MicroRNA-related genetic variants in iron regulatory genes, dietary iron intake, microRNAs and lung cancer risk
Autor: | Huakang Tu, John V. Heymach, Michelle A.T. Hildebrandt, Lina Zhao, Jack A. Roth, Y. Ye, Xifeng Wu, Liren Zhang |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
medicine.medical_specialty Lung Neoplasms Single-nucleotide polymorphism MiRNA binding medicine.disease_cause Polymorphism Single Nucleotide 03 medical and health sciences 0302 clinical medicine Risk Factors Internal medicine Genotype microRNA Genetic variation medicine SNP Humans Genetic Predisposition to Disease Genetic Association Studies Genetics business.industry Cancer Hematology Original Articles medicine.disease MicroRNAs 030104 developmental biology Endocrinology Oncology Genetic Loci 030220 oncology & carcinogenesis Carcinogenesis business Iron Dietary Metabolic Networks and Pathways |
Zdroj: | Annals of oncology : official journal of the European Society for Medical Oncology. 28(5) |
ISSN: | 1569-8041 |
Popis: | Background Genetic variations in MicroRNA (miRNA) binding sites may alter structural accessibility of miRNA binding sites to modulate risk of cancer. This large-scale integrative multistage study was aimed to evaluate the interplay of genetic variations in miRNA binding sites of iron regulatory pathway, dietary iron intake and lung cancer (LC) risk. Patients and methods The interplay of genetic variant, dietary iron intake and LC risk was assessed in large-scale case–control study. Functional characterization of the validated SNP and analysis of target miRNAs were performed. Results We found that the miRNA binding site SNP rs1062980 in 3’ UTR of Iron-Responsive Element Binding protein 2 gene (IREB2) was associated with a 14% reduced LC risk (P value = 4.9×10 − 9). Comparing to AA genotype, GG genotype was associated with a 27% reduced LC risk. This association was evident in males and ever-smokers but not in females and never-smokers. Higher level of dietary iron intake was significantly associated with 39% reduced LC risk (P value = 2.0×10 − 8). This association was only present in individuals with AG + AA genotypes with a 46% reduced risk (P value = 1.0×10 − 10), but not in GG genotype. The eQTL-analysis showed that rs1062980 significantly alters IREB2 expression level. Rs1062980 is predicted to alter a miR-29 binding site on IREB2 and indeed the expression of miR-29 is inversely correlated with IREB2 expression. Further, we found that higher circulating miR-29a level was significantly associated with 78% increased LC risk. Conclusion The miRNA binding site SNP rs1062980 in iron regulatory pathway, which may alter the expression of IREB2 potentially through modulating the binding of miR-29a, together with dietary iron intake may modify risk of LC both individually and jointly. These discoveries reveal novel pathway for understanding lung cancer tumorigenesis and risk stratification. |
Databáze: | OpenAIRE |
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