| Title: | Genetic determinants of blood-cell traits influence susceptibility to childhood acute lymphoblastic leukemia |
| Journal: | American Journal of Human Genetics |
| Published: | 31 Aug 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/34469753/ |
| DOI: | https://doi.org/10.1016/j.ajhg.2021.08.004 |
| URL: | http://www.cell.com/article/S0002929721003037/pdf |
Publication 4910
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Abstract
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Despite overlap between genetic risk loci for ALL and hematologic traits, the etiological relevance of dysregulated blood-cell homeostasis remains unclear. We investigated this question in a genome-wide association study (GWAS) of childhood ALL (2,666 affected individuals, 60,272 control individuals) and a multi-trait GWAS of nine blood-cell indices in the UK Biobank. We identified 3,000 blood-cell-trait-associated (p < 5.0 × 10-8) variants, explaining 4.0% to 23.9% of trait variation and including 115 loci associated with blood-cell ratios (LMR, lymphocyte-to-monocyte ratio; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio). ALL susceptibility was genetically correlated with lymphocyte counts (rg = 0.088, p = 4.0 × 10-4) and PLR (rg = -0.072, p = 0.0017). In Mendelian randomization analyses, genetically predicted increase in lymphocyte counts was associated with increased ALL risk (odds ratio [OR] = 1.16, p = 0.031) and strengthened after accounting for other cell types (OR = 1.43, p = 8.8 × 10-4). We observed positive associations with increasing LMR (OR = 1.22, p = 0.0017) and inverse effects for NLR (OR = 0.67, p = 3.1 × 10-4) and PLR (OR = 0.80, p = 0.002). Our study shows that a genetically induced shift toward higher lymphocyte counts, overall and in relation to monocytes, neutrophils, and platelets, confers an increased susceptibility to childhood ALL.</p>
9 Authors
- Linda Kachuri
- Soyoung Jeon
- Andrew T DeWan
- Catherine Metayer
- Xiaomei Ma
- John S Witte
- Charleston W K Chiang
- Joseph L Wiemels
- Adam J de Smith
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