|
|||||
|
|
Genetic variation associated with chromosomal aberration frequency: A genome-wide association study |
|
| Authors: | Yasmeen Niazi Hauke Thomsen Bozena Smolkova Ludmila Vodickova Sona Vodenkova Michal Kroupa Veronika Vymetalkova Alena Kazimirova Magdalena Barancokova Katarina Volkovova Marta Staruchova Per Hoffmann Markus M. Nöthen Maria Dušinská Ludovit Musak Pavel Vodicka Kari Hemminki Asta Försti |
| Affiliation: | 1. Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany;2. Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovakia;3. Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic;4. Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic Department of Medical Genetics, Third Faculty of Medicine, Charles University, Prague, Czech Republic;5. Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic;6. Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic;7. Department of Biology, Faculty of Medicine, Slovak Medical University, Limbova 12, 833 03 Bratislava, Slovakia;8. Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany Division of Medical Genetics, Department of Biomedicine, University of Basel, 4003 Basel, Switzerland;9. Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany Department of Genomics, Life & Brain Center, University of Bonn, D-53127 Bonn, Germany;10. Health Effects Laboratory, Department of Environmental Chemistry, NILU-Norwegian Institute for Air Research, Instituttveien 18, 2007 Kjeller, Norway;11. Clinic of Occupational Medicine and Toxicology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava and University Hospital Martin, Kollarova 2, 03601 Martin, Slovakia;12. Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany Center of Primary Health Care Research, Clinical Research Center, Lund University, 20502 Malmö, Sweden |
| Abstract: | Chromosomal aberrations (CAs) in human peripheral blood lymphocytes (PBL) measured with the conventional cytogenetic assay have been used for human biomonitoring of genotoxic exposure for decades. CA frequency in peripheral blood is a marker of cancer susceptibility. Previous studies have shown associations between genetic variants in metabolic pathway, DNA repair and major mitotic checkpoint genes and CAs. We conducted a genome-wide association study on 576 individuals from the Czech Republic and Slovakia followed by a replication in two different sample sets of 482 (replication 1) and 1288 (replication 2) samples. To have a broad look at the genetic susceptibility associated with CA frequency, the sample sets composed of individuals either differentially exposed to smoking, occupational/environmental hazards, or they were untreated cancer patients. Phenotypes were divided into chromosome- and chromatid-type aberrations (CSAs and CTAs, respectively) and total chromosomal aberrations (CAtot). The arbitrary cutoff point between individuals with high and low CA frequency was 2% for CAtot and 1% for CSA and CTA. The data were analyzed using age, sex, occupation/cancer and smoking history as covariates. Altogether 11 loci reached the P-value of 10−5 in the GWAS. Replication 1 supported the association of rs1383997 (8q13.3) and rs2824215 (21q21.1) in CAtot and rs983889 (5p15.1) in CTA analysis. These loci were found to be associated with genes involved in mitosis, response to environmental and chemical factors and genes involved in syndromes linked to chromosomal abnormalities. Identification of new genetic variants for the frequency of CAs offers prediction tools for cancer risk in future. Environ. Mol. Mutagen. 60:17–28, 2019. © 2018 Wiley Periodicals, Inc. |
| Keywords: | chromosome-type aberrations chromatid-type aberrations GWAS single-nucleotide polymorphism |