Aim: To evaluate the association between candidate genetic polymorphisms and glucocorticoid-induced osteonecrosis in Arab children treated for acute lymphoblastic leukemia. Methods: A total of 189 children treated for acute lymphoblastic leukemia were genotyped for four SNPs with allele discrimination assays. The incidence and timing of radiologically confirmed symptomatic grade 4 osteonecrosis were classified based on the Ponte di Legno toxicity working group consensus definition. Results: Thirteen children developed grade 4 osteonecrosis (6.8%), of whom 12 received the intermediate/high-risk treatment protocol. GRIN3A variant allele carriers had to stop dexamethasone therapy earlier resulting in significantly shorter duration of dexamethasone treatment (mean [95% CI]: 75.17 [64.28-86.06] vs 85.90 [81.22-90.58] weeks; p = 0.054) and lower cumulative dose (mean [95% CI]: 1118.11 [954.94-1281.29] vs 1341.14 [1264.17-1418.11] mg/m2; p = 0.011). Conclusion: This is the first pharmacogenomics evaluation of the association between GRIN3A variants and glucocorticoid-induced osteonecrosis in Arab children.
Keywords: Arab; GRIN3A; acute lymphoblastic leukemia; children; dexamethasone; genetic polymorphisms; glucocorticoids; osteonecrosis; pharmacogenetics.
Lay abstract This study aimed at uncovering variants in the genetic material of Arab children, that might predispose them to develop a specific treatment-related adverse effect, during their therapy for acute lymphoblastic leukemia (a type of blood cancer). We looked at specific changes in the DNA of our patient cohort that might predispose them to develop treatment-induced osteonecrosis. Osteonecrosis is by definition a loss of blood flow to the bone tissue in one's body, causing the bone to die. Osteonecrosis may be caused by long-term exposure to steroid-based medication, among which dexamethasone. Dexamethasone a main component of the combination of chemotherapeutic agents used to treat acute lymphoblastic leukemia. Our findings suggested that children who had one of the variants detected in a specific location of DNA, the GRIN3A gene, were more likely to develop osteonecrosis earlier and had to stop dexamethasone earlier during therapy.