Interaction between maternal killer immunoglobulin-like receptors and offspring HLAs and susceptibility of childhood ALL

Abstract

Acute lymphoblastic leukemia (ALL) in children is associated with a distinct neonatal cytokine profile. The basis of this neonatal immune phenotype is unknown but potentially related to maternal-fetal immune receptor interactions. We conducted a case-control study of 226 case child-mother pairs and 404 control child-mother pairs to evaluate the role of interaction between HLA genotypes in the offspring and maternal killer immunoglobulin-like receptor (KIR) genotypes in the etiology of childhood ALL, while considering potential mediation by neonatal cytokines and the immune-modulating enzyme arginase-II (ARG-II). We observed different associations between offspring HLA-maternal KIR activating profiles and the risk of ALL in different predicted genetic ancestry groups. For instance, in Latino subjects who experience the highest risk of childhood leukemia, activating profiles were significantly associated with a lower risk of childhood ALL (odds ratio [OR] = 0.59; 95% confidence interval [CI], 0.49-0.71) and a higher level of ARG-II at birth (coefficient = 0.13; 95% CI, 0.04-0.22). HLA-KIR activating profiles were also associated with a lower risk of ALL in non-Latino Asians (OR = 0.63; 95% CI, 0.38-1.01), although they had a lower tumor necrosis factor-α level (coefficient = -0.27; 95% CI, -0.49 to -0.06). Among non-Latino White subjects, no significant association was observed between offspring HLA-maternal KIR interaction and ALL risk or cytokine levels. The current study reports the association between offspring HLA-maternal KIR interaction and the development of childhood ALL with variation by predicted genetic ancestry. We also observed some associations between activating profiles and immune factors related to cytokine control; however, cytokines did not demonstrate causal mediation of the activating profiles on ALL risk.

Graphical abstract

Figure 1.

Linear regression model assessing the association between VSN normalized cytokines and activation/inhibition scores. Unadjusted model: model with cytokines as the outcome, activation, and inhibition scores as predictors. Full model: model with cytokines as the outcome, activation, and inhibition scores as predictors, adjusting for age at cytokine collection, birth weight, and gestation week. Cytokines were normalized on case/control status, birth year, protein, batch, and plate spot. *Coefficient statistically significantly different from the null with P < .05. (A) Association between VSN normalized cytokines and activation/inhibition scores among Latino subjects. (B) Association between VSN normalized cytokines and activation/inhibition scores among non-Latino White subjects. (C) Association between VSN normalized cytokines and activation/inhibition scores among non-Latino Asian subjects. INF, interferon; SE, standard error; VEGF, vascular endothelial growth factor.