Pharmacogenomics and Personalized Medicine (Aug 2020)
IL-6 −572C>G and CARD8 304T>A Genetic Polymorphisms are Associated with the Absolute Neutrophil Count in Patients with Hematological Malignancies Under Chemotherapy: An Application of Multilevel Models to a Preliminary Pharmacogenetic Study
Abstract
Matias F Martinez,1,2 Enzo Alveal,1 Tomas G Soto,1,3 Eva I Bustamante,4 Fernanda Ávila,5 Shrikant I Bangdiwala,6,7 Ivonne Flores,4 Claudia Benavides,4 Ricardo Morales,4 Nelson M Varela,1,2 Luis A Quiñones1,2 1Laboratory of Chemical Carcinogenesis and Pharmacogenetics (CQF), Department of Basic and Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago, Chile; 2Latin American Network for the Implementation and Validation of Pharmacogenomic Clinical Guidelines (RELIVAF-CYTED), Madrid, Spain; 3Departamento De Ciencias Básicas Santiago, Facultad De Ciencias, Universidad Santo Tomás, Santiago, Chile; 4Cancer Institute Arturo López Pérez Foundation, Santiago, Chile; 5Infectology Section, Medicine Department, Clinical Hospital of the University of Chile, Santiago, Chile; 6Population Health Research Institute, McMaster University, Hamilton, ON, Canada; 7Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: Luis A Quiñones; Nelson M VarelaLaboratory of Chemical Carcinogenesis and Pharmacogenetics (CQF), Department of Basic and Clinical Oncology (DBOC), Faculty of Medicine, University of Chile, Santiago, ChileTel +56-2-29770741; Tel +56-2-29770743Email [email protected]; [email protected]: Neutropenia is a common event in patients undergoing cytotoxic chemotherapy for the treatment of a hematological malignancy. Some polymorphisms, as IL-6 − 572C>G (rs1800796), IL-1β − 31 G>A (rs1143627), and CARD8 304T>A (rs2043211), in genes related to the inflammatory process, could affect the level of absolute neutrophil count (ANC) after chemotherapy. Since an efficient inflammatory process enhances neutrophil survival, we hypothesize that these polymorphisms are associated with ANC.Patients and Methods: We carried out a prospective cohort study in two hospitals in Santiago, Chile. The patients included were adults diagnosed with acute myeloblastic leukemia, acute lymphoblastic leukemia, or non-Hodgkin’s lymphoma, undergoing cytotoxic chemotherapy. We use a multilevel linear regression model to test our hypothesis. The best model was selected using the Akaike’s information criterion (AIC).Results: We analyzed 1726 hemograms and ANCs from 172 hospitalizations from 32 patients. The results show that CC and CG genotypes of IL-6 − 572 C>G polymorphism are associated with higher ANCs compared with the GG genotype (Ln (ANC) ∼ 0.81 IC95% 0.02– 1.55). Similarly, TT and AT genotypes of CARD8 304T>A polymorphism were related to higher ANCs compared with AA (Ln (ANC) ∼ 0.95 IC95% 0.02– 1.82). IL-1β genetic polymorphism had no statistically significant association with ANC.Conclusion: IL-6 rs1800796 − 572C>G and CARD8 rs2043211 304T>A polymorphisms are associated with the absolute neutrophil count in patients undergoing cytotoxic chemotherapy for treatment of hematological malignancies. Our findings might be useful to improve the safety of chemotherapy through predictive ANC models.Keywords: pharmacogenetics, neutropenia, hematological neoplasms, leukemia, lymphoma, interleukin-6, CARD8 protein
