Blood. 2018 Apr 2. pii: blood-2017-11-817973. doi: 10.1182/blood-2017-11-817973. [Epub ahead of print]
Exomechip Analyses Identify Genes Affecting Mortality after HLA-Matched Unrelated Donor Blood and Marrow Transplantation.
Zhu Q1, Yan L2, Liu Q2, Zhang C3, Wei L2, Hu Q2, Preus L4, Clay-Gilmour AI5, Onel K6, Stram DO7, Pooler L7, Sheng X8, Haiman CA7, Zhu X9, Spellman SR10, Pasquini M9, McCarthy PL11, Liu S2, Hahn T11, Sucheston-Campbell LE12.
Abstract
While
survival outcomes have significantly improved, up to 40% of patients
die within 1-year after HLA-matched unrelated donor (URD) blood and
marrow transplant (BMT). To identify non-HLA genetic contributors to
mortality after BMT, we performed the first exome-wide association study
in the DISCOVeRY-BMT cohorts using the Illumina HumanExome BeadChip.
This study includes 2,473 AML, ALL, MDS patients and 2,221 10/10 HLA
matched donors treated from 2000-2011. Single variant and gene-level
analyses were performed with overall survival (OS), transplant-related
mortality (TRM), and disease-related mortality (DRM). Genotype
mismatches between recipients and donors in a rare nonsynonymous variant
of a testis expressed gene TEX38 significantly increased risk of
TRM, which was more dramatic when either the recipient or donor was
female. Using SKAT-O test to evaluate gene-level effects, variant
genotypes of OR51D1 in recipients were significantly associated with OS and TRM. In donors, four (ALPP, EMID1, SLC44A5, LRP1), one (HHAT), and two (LYZL4, NT5E)
genes were significantly associated with OS, TRM, and DRM,
respectively. Inspection of NT5E crystal structures shows four of the
associated variants impact the enzyme structure and likely decrease the
enzyme's catalytic efficiency. Further confirmation of these findings
and additional functional studies may provide individualized risk
prediction and prognosis, as well as alternative donor selection
strategies.
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