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:	Thies Bartram, Peter Schütte, Anja Möricke, Richard S. Houlston, Eva Ellinghaus, Martin Zimmermann, Anke Bergmann, Britt-Sabina Löscher, Norman Klein, Laura Hinze, Stefanie V. Junk, Michael Forster, Claus R. Bartram, Rolf Köhler, Andre Franke, Martin Schrappe, Christian P. Kratz, Gunnar Cario, Martin Stanulla
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	acute lymphoblastic leukemia L-asparaginase acute pancreatitis polymorphism SNV <i>ABCC4</i> Medicine R
Acceso en línea:	https://doaj.org/article/615d53304ff54ea3b6b7addc071c6c17
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spelling	oai:doaj.org-article:615d53304ff54ea3b6b7addc071c6c172021-11-11T17:29:26ZGenetic Variation in <i>ABCC4</i> and <i>CFTR</i> and Acute Pancreatitis during Treatment of Pediatric Acute Lymphoblastic Leukemia10.3390/jcm102148152077-0383https://doaj.org/article/615d53304ff54ea3b6b7addc071c6c172021-10-01T00:00:00Zhttps://www.mdpi.com/2077-0383/10/21/4815https://doaj.org/toc/2077-0383Background: 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.Thies BartramPeter SchütteAnja MörickeRichard S. HoulstonEva EllinghausMartin ZimmermannAnke BergmannBritt-Sabina LöscherNorman KleinLaura HinzeStefanie V. JunkMichael ForsterClaus R. BartramRolf KöhlerAndre FrankeMartin SchrappeChristian P. KratzGunnar CarioMartin StanullaMDPI AGarticleacute lymphoblastic leukemiaL-asparaginaseacute pancreatitispolymorphismSNV<i>ABCC4</i>MedicineRENJournal of Clinical Medicine, Vol 10, Iss 4815, p 4815 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	acute lymphoblastic leukemia L-asparaginase acute pancreatitis polymorphism SNV <i>ABCC4</i> Medicine R
spellingShingle	acute lymphoblastic leukemia L-asparaginase acute pancreatitis polymorphism SNV <i>ABCC4</i> Medicine R Thies Bartram Peter Schütte Anja Möricke Richard S. Houlston Eva Ellinghaus Martin Zimmermann Anke Bergmann Britt-Sabina Löscher Norman Klein Laura Hinze Stefanie V. Junk Michael Forster Claus R. Bartram Rolf Köhler Andre Franke Martin Schrappe Christian P. Kratz Gunnar Cario Martin Stanulla Genetic Variation in <i>ABCC4</i> and <i>CFTR</i> and Acute Pancreatitis during Treatment of Pediatric Acute Lymphoblastic Leukemia
description	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.
format	article
author	Thies Bartram Peter Schütte Anja Möricke Richard S. Houlston Eva Ellinghaus Martin Zimmermann Anke Bergmann Britt-Sabina Löscher Norman Klein Laura Hinze Stefanie V. Junk Michael Forster Claus R. Bartram Rolf Köhler Andre Franke Martin Schrappe Christian P. Kratz Gunnar Cario Martin Stanulla
author_facet	Thies Bartram Peter Schütte Anja Möricke Richard S. Houlston Eva Ellinghaus Martin Zimmermann Anke Bergmann Britt-Sabina Löscher Norman Klein Laura Hinze Stefanie V. Junk Michael Forster Claus R. Bartram Rolf Köhler Andre Franke Martin Schrappe Christian P. Kratz Gunnar Cario Martin Stanulla
author_sort	Thies Bartram
title	Genetic Variation in <i>ABCC4</i> and <i>CFTR</i> and Acute Pancreatitis during Treatment of Pediatric Acute Lymphoblastic Leukemia
title_short	Genetic Variation in <i>ABCC4</i> and <i>CFTR</i> and Acute Pancreatitis during Treatment of Pediatric Acute Lymphoblastic Leukemia
title_full	Genetic Variation in <i>ABCC4</i> and <i>CFTR</i> and Acute Pancreatitis during Treatment of Pediatric Acute Lymphoblastic Leukemia
title_fullStr	Genetic Variation in <i>ABCC4</i> and <i>CFTR</i> and Acute Pancreatitis during Treatment of Pediatric Acute Lymphoblastic Leukemia
title_full_unstemmed	Genetic Variation in <i>ABCC4</i> and <i>CFTR</i> and Acute Pancreatitis during Treatment of Pediatric Acute Lymphoblastic Leukemia
title_sort	genetic variation in <i>abcc4</i> and <i>cftr</i> and acute pancreatitis during treatment of pediatric acute lymphoblastic leukemia
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/615d53304ff54ea3b6b7addc071c6c17
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Genetic Variation in <i>ABCC4</i> and <i>CFTR</i> and Acute Pancreatitis during Treatment of Pediatric Acute Lymphoblastic Leukemia

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