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Multiple functional variants in the IL1RL1 region are pretransplant markers for risk of GVHD and infection deaths. Blood Adv 2019 08 27;3(16):2512-2524

Date

08/29/2019

Pubmed ID

31455667

Pubmed Central ID

PMC6712530

DOI

10.1182/bloodadvances.2019000075

Scopus ID

2-s2.0-85072287558   2 Citations

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.

Author List

Karaesmen E, Hahn T, Dile AJ, Rizvi AA, Wang J, Wang T, Haagenson MD, Preus L, Zhu Q, Liu Q, Yan L, Liu S, Haiman CA, Stram D, Pooler L, Sheng X, Van Den Berg D, Brock G, Webb A, McCarthy PL, Pasquini MC, Spellman SR, Lee SJ, Paczesny S, Sucheston-Campbell LE

Authors

Marcelo C. Pasquini MD, MS Professor in the Medicine department at Medical College of Wisconsin
Tao Wang PhD Associate Professor in the Institute for Health and Equity department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adult
Biomarkers
Computational Biology
Female
Genetic Predisposition to Disease
Genetic Variation
Genotype
Graft vs Host Disease
Hematopoietic Stem Cell Transplantation
Humans
Interleukin-1 Receptor-Like 1 Protein
Linkage Disequilibrium
Male
Middle Aged
Molecular Sequence Annotation
Polymorphism, Single Nucleotide
Prognosis
Tissue Donors
Transplantation, Homologous
Young Adult
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a