TY - JOUR
T1 - Multiple functional variants in the IL1RL1 region are pretransplant markers for risk of GVHD and infection deaths
AU - Karaesmen, Ezgi
AU - Hahn, Theresa
AU - Dile, Alexander James
AU - Rizvi, Abbas A.
AU - Wang, Junke
AU - Wang, Tao
AU - Haagenson, Michael D.
AU - Preus, Leah
AU - Zhu, Qianqian
AU - Liu, Qian
AU - Yan, Li
AU - Liu, Song
AU - Haiman, Christopher A.
AU - Stram, Daniel
AU - Pooler, Loreall
AU - Sheng, Xin
AU - Van Den Berg, David
AU - Brock, Guy
AU - Webb, Amy
AU - McCarthy, Philip L.
AU - Pasquini, Marcelo C.
AU - Spellman, Stephen R.
AU - Lee, Stephanie J.
AU - Paczesny, Sophie
AU - Sucheston-Campbell, Lara E.
N1 - Publisher Copyright:
© 2019 by The American Society of Hematology.
PY - 2019/8/27
Y1 - 2019/8/27
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85072287558
U2 - 10.1182/bloodadvances.2019000075
DO - 10.1182/bloodadvances.2019000075
M3 - Article
C2 - 31455667
AN - SCOPUS:85072287558
SN - 2473-9529
VL - 3
SP - 2512
EP - 2524
JO - Blood Advances
JF - Blood Advances
IS - 16
ER -