Multiple Functional Donor Polymorphisms in IL1RL1 region Associate with Death Due to GvHD or Infection after Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation (HCT) for AML and MDS

The last two authors contributed equallyElevated soluble Stimulation-2 (sST2), the decoy IL-33 receptor, in plasma/serum post-HSCT is a biomarker for death due to GvHD. ST2 is the product of IL1RL1 (2q12.1) and this ~.5Mb region contains >300 single nucleotide polymorphisms (SNPs) significantly associated (P<5x10-8) with plasma levels of sST2 in healthy participants from the Framingham Heart Study (FHS). Many of these SNPs are genome-wide associated with infection-related phenotypes, including asthma, Crohn's disease, ulcerative colitis and celiac disease. Given these relationships, we analyzed the association of ST2 SNPs with death due to GvHD or infection within one year after HLA-matched unrelated donor HCT for AML or MDS to identify functional SNPs that could potentially aid in donor selection.We measured plasma/serum sST2 levels in pre-HCT samples in a subset of AML and MDS patients (n=759) and their donors (n=757) from DISCOVeRY-BMT, a GWAS of >3,000 recipient-unrelated donor pairs reported to the CIBMTR between 2000-2011. After quality control (info>.8, MAF>.005), 3613 SNPs in the IL1RL1 region were tested for association with sST2 levels; 1541 donor SNPs associated with sST2 levels (P<.05), which validated 99% of the FHS sST2 SNP associations. To assess the contribution of these donor variants to post-HCT survival, we constructed competing risk models with clinical variables using stepwise Akaike Information Criterion (AIC), then tested each of the 1...
Source: Blood - Category: Hematology Authors: Tags: 732. Clinical Allogeneic Transplantation: Results: Optimizing Outcomes After Allogeneic Transplantation Source Type: research