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4198 Heritable Variation in Lymphocyte-Related Traits and Risk of Down Syndrome Acute Lymphoblastic Leukemia: A Mendelian Randomization Study

Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemias: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Lymphoid Leukemias, ALL, genomics, pediatric, Diseases, immune mechanism, Lymphoid Malignancies, Biological Processes, Technology and Procedures, Study Population, Human, omics technologies
Monday, December 11, 2023, 6:00 PM-8:00 PM

Yunqi Li1*, Melissa A. Richard, PhD2*, Linda Kachuri, PhD, MPH3*, Yao Yu, PhD4*, Ching-Ju Ruu Hsu5*, Tracie C. Rosser, PhD6*, Elizabeth J. Leslie, PhD6*, Meenakshi Devidas, PhD, MBA7, Elizabeth A. Raetz, MD8, Mignon L. Loh, MD9, Stephen P. Hunger, MD10, Neetha Paul Eduthan, MS11*, Matthew D. Galbraith, PhD11*, Joaquin Espinosa, PhD11*, Jun J. J. Yang, PhD12, Stephanie L. Sherman, PhD13*, Chad D. Huff, PhD14*, Karen R. Rabin, MD, PhD15, Philip J. Lupo, PhD16* and Adam J. de Smith, PhD17

1Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, Kansas City, MO
2Department of Pediatrics, Baylor College of Medicine, Houston, TX
3Department of Epidemiology and Population Health, Stanford University School of Medicine, San Francisco, CA
4Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX
5Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX
6Emory University, Atlanta, GA
7St Jude Children's Research Hospital, Memphis, TN
8Department of Pediatrics, NYU Langone Health, New York, NY
9Ben Towne Center for Childhood Cancer Research, Seattle Children’s Hospital, Seattle, WA
10Childrens Hospital of Philadelphia, Philadelphia
11Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO
12Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, MEMPHIS, TN
13Department of Human Genetics, Emory University, Atlanta, GA
14Department of Epidemiology, UT MD Anderson Cancer Center, Houston, TX
15Department of Pediatrics, Baylor College of Medicine, Baylor College of Medicine TX Children's Cancer Center, Houston, TX
16Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX
17Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA

Introduction: The risk of developing acute lymphoblastic leukemia (ALL) is up to 30-fold higher in children with Down syndrome (DS). While trisomy 21 increases the risk of leukemia, only ~1% of children with DS develop ALL (DS-ALL), suggesting that additional modifying risk factors exist. A recent study in individuals without DS revealed that a genetic propensity for increased lymphocyte production was associated with an increased risk of childhood ALL. Additionally, a previous genome-wide association study (GWAS) of DS-ALL identified associations in genes involved in lymphoid development. Here, we investigated whether genetic variation in lymphocyte-related traits is associated with DS-ALL risk, with the hypothesis that a genetic predisposition for lymphocyte overproduction is associated with an increased risk of DS-ALL.

Methods: We performed Mendelian randomization (MR) analyses to investigate the potential causal relationship between variation in four lymphocyte-related traits – lymphocyte counts, the lymphocytes to monocytes ratio (LMR), the neutrophils to lymphocytes ratio (NLR), and the platelets to lymphocytes ratio (PLR) – and DS-ALL risk. Genetic variants associated with each lymphocyte-related trait (“exposure”) at P < 5x10-8 and their corresponding effect sizes and standard errors were obtained from GWAS of blood cell traits performed in 413,810 cancer-free individuals of European ancestry in the UK Biobank. A GWAS of DS-ALL (“outcome”) was carried out using germline whole-genome sequencing data from 222 DS-ALL cases and 1,010 individuals without ALL from DS research cohorts, limited to individuals of non-Hispanic White race/ethnicity. We examined consistency across multiple MR methods, including the inverse-variance weighted (IVW), weighted median (WM), MR robust adjusted profile score (RAPS), and MR pleiotropy residual sum and outlier (PRESSO) estimators.

Results: Among the lymphocyte-related traits, we found a significant association between LMR and DS-ALL risk that was consistent across MR estimators. Specifically, each 1-unit increase in LMR was associated with a 41%–53% decrease in ALL risk in children with DS (odds ratio [ORIVW] = 0.56; 95% CI: 0.35–0.90, p = 0.016; ORWM = 0.47; 95% CI: 0.21–1.04, p = 0.051; ORRAPS = 0.59; 95% CI: 0.36–0.97, p = 0.038; ORPRESSO = 0.55; 95% CI: 0.34–0.88, p = 0.014). There were no statistically significant associations between the remaining blood cell traits (lymphocyte count, PLR, and NLR) and DS-ALL risk, although increased lymphocyte counts conferred a modest increase in risk of DS-ALL (ORIVW=1.24, p=0.40).

Conclusions: We discovered that genetic predisposition to shifts in the ratio of lymphocytes relative to monocytes may be a novel risk factor for the development of DS-ALL, with a deficit of lymphocytes to monocytes conferring an increased risk of DS-ALL. This observed direction of effect contrasts with previous findings for ALL in the non-DS population, suggesting a distinct etiology of ALL in the context of DS that may be influenced by the profound effects of trisomy 21 on immune function. Replication of our findings in independent DS-ALL studies is underway, and analysis of polygenic risk scores for lymphocyte traits may further improve identification of children with a high risk of DS-ALL.

Disclosures: Raetz: Pfizer: Research Funding; Bristol Myer Squibb: Other: DSMC. Hunger: Novartis: Consultancy; Amgen: Current equity holder in publicly-traded company, Honoraria; Servier: Honoraria; Jazz: Honoraria. Yang: Takeda Pharmaceutical Company: Research Funding; AstraZeneca plc: Research Funding.

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