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©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
Polymorphisms of microRNA target genes IL12B, INSR, CCND1 and IL10 in gastric cancer
Vytenis Petkevicius, Violeta Salteniene, Simonas Juzenas, Thomas Wex, Alexander Link, Marcis Leja, Ruta Steponaitiene, Jurgita Skieceviciene, Limas Kupcinskas, Laimas Jonaitis, Gediminas Kiudelis, Peter Malfertheiner, Juozas Kupcinskas
Vytenis Petkevicius, Violeta Salteniene, Limas Kupcinskas, Laimas Jonaitis, Gediminas Kiudelis, Juozas Kupcinskas, Department of Gastroenterology, Lithuanian University of Health Sciences, 50009 Kaunas, Lithuania
Simonas Juzenas, Ruta Steponaitiene, Jurgita Skieceviciene, Limas Kupcinskas, Laimas Jonaitis, Gediminas Kiudelis, Juozas Kupcinskas, Institute for Digestive Research, Lithuanian University of Health Sciences, 50009 Kaunas, Lithuania
Thomas Wex, Alexander Link, Peter Malfertheiner, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, 39106 Magdeburg, Germany
Thomas Wex, Medical Laboratory for Clinical Chemistry, Microbiology and Infectious Diseases, Department of Molecular Genetics, Otto-von-Guericke University, 39106 Magdeburg, Germany
Marcis Leja, Institute for Clinical and Preventive Medicine, University of Latvia, 1586 Riga, Latvia
Marcis Leja, Faculty of Medicine, University of Latvia, 1586 Riga, Latvia
Marcis Leja, Riga East University Hospital, 1079 Riga, Latvia
Author contributions: Petkevicius V and Salteniene V contributed equally to this work; Wex T, Kupcinskas L, Malfertheiner P and Kupcinskas J designed the research; Juzenas S, Steponaitiene R, Skieceviciene J, Jonaitis L and Kiudelis G performed analysis and interpretation of data; Petkevicius V, Salteniene V and Kupcinskas J drafted the manuscript; Wex T, Link A, Leja M and Kupcinskas L provided critical revision of the manuscript for important intellectual content.
Supported by Lithuanian Research Council Grant, No. MIP-14418.
Institutional review board statement: The study was approved by the Ethics Committees of the Otto-von-Guericke University Magdeburg (Protocols No. 63/08 and No. 34/08), Lithuanian University of Health Sciences (Protocol No. BE-10-2) and Central Medical Ethics Committee of Latvia (Protocol No. 91-29.1/20 dated 22.09.2011).
Informed consent statement: All patients have signed an informed consent form to participate in the study.
Conflict-of-interest statement: The authors declare no conflicts.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Juozas Kupcinskas, MD, PhD, Gastroenterologist, Chief Researcher, Department of Gastroenterology, Lithuanian University of Health Sciences, Eiveniu str. 2, Kaunas 50009, Lithuania.
juozas.kupcinskas@lsmuni.lt
Telephone: +370-37-326508
Received: December 23, 2016
Peer-review started: December 25, 2016
First decision: January 19, 2017
Revised: February 23, 2017
Accepted: March 21, 2017
Article in press: March 21, 2017
Published online: May 21, 2017
Processing time: 148 Days and 8.3 Hours
AIM
To evaluate associations between miRNA target genes IL12B, INSR, CCND1 and IL10 polymorphisms and gastric cancer (GC) in European population.
METHODS
Gene polymorphisms were analyzed in 508 controls and 474 GC patients from 3 tertiary centers in Germany, Lithuania and Latvia. Controls were patients from the out-patient departments, who were referred for upper endoscopy because of dyspeptic symptoms and had no history of previous malignancy. Gastric cancer (GC) patients had histopathological verification of gastric adenocarcinoma. Genomic DNA was extracted using salting out method from peripheral blood mononuclear cells. IL12B T>G (rs1368439), INSR T>C (rs1051690), CCND1 A>C (rs7177) and IL10 T>C (rs3024498) SNPs were genotyped by the real-time polymerase chain reaction. Associations between gene polymorphism and GC were evaluated using multiple logistic regression analysis with adjustment for sex, age and country of birth.
RESULTS
We observed similar distribution of genotypes and allelic frequencies of all polymorphisms between GC patients and controls except of INSR rs1051690. The frequency of the T allele of INSR gene was significantly higher in GC patients than in controls (23.26% and 19.19% respectively, P = 0.028). CT genotype was also more prevalent in patients compared to control group (38.48% and 30.12% respectively, P < 0.021). Logistic regression analysis revealed that only one polymorphism (rs1051690 in INSR gene) was associated with increased risk of GC. Carriers of CT genotype had higher odds of GC when compared to CC genotype (OR = 1.45, 95%PI: 1.08-1.95, P = 0.01). Similar association was observed in a dominant model for INSR gene, where comparison of TT+CT vs CC genotypes showed an increased risk of GC (OR = 1.44, 95%PI: 1.08-1.90, P = 0.01). Other analyzed SNPs were not associated with the presence of GC.
CONCLUSION
INSR rs1051690 SNP is associated with increased risk of GC, while polymorphisms in IL12B, CCND1 and IL10 genes are not linked with the presence of GC.
Core tip: Several studies have evaluated an association between single-nucleotide polymorphisms (SNPs) and gastric cancer (GC) risk. Here we used novel approach. Using bioinformatical analysis tools, several SNPs were identified as potential target sites of microRNAs that previously have been linked with gastric carcinogenesis. This study evaluated an association between SNPs in the INSR (rs1051690), IL12B (rs1368439), CCND1 (rs7177), and IL10 (rs3024498) genes and risk of GC in subjects of European descent. The study found that INSR rs1051690 SNP was associated with increased risk of GC, while polymorphisms in IL12B, CCND1 and IL10 genes showed no association with GC.
