Effect of NK cell receptor genetic variation on allogeneic stem cell transplantation outcome and in vitro NK cell cytotoxicity

Abstract Natural killer (NK) cells recognize malignant cells via their cell surface receptors and may kill them. Killer cell immunoglobulin-like receptors (KIR) genotypes of donors have been reported to adjust the risk of relapse after allogeneic stem cell transplantation (HSCT), particularly in patients with acute myeloid leukemia. To test whether non-KIR NK cell receptors have a similar effect, we screened 796 genetic polymorphisms in 14 non-KIR NK cell receptor genes for their associations with relapse and graft-versus-host disease (GVHD) after HSCT in 1,491 HSCT donors (from Finland, the UK, Spain, and Poland), divided into a discovery and replication cohort. Two polymorphisms flanking the gene CD226 (DNAM-1) and two flanking FCGR3A (CD16a) were associated with a nominally reduced risk for relapse and chronic GVHD, respectively. These associations could not be confirmed in the replication cohort of 446 HSCT donors from the same populations. The blood donor NK cells carrying these nominally protective genetic alleles had a higher in vitro killing activity than the noncarriers, potentially indicating functional effects. Taken together, these results show no robust effects of genetic variation in tested non-KIR NK cell receptors on the outcome of HSCT.