biochemistry

Abstract

Zbog velike pojavnosti kardiovaskularnih bolesti, klopidogrel je često propisivan lijek. Kao i kod svakog lijeka važno je pogoditi optimalnu dozu kako pacijent ne bi bio poddoziran i tako imao povećan rizik od razvoja nuspojava poput moždanog udara i infarkta miokarda. No, isto tako može doći i to predoziranja i time rizika od krvarenja. Budući da je klopidogrel prolijek, kako bi ispoljio svoj učinak mora se aktivirati. Jedan od važnijih enzima koji sudjeluje u aktivaciji je enzim CYP2C19. Ovaj enzim je važan za metabolizam više od 30 lijekova te je njegova polimorfnost povezana s velikim interindividualnim varijacijama u terapijskom odgovoru. Novije studije pokazale su mogući utjecaj novog haplotipa CYP2C:TG na aktivnost enzima CYP2C19 i posljedično brzinu aktivacije klopidogrela. U ovom radu ispitivana je povezanost polimorfizama gena CYP2C19 (rs4244285 i rs12248560) i CYP2C (rs2860840 i rs 11188059) s nuspojavama krvarenja ili neučinkovitosti klopidogrela. Genotipizirano je 145 ispitanika koji su primali klopidogrel kao dio terapije različitih kardiovaskularnih i cerebrovaskularnih bolesti. Genotipizacija je učinjena metodom TaqMan®. Pokazana je statistički značajna povezanost između nefunkcionalnog alela (CYP2C19*2) i neučinkovitosti klopidogrela (p=0,043), što se slaže s mnogobrojnim studijama koje su to dokazale. Naspram tome, nije dokazana povezanost alela povećane funkcije CYP2C19*17 i novog haplotipa CYP2C:TG niti s neučinkovitošću, niti sa pojavom krvarenja. Potrebna su daljnja istraživanja na većem broju ispitanika kako bi se ispitala povezanost polimorfizma ovog enzima i haplotipa CYP2C:TG s varijacijama u terapijskom odgovoru na klopidogrel.

Abstract (english)

Due to the high occurrence of cardiovascular diseases, clopidogrel is a frequently prescribed drug. As with any drug, it is important to find the optimal dose so that the patient is not underdosed and thus has an increased risk of developing side effects such as stroke and myocardial infarction. However, there can also be an overdose and thus the risk of bleeding. Because clopidogrel is a prodrug, it must be activated in order to exert its effect. One of the most important enzymes involved in activation is the CYP2C19 enzyme. This enzyme is important for more than 30 drugs, and its polymorphisms are associated with large interindividual variations in therapeutic response. Recent studies have shown a possible influence of the new haplotype CYP2C:TG on CYP2C19 enzyme activity and consequently clopidogrel activation. This study investigated the association of CYP2C19 (rs4244285 and rs12248560) and CYP2C (rs2860840 and rs 11188059) gene polymorphisms with the side effect of bleeding or ineffectiveness of clopidogrel. 145 subjects who received clopidogrel as part of therapy for various cardiovascular and cerebrovascular diseases were genotyped. Genotyping was done using the TaqMan® method. A statistically significant association between the allele without function (CYP2C19*2) and the ineffectiveness of clopidogrel was shown (p=0.043), which is in-line with several studies that have proven this. In contrast, we were unable to prove the association of the allele of accelerated CYP2C19*17 function and the new haplotype CYP2C:TG neither with ineffectiveness nor with the occurrence of bleeding. Further research is needed on a larger number of subjects in order investigate the association of the polymorphism of this enzyme and the CYP2C:TG haplotype with variability in clopidogrel therapeutic response.

• Keywords: farmakogenetika; polimorfizam; citokrom P450; CYP2C19; CYP2C klaster; klopidogrel
• Keywords (english): pharmacogenetics; polymorphism; clopidogrel cytochrome P450; CYP2C19; CYP2C cluster
• Language: croatian
• URN:NBN: urn:nbn:hr:163:094478
• Study programme: Title: Medical biochemistry - integrated undergraduate and graduate - university study; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: sveučilišni magistar medicinske biokemije i laboratorijske medicine (sveučilišni magistar medicinske biokemije i laboratorijske medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2024-09-25 10:19:25