Genetic Variation in <i>ABCC4</i> and <i>CFTR</i> and Acute Pancreatitis during Treatment of Pediatric Acute Lymphoblastic Leukemia
Background: Acute pancreatitis (AP) is a serious, mechanistically not entirely resolved side effect of L-asparaginase-containing treatment for acute lymphoblastic leukemia (ALL). To find new candidate variations for AP, we conducted a genome-wide association study (GWAS). Methods: In all, 1,004,623...
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| Autores principales: | , , , , , , , , , , , , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/615d53304ff54ea3b6b7addc071c6c17 |
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| Sumario: | Background: Acute pancreatitis (AP) is a serious, mechanistically not entirely resolved side effect of L-asparaginase-containing treatment for acute lymphoblastic leukemia (ALL). To find new candidate variations for AP, we conducted a genome-wide association study (GWAS). Methods: In all, 1,004,623 single-nucleotide variants (SNVs) were analyzed in 51 pediatric ALL patients with AP (cases) and 1388 patients without AP (controls). Replication used independent patients. Results: The top-ranked SNV (rs4148513) was located within the <i>ABCC4</i> gene (odds ratio (OR) 84.1; <i>p</i> = 1.04 × 10<sup>−14</sup>). Independent replication of our 20 top SNVs was not supportive of initial results, partly because rare variants were neither present in cases nor present in controls. However, results of combined analysis (GWAS and replication cohorts) remained significant (e.g., rs4148513; OR = 47.2; <i>p</i> = 7.31 × 10<sup>−9</sup>). Subsequently, we sequenced the entire <i>ABCC4</i> gene and its close relative, the cystic fibrosis associated <i>CFTR</i> gene, a strong AP candidate gene, in 48 cases and 47 controls. Six AP-associated variants in <i>ABCC4</i> and one variant in <i>CFTR</i> were detected. Replication confirmed the six <i>ABCC4</i> variants but not the <i>CFTR</i> variant. Conclusions: Genetic variation within the <i>ABCC4</i> gene was associated with AP during the treatment of ALL. No association of AP with <i>CFTR</i> was observed. Larger international studies are necessary to more conclusively assess the risk of rare clinical phenotypes. |
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