Association Between NR3C1 Gene Polymorphisms and Toxicity Induced by Glucocorticoids Therapy in Saudi Children with Acute Lymphoblastic Leukemia

Background: Glucocorticoids (GCs) are key hormones used for the treatment of acute lymphoblastic leukemia (ALL) in children, but their cytotoxic effects are not well defined. The aim of this study was to evaluate the association between polymorphisms in NR3C1 encoding for protein involved in the GCs metabolism and its role in the development of ALL and the toxicity outcome, in terms of liver toxicity, glucose abnormality and infections, in ALL Saudi children. Methods: The following polymorphisms BCII rs41423247, ER22/23 EK rs6189 and rs6190 and N363S rs6195 in NR3C1 were analyzed in 70 children with ALL treated according to the ALL 2000 study protocol in comparison to 60 control subjects. Treatment toxicities and their association with genotypes were evaluated according to Common Toxicity Criteria (NCI-CTC). Results: This study demonstrated that the NR3C1 did not contribute to the development of childhood ALL. Homozygous ER22/23EK polymorphism was not found in both ALL patients and in control group whereas the heterozygous polymorphism was only observed in the control group (6.66%). The toxicology data in this study showed a significant difference between ALL patients carrying N363S polymorphism and wild type (40% and 6.51% respectively, P= 0.009) and a high-risk factor in the toxicity of glucose abnormality (OR=10.167; 1.302-79.339). BCII shows increased risk factors towards the liver toxicity (OR=2.667; 0.526-7.330) as well as the glucose abnormality (OR=7.5; 1.039-54.116). Conclusion: This study suggested that the polymorphisms in NR3C1 were not associated with the development of ALL in children. N363S polymorphism was sensitive to glucocorticoids and it may contribute to the glucose abnormality for these patients.