Interplay of IL6 and CRIM1 on thiopurine-induced neutropenia in leukemic patients with wild-type NUDT15 and TPMT

Background NUDT15 and TPMT variants are strong genetic determinants of thiopurine-induced hematological toxicity. Despite recent discovery of homozygous CRIM1 effect on thiopurine toxicity, many patients with wild-type NUDT15, TPMT , and CRIM1 still suffer from thiopurine toxicity, and therapeutic failure and relapse of acute lymphoblastic leukemia (ALL). Methods Novel PGx interactions associated with thiopurine toxicity in 320 pediatric ALL patients were investigated using whole-exome sequencing technology for the last-cycle 6-Mercaptopurine dose intensity percentage (DIP) tolerated by pediatric ALL patients. Results IL6 rs13306435 carriers ( N =19) exhibited significantly lower DIP (48.0±27.3%) than non-carriers ( N =209, 69.9±29.0%; p =0.0016 and 0.0028 by t -test and multiple linear regression, respectively). Of the 19 carriers, seven with both heterozygous IL6 rs13306435 and CRIM1 rs3821169 showed significantly decreased DIP (24.7±8.9%) than those with IL6 ( N =12, 61.6±25.1%) or CRIM1 ( N =94, 68.1±28.4%) variant only. Both IL6 and CRIM1 variants showed marked inter-ethnic variability. Significant interplay between IL6 and CRIM1 in thiopurine toxicity was suggested. GVB (Gene-wise Variant Burden)-based four-gene-interplay model showed the best odds ratio (8.06) and potential population impact (i.e., relative risk (5.73), population attributable fraction (58%), number needed to treat (3.67) and number needed to genotype (12.50)). Conclusions Interplay of IL6 rs13306435 and CRIM1 rs3821169 was suggested as independent and/or additive genetic determinant of thiopurine toxicity beyond NUDT15 and TPMT in pediatric ALL.