Genome Wide Interaction Analysis Identifies Expression Quantitative Trait Loci Associated With Reduced Survival After Reduced Intensity Conditioning Hla-Matched Unrelated Donor Allogeneic Hematopoietic Cell Transplant

Conditioning regimen intensity before allogeneic blood or marrow transplant (BMT) can be modified from myeloablative (MAC) to reduced intensity (RIC) to promote a graft versus tumor effect or minimize toxicity in older patients or those with comorbidities. However, the benefits of using RIC over MAC remain inconclusive as overall survival (OS) rates are similar. Prior genome wide association studies (GWAS) in solid tumor and autoimmune patients have shown that single nucleotide polymorphisms (SNPs) can affect patient response and toxicity after treatment with cyclophosphamide, busulfan and melphalan. Thus, it is possible SNPs may also affect patient response or toxicity to a given conditioning regimen or regimen intensity, guide regimen selection for a given patient or determine if disease recurrence is more likely for a given regimen or intensity. SNPs associated with patient response are significantly enriched for expression quantitative trait loci (eQTLs). eQTLs are genomic loci that explain significant proportions of inter-individual variability in mRNA levels in a given tissue for one or more genes. This suggests that selecting eQTLs a priori for the identification of genetic predictors for patient response could provide important insights into the likely function of identified SNPs. We hypothesized that recipient eQTL SNPs may interact with conditioning intensity to impact post-BMT OS and performed a genome wide interaction study (GWIS) to test the interaction of eQTL SNPs with conditioning intensity (MAC or RIC) and post-BMT OS in a large cohort of AML, MDS and ALL patients.