Abstract

The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr = 0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr = 0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.

Details

Title
Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium
Author
Sánchez-Maldonado, J M 1 ; Campa, D 2 ; Springer, J 3 ; Badiola, J 4   VIAFID ORCID Logo  ; Niazi, Y 5 ; Moñiz-Díez, A 1 ; Hernández-Mohedo, F 4 ; González-Sierra, P 4   VIAFID ORCID Logo  ; Ter, Horst R 6 ; Macauda, A 7 ; Brezina, S 8   VIAFID ORCID Logo  ; Cunha, C 9 ; Lackner, M 10 ; López-Nevot, M A 11 ; Fianchi, L 12 ; Pagano, L 13   VIAFID ORCID Logo  ; López-Fernández, E 4 ; Potenza, L 13 ; Luppi, M 13 ; Moratalla, L 4 ; Rodríguez-Sevilla, J J 14 ; Fonseca, J E 15 ; Tormo, M 16 ; Solano, C 16 ; Clavero, E 17 ; Romero, A 17 ; Li Y 18 ; Lass-Flörl, C 10 ; Einsele, H 3 ; Vazquez, L 19 ; Loeffler, J 3 ; Hemminki, K 20 ; Carvalho, A 9   VIAFID ORCID Logo  ; Netea, M G 21 ; Gsur, A 8   VIAFID ORCID Logo  ; Dumontet, C 22 ; Canzian, F 23 ; Försti, A 5 ; Jurado, M 1 ; Sainz, J 24   VIAFID ORCID Logo 

1  Centre for Genomics and Oncological Research: Pfizer / University of Granada / Andalusian Regional Government, PTS Granada, Genomic Oncology Area, GENYO, Granada, Spain (GRID:grid.4489.1) (ISNI:0000000121678994); Virgen de las Nieves University Hospital, Hematology department, Granada, Spain (GRID:grid.411380.f) (ISNI:0000 0000 8771 3783); Complejo Hospitales Universitarios de Granada/Universidad de Granada, Instituto de Investigación Biosanitaria de Granada (ibs.Granada), Granada, Spain (GRID:grid.4489.1) (ISNI:0000000121678994) 
2  University of Pisa, Department of Genetics, Pisa, Italy (GRID:grid.5395.a) (ISNI:0000 0004 1757 3729) 
3  Universitätsklinikum Würzburg, Medizinische Klinik II, Würzburg, Germany (GRID:grid.411760.5) (ISNI:0000 0001 1378 7891) 
4  Virgen de las Nieves University Hospital, Hematology department, Granada, Spain (GRID:grid.411380.f) (ISNI:0000 0000 8771 3783); Complejo Hospitales Universitarios de Granada/Universidad de Granada, Instituto de Investigación Biosanitaria de Granada (ibs.Granada), Granada, Spain (GRID:grid.4489.1) (ISNI:0000000121678994) 
5  German Cancer Research Center (DKFZ), Division of Molecular Genetic Epidemiology, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany (GRID:grid.7497.d); German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Division of Pediatric Neurooncology, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584) 
6  Radboud University Nijmegen Medical Center, Department of Internal Medicine and Radboud Center for Infectious Diseases, Nijmegen, The Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382) 
7  University of Pisa, Department of Genetics, Pisa, Italy (GRID:grid.5395.a) (ISNI:0000 0004 1757 3729); German Cancer Research Center (DKFZ), Genomic Epidemiology Group, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584) 
8  Medical University of Vienna, Institute of Cancer Research, Department of Medicine I, Vienna, Austria (GRID:grid.22937.3d) (ISNI:0000 0000 9259 8492) 
9  University of Minho, Life and Health Sciences Research Institute (ICVS), School of Medicine, Braga, Portugal (GRID:grid.10328.38) (ISNI:0000 0001 2159 175X); ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Guimarães, Portugal (GRID:grid.10328.38) (ISNI:0000 0001 2159 175X) 
10  Medical University of Innsbruck, Division of Hygiene and Medical Microbiology, Innsbruck, Austria (GRID:grid.5361.1) (ISNI:0000 0000 8853 2677) 
11  Virgen de las Nieves University Hospital, Immunology department, Granada, Spain (GRID:grid.411380.f) (ISNI:0000 0000 8771 3783) 
12  Università Cattolica del S. Cuore, Istituto di Ematologia, Rome, Italy (GRID:grid.8142.f) (ISNI:0000 0001 0941 3192) 
13  University of Modena and Reggio Emilia, AOU Policlinico, Department of Medical and Surgical Sciences, Modena, Italy (GRID:grid.7548.e) (ISNI:0000000121697570) 
14  Hospital del Mar, Hematology department, Barcelona, Spain (GRID:grid.411142.3) (ISNI:0000 0004 1767 8811) 
15  Hospital de Santa Maria, CHLN, Rheumatology and Metabolic Bone Diseases department, Lisbon, Portugal (GRID:grid.411265.5) (ISNI:0000 0001 2295 9747); University of Lisbon, Lisbon Academic Medical Center, Rheumatology Research Unit, Instituto de Medicina Molecular, Faculty of Medicine, Lisbon, Portugal (GRID:grid.9983.b) (ISNI:0000 0001 2181 4263) 
16  University of Valencia, Hematology department, Hospital Clinico Universitario-INCLIVA, Valencia, Spain (GRID:grid.5338.d) (ISNI:0000 0001 2173 938X) 
17  Virgen de las Nieves University Hospital, Hematology department, Granada, Spain (GRID:grid.411380.f) (ISNI:0000 0000 8771 3783) 
18  Radboud University Nijmegen Medical Center, Department of Internal Medicine and Radboud Center for Infectious Diseases, Nijmegen, The Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382); joint ventures between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Centre for Individualised Infection Medicine (CiiM) & TWINCORE, Hannover, Germany (GRID:grid.10417.33) 
19  University Hospital of Salamanca, Hematology department, Salamanca, Spain (GRID:grid.411258.b) 
20  German Cancer Research Center (DKFZ), Division of Molecular Genetic Epidemiology, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); German Cancer Research Centre (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); Charles University in Prague, Faculty of Medicine and Biomedical Center in Pilsen, Pilsen, Czech Republic (GRID:grid.4491.8) (ISNI:0000 0004 1937 116X) 
21  Radboud University Nijmegen Medical Center, Department of Internal Medicine and Radboud Center for Infectious Diseases, Nijmegen, The Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382); University of Bonn, Department for Immunology & Metabolism, Life and Medical Sciences Institute (LIMES), Bonn, Germany (GRID:grid.10388.32) (ISNI:0000 0001 2240 3300) 
22  Université Claude Bernard Lyon I, Lyon, France (GRID:grid.7849.2) (ISNI:0000 0001 2150 7757) 
23  German Cancer Research Center (DKFZ), Genomic Epidemiology Group, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584) 
24  Centre for Genomics and Oncological Research: Pfizer / University of Granada / Andalusian Regional Government, PTS Granada, Genomic Oncology Area, GENYO, Granada, Spain (GRID:grid.4489.1) (ISNI:0000000121678994); Virgen de las Nieves University Hospital, Hematology department, Granada, Spain (GRID:grid.411380.f) (ISNI:0000 0000 8771 3783); Complejo Hospitales Universitarios de Granada/Universidad de Granada, Instituto de Investigación Biosanitaria de Granada (ibs.Granada), Granada, Spain (GRID:grid.4489.1) (ISNI:0000000121678994); University of Granada, Department of Medicine, Granada, Spain (GRID:grid.4489.1) (ISNI:0000000121678994) 
Publication year
2020
Publication date
Jul 2020
Publisher
Springer Nature B.V.
e-ISSN
20445385
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41408-020-00341-y
ProQuest document ID
2424342576
Copyright
© The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.