Abstract 2002: A genome-wide association study identifies novel sepsis risk loci in children with Down syndrome-associated acute lymphoblastic leukemia: A report from the Children’s Oncology Group
Authors: Richard Melissa A. , Devidas Meenakshi , Yang Wenjian , Woodhouse John P. , Rodriguez Vilmarie , Hitzler Johann K. , Schore Reuven J. , Angiolillo Anne L. , Burke Michael J. , Salzer Wanda L. , Raetz Elizabeth A. , Loh Mignon L. , Hunger Stephen P. , Yang Jun J. , Lupo Philip J. , Rabin Karen R. 
Published: June 2022

Abstract
Background: Children with Down syndrome (DS) have an increased risk of acute lymphoblastic leukemia (ALL) and are more likely to experience morbidity and mortality from infectious toxicities during treatment compared to those without DS. We sought to characterize genetic risk factors for sepsis among individuals with DS-ALL.
Methods: We performed a germline genome-wide association (GWAS) study for sepsis among 264 subjects with DS-ALL treated on Children’s Oncology Group (COG) protocols AALL0932 (N=181) and AALL1131 (N=83), for newly-diagnosed standard risk and high risk B-ALL, respectively. Sepsis was defined using Common Terminology Criteria for Adverse Events (v4.0), with a microbiologically confirmed grade 4 or 5 sepsis event reported during any phase of treatment to define the case and comparison groups. Germline genotyping on the Affymetrix SNP 6.0 or Illumina Omni 2.5Exome arrays was imputed to the Haplotype Reference Consortium panel and filtered for quality control. Logistic regression models were used to compare individuals with DS-ALL who experienced sepsis to those who never developed sepsis during treatment. Models were adjusted for principal components of population structure and COG protocol. Analyses included autosomal variants with a minor allele frequency &gt;1% and excluded chromosome 21.
Results: We identified 29 individuals (10.9%) with DS-ALL who developed one or more sepsis events during treatment. In genome-wide analyses, we observed 52 variants in eight genomic loci associated with sepsis at P&lt;10-5 among individuals with DS-ALL. Our top signal was rs77917748 (P=6.02x10-7), an intronic variant in a regulatory region of TMEM163, a protein that is essential for zinc homeostasis. Additionally, we identified a strong linkage signal at rs56288508 on chr6p21.2 (P=5.29x10-6). According to data from the Genotype-Tissue Expression (GTEx) project, this locus is associated with whole blood expression of ZFAND3, a zinc finger protein and transcriptional regulator. Additionally, this variant is associated with intestinal infections (P=0.012) in the UK Biobank. Finally, a third variant we identified in our GWAS is on chr6q24.2 (P=4.33x10-6) and shows strong linkage in GTEx with peripheral blood mononuclear cell expression of APOBEC3A, a viral deaminase that lacks zinc binding activity. Notably, this variant is associated with respiratory failure (P=0.0099) in the UK Biobank.
Conclusion: We identified evidence of genetic associations for sepsis risk in DS-ALL. These findings suggest zinc homeostasis may be an important factor mediating risk of sepsis during treatment of individuals with DS-ALL. Confirmatory studies and validation in additional cohorts are ongoing.
Citation Format: Melissa A. Richard, Meenakshi Devidas, Wenjian Yang, John P. Woodhouse, Vilmarie Rodriguez, Johann K. Hitzler, Reuven J. Schore, Anne L. Angiolillo, Michael J. Burke, Wanda L. Salzer, Elizabeth A. Raetz, Mignon L. Loh, Stephen P. Hunger, Jun J. Yang, Philip J. Lupo, Karen R. Rabin. A genome-wide association study identifies novel sepsis risk loci in children with Down syndrome-associated acute lymphoblastic leukemia: A report from the Children’s Oncology Group [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2002.