STAMPEED: Whole Genome Association Analysis of Hematopoietic Cell Transplant (HCT) Outcomes

This retrospective cohort study was designed to identify single nucleotide polymorphisms (SNPs) that are associated with complications after allogeneic hematopoietic cell transplantation (HCT). Validated discoveries provide information to improve risk assessment, counseling and treatment planning and to direct future mechanistic studies of the genes and pathways that influence outcomes, thereby providing insight and rationale for new targeted therapies. The study was conducted with the use of 3 different approaches. (1) We used GWAS discovery and replication analyses to identify SNPs variants associated with outcomes after HCT. (2) We tested SNP alleles in HLA-matched sibling donors and recipients to determine whether mismatching in the recipient is associated with graft-versus-host disease (GVHD) or the risk of recurrent malignancy after HCT. Such associations would suggest that the peptide encoded by the SNP allele functions as a minor histocompatibility antigen. (3) We performed in silico candidate SNP studies to determine the validity of previously published results showing associations with outcomes after HCT. The study population represents a large cohort from the Fred Hutchinson Cancer Research Center and consists of 4,471 recipients and 4,628 donors containing 4,258 recipient-donor pairs. Recipients suffered from a hematologic malignancy or myelodysplastic syndrome and were treated in a highly structured clinical research environment with comprehensive monitoring and systematic data recording. We used proportional hazards analyses to test for associations with acute and chronic GVHD, acute kidney injury, gram-negative bacteremia, invasive fungal disease, CMV infection and disease, recurrent malignancy, death not attributable to recurrent malignancy, and death after recurrent or progressive malignancy.]]>
Patient eligibility criteria included: 1) a diagnosis of myelodysplastic syndrome (MDS) or hematologic malignancy, 2) first allogeneic transplant with bone marrow or growth factor-mobilized blood cells at the Fred Hutchinson Cancer Research Center with either myeloablative or nonmyeloablative pretransplant conditioning between 1990 and 2011, and 3) availability of blood cells or DNA from the donor or recipient (ideally both). Cord blood transplants were excluded because of small numbers.]]>
This GWAS-HCT effort began in 2006 with a successful response to RFA HL-06-012 (RO1 HL087690) and three years of support, which generated genotypes for ~3,000 patient and donor samples (FHCRC cohort I) using the Affymetrix 500K Human Gene chip. The project was continued with funding from RO1 HL105914 (01/01/2011-12/31/2014) which supported the genotyping of an additional ~6,000 recipient and donor samples (cohort II). Genotyping for cohort II was performed in three batches due to constraints on annual funding levels, one every 12 months (FY01-03), using two platforms. The Illumina 1M Quad was used for genotyping in FY01 and 02 (cohorts IIa and IIb), but due to discontinuation of the 1M array, the Illumina 2.5M array was utilized for the remaining FY03 samples (cohort IIc). The genotype data from the four batches have been integrated and harmonized, and the genotype of each subject at the full set of 35 million variants included in the 1000 Genomes Project has been determined by imputation.]]>