تأثير تعدد الأشكال الجيني ABCC2 على حدوث التسمم الكبدي في مرضى الثلاسيميا المعالجين بديفيراسيروكس في العراق

The Impact of ABCC2 Gene Polymorphism on Deferasirox Induced Hepatic Toxicity in Thalassemia Patients in Kerbala

Abstract
Background: β thalassemia is a hereditary disorder in which genetic mutations influencing the β-globin gene lead to reduced synthesis of functional β-globin protein, which results in an imbalance between α- and β-globin chains and ineffective erythropoiesis. severe anemia requiring life-long blood transfusions. In transfusion-dependent patients, regular transfusion leads to iron overload. the accumulation of iron results in progressive dysfunction of the heart, liver, and endocrine glands. Iron chelation in the transfusion-dependent thalassemia management is essential to prevent organ damage and to improve survival. Deferasirox is a once-daily oral iron chelator for therapy of blood transfusion-related iron overload in patients with thalassemia. Deferasirox is mainly metabolized in the liver by (glucuronidation) and eliminated through hepatobiliary excretion in feces. Deferasirox and metabolites are mostly excreted in bile through multidrug resistance protein 2 (MRP2, also known as ABCC2). Multidrug resistance protein 2 is a unidirectional efflux transporter. multidrug resistance protein 2 localizes to the apical membrane domain of polarized cells such as hepatocytes, renal proximal tubule cells, and intestinal epithelia, where it mediates unidirectional transport of substrates to the luminal side of the organ, therefore acting as an ATP-dependent efflux pump. Multidrug resistance protein 2 appears to have a role in the deferasirox anion’s elimination from the liver into the bile. As a result, people who have a genetic variation in the ABCC2 gene may be more likely to have hepatotoxicity. Multidrug resistance protein 2 may reduce the biliary elimination of deferasirox, according to ABCC2 polymorphisms.
Aim of study: the study aims to investigate the effect of ABCC2 gene polymorphism on hepatotoxicity by deferasirox in thalassemia patients.

Patients and methods: Cross sectional study with a total of 200 participants, both male and female, ranging in age from 14 to 61 years old.100 thalassemia patients and 100 healthy control to compare the parameters receiving deferasiox as monotherapy for at least three months were involved in the study. Five ml of blood was drawn from the vein of all subjects by using a disposable syringe and then divided into two parts: The first part (3ml) was placed in a gel tube which was used for the determination of biomarker levels. The remaining blood was saved in an EDTA tube and stored freezing at -40˚C until used for DNA extraction and molecular analysis.The allele specific polymerase chain reaction technique (pcr) was used to detect the (G>A, rs 8187710) and (C>T, rs 717620 single nucleotide polymorphism (SNP).
Results: The genotypes for ABCC2 (G>A, rs 8187710), the percentage of wild genotype (GG) in 100 thalassemia patients was 58%, the heterozygous type (GA) presented with percentage of 32%, and finally the homozygous type (AA) appeared with percentage of 10%. And forABCC2 (C>T, rs 717620), the percentage of wild genotype (CC) in 100 thalassemia patients was 56%, the heterozygous type (CT) presented with percentage of 31%, and finally the homozygous type (TT) appeared with percentage of 13%.The results were indicted that there was highly significant difference found between the measured biomarkers and ABCC2 (G> A, rs 8187710) genotype, (p =<0.001). The results were indicted that there was highly significant difference found between the measured biomarkers and ABCC2 (C>T, rs717620) genotype, (p =<0.001).
Conclusion: According to the results of the currents study, the genetic variation of ABCC2 gene is associated with hepatotoxicity in patients taking deferasirox and the wild group of patients are at risk of hepatotoxicity.