Multiple functional variants in the IL1RL1 region are pretransplant markers for risk of GVHD and infection deaths
Year: 2019
Type: article
Abstract: Graft-versus-host disease (GVHD) and infections are the 2 main causes of death without relapse after allogeneic hematopoietic cell transplantation (HCT). Elevated soluble serum simulation-2 (sST2), the product of IL1RL1 in plasma/serum post-HCT, is a validated GVHD biomarker. Hundreds of SNPs at 2q12.1 have been shown to be strongly associated with sST2 concentrations in healthy populations. We therefore hypothesized that the donor genetic variants in IL1RL1 correlate with sST2 protein levels associated with patient survival outcomes after HCT. We used DISCOVeRY-BMT (Determining the Influence of Susceptibility Conveying Variants Related to 1-Year Mortality after Blood and Marrow Transplantation), a genomic study of >3000 donor–recipient pairs, to inform our hypothesis. We first measured pre-HCT plasma/serum sST2 levels in a subset of DISCOVeRY-BMT donors (n = 757) and tested the association of donor sST2 levels with donor single nucleotide polymorphisms (SNPs) in the 2q12.1 region. Donor SNPs associated with sST2 levels were then tested for association with recipient death caused by acute GVHD (aGVHD)–, infection-, and transplant-related mortality in cohorts 1 and 2. Meta-analyses of cohorts 1 and 2 were performed using fixed-effects inverse variance weighting, and P values were corrected for multiple comparisons. Donor risk alleles in rs22441131 (Pmeta = .00026) and rs2310241 (Pmeta = .00033) increased the cumulative incidence of aGVHD death up to fourfold and were associated with high sST2 levels. Donor risk alleles at rs4851601 (Pmeta = 9.7 × 10−7), rs13019803 (Pmeta = 8.9 × 10−6), and rs13015714 (Pmeta = 5.3 × 10−4) increased cumulative incidence of infection death to almost sevenfold and were associated with low sST2 levels. These functional variants are biomarkers of infection or aGVHD death and could facilitate donor selection, prophylaxis, and a conditioning regimen to reduce post-HCT mortality.
Source: Blood Advances
Authors: Ezgi Karaesmen, Theresa Hahn, Alexander James Dile, Abbas A. Rizvi, Junke Wang, Tao Wang, Michael D. Haagenson, Leah Preus, Qianqian Zhu, Qian Liu, Li Yan, Song Liu, Christopher A. Haiman, Daniel Stram, Loreall Pooler, Xin Sheng, David Van Den Berg, Guy Brock, Amy Webb, Philip L. McCarthy, Marcelo C. Pasquini, Stephen R. Spellman, Stephanie J. Lee, Sophie Paczesny, Lara E. Sucheston-Campbell
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
Funders: U.S. Department of Defense, U.S. Department of Health and Human Services, Be The Match Foundation, Amgen, Bristol-Myers Squibb, Pfizer, Astellas Pharma US, AstraZeneca, Sanofi, WellPoint, Gilead Sciences, Health Research, Alexion Pharmaceuticals, Spectrum Pharmaceuticals, Celgene, HistoGenetics, Ohio State University, University of Minnesota, Novartis Pharmaceuticals Corporation, Medical College of Wisconsin, Otsuka America Pharmaceutical, Jazz Pharmaceuticals, Sunesis, Pelotonia, bluebird bio, Chimerix, Telomere Diagnostics, Janssen Scientific Affairs, Incyte, Otsuka America, Astellas Pharma, Otsuka Pharmaceutical, Swedish Orphan Biovitrum, Medac, National Institutes of Health, Health Resources and Services Administration, Genentech, Onyx Pharmaceuticals, U.S. Navy, Takeda Oncology, National Heart, Lung, and Blood Institute, Office of Naval Research, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: The OSU Center for Clinical and Translational Science: Advancing Today's Discoveries to Improve Health, G1384772222, G1626132361, G1769371581, Genetic susceptibility to unrelated donor stem cell transplant-related mortality, G2814340220, G3564874410, G3816434386, G3847019374, Translating Novel Drug-Targetable Biomarkers to Treat Graft versus Host Disease, G4298420724, G4373273904, G4930744573, Indiana University Center for Pediatric Pharmacology and Precision Medicine, G5214925129, Genetic susceptibility to acute lymphocytic and myeloid leukemia, G6771248800, Bridging Pediatric and Adult Biomarkers of Graft-Versus-Host-Disease, G6850693576, Blood & Marrow Transplant Clinical Trials Network Data Coordinating Center, G8649229721, G8876996369, A Data Resource for Blood and Marrow Transplants and Adoptive Cellular Therapy Research
OpenAlex ID: W2970016120