Potentially functional genetic variants in PLIN2, SULT2A1 and UGT1A9 genes of the ketone pathway and survival of nonsmall cell lung cancer
| Autor: | Sipeng Shen, Carolyn Glass, Jeffrey M. Clarke, David C. Christiani, Qingyi Wei, Dongfang Tang, Sheng Luo, Hongliang Liu, Wen Gao, Li Su, Yu Chen Zhao |
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| Rok vydání: | 2019 |
| Předmět: |
Oncology
Male Cancer Research medicine.medical_specialty Lung Neoplasms Quantitative Trait Loci Datasets as Topic Single-nucleotide polymorphism Genome-wide association study Biology Polymorphism Single Nucleotide Perilipin-2 Article 03 medical and health sciences 0302 clinical medicine Internal medicine Carcinoma Non-Small-Cell Lung Genotype medicine Genetic predisposition Humans RNA Messenger Glucuronosyltransferase Genotyping Lung Alleles Genetic association Aged Models Genetic Ketones Middle Aged Lung cancer susceptibility Survival Analysis 030220 oncology & carcinogenesis Expression quantitative trait loci UDP-Glucuronosyltransferase 1A9 Female Sulfotransferases Metabolic Networks and Pathways Follow-Up Studies Genome-Wide Association Study |
| Zdroj: | Int J Cancer |
| ISSN: | 1097-0215 |
| Popis: | The ketone metabolic pathway is a principle procedure in physiological homeostasis and induces cancer cells to switch between glycolysis and oxidative phosphorylation as their main energy production. We conducted a two-phase analysis for associations between genetic variants in the ketone metabolism pathway genes and survival of non-small cell lung cancer (NSCLC) by using genotyping data from published genome-wide association studies (GWASs). The discovery used genotyping dataset from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial in the multivariate Cox proportional hazards regression analysis with Bayesian false discovery probability (≤0.80) for multiple testing correction to evaluate associations between 27,322 (2,176 genotyped and 25,146 imputed) single-nucleotide polymorphisms (SNPs) in 162 genes and survival of 1,185 NSCLC patients. Subsequently, significant SNPs were further validated with 984 NSCLC patients in another dataset from the Harvard Lung Cancer Susceptibility GWAS study. Finally, three independent and potentially functional SNPs in three different genes (i.e., PLIN2 rs7867814 G>A, SULT2A1 rs2547235 C>T and UGT1A9 rs2011404 C>T and) were independently associated with NSCLC overall survival, with a combined hazards ratio of 1.22 [95% confidence interval = 1.09–1.36 and P=0.0003], 0.82 (0.74–0.91 and P=0.0002) and 1.21 (1.10–1.33 and P=0.0001), respectively. Additional expression quantitative trait loci analysis found that the survival-associated PLIN2 rs7867814 GA+AA genotypes, but not UGT1A9 rs2011404 CT+TT genotypes and SULT2A1 rs2547235 CT+TT genotypes, were significantly associated with increased mRNA expression levels in 373 lymphoblastoid cell lines. These results indicated that PLIN2 variants may be potential predictors of NSCLC survival through regulating the PLIN2 expression. |
| Databáze: | OpenAIRE |
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