Browsing by Subject "single-nucleotide polymorphism (SNP)"
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Item Open Access Association of genetic variants of TMEM135 and PEX5 in the peroxisome pathway with cutaneous melanoma-specific survival.(Annals of translational medicine, 2021-03) Wang, Haijiao; Liu, Hongliang; Dai, Wei; Luo, Sheng; Amos, Christopher I; Lee, Jeffrey E; Li, Xin; Yue, Ying; Nan, Hongmei; Wei, QingyiBackground
Peroxisomes are ubiquitous and dynamic organelles that are involved in the metabolism of reactive oxygen species (ROS) and lipids. However, whether genetic variants in the peroxisome pathway genes are associated with survival in patients with melanoma has not been established. Therefore, our aim was to identify additional genetic variants in the peroxisome pathway that may provide new prognostic biomarkers for cutaneous melanoma (CM).Methods
We assessed the associations between 8,397 common single-nucleotide polymorphisms (SNPs) in 88 peroxisome pathway genes and CM disease-specific survival (CMSS) in a two-stage analysis. For the discovery, we extracted the data from a published genome-wide association study from The University of Texas MD Anderson Cancer Center (MDACC). We then replicated the results in another dataset from the Nurse Health Study (NHS)/Health Professionals Follow-up Study (HPFS).Results
Overall, 95 (11.1%) patients in the MDACC dataset and 48 (11.7%) patients in the NHS/HPFS dataset died of CM. We found 27 significant SNPs in the peroxisome pathway genes to be associated with CMSS in both datasets after multiple comparison correction using the Bayesian false-discovery probability method. In stepwise Cox proportional hazards regression analysis, with adjustment for other covariates and previously published SNPs in the MDACC dataset, we identified 2 independent SNPs (TMEM135 rs567403 C>G and PEX5 rs7969508 A>G) that predicted CMSS (P=0.003 and 0.031, respectively, in an additive genetic model). The expression quantitative trait loci analysis further revealed that the TMEM135 rs567403 GG and PEX5 rs7969508 GG genotypes were associated with increased and decreased levels of mRNA expression of their genes, respectively.Conclusions
Once our findings are replicated by other investigators, these genetic variants may serve as novel biomarkers for the prediction of survival in patients with CM.Item Open Access Genetic variants in the liver kinase B1-AMP-activated protein kinase pathway genes and pancreatic cancer risk.(Molecular carcinogenesis, 2019-04-17) Xu, Xinyuan; Qian, Danwen; Liu, Hongliang; Cruz, Diana; Luo, Sheng; Walsh, Kyle M; Abbruzzese, James L; Zhang, Xuefeng; Wei, QingyiThe liver kinase B1-AMP-activated protein kinase (LKB1-AMPK) pathway has been identified as a new target for cancer therapy, because it controls the glucose and lipid metabolism in response to alterations in nutrients and intracellular energy levels. In the present study, we aimed to identify genetic variants of the LKB1-AMPK pathway genes and their associations with pancreatic cancer (PanC) risk using 15 418 participants of European ancestry from two previously published PanC genome-wide association studies. We found that six novel tagging single-nucleotide polymorphisms (SNPs) (i.e, MAP2 rs35075084 T > deletion, PRKAG2 rs2727572 C > T and rs34852782 A > deletion, TP53 rs9895829 A > G, and RPTOR rs62068300 G > A and rs3751936 G > C) were significantly associated with an increased PanC risk. The multivariate logistic regression model incorporating the number of unfavorable genotypes (NUGs) with adjustment for age and sex showed that carriers with five to six NUGs had an increased PanC risk (odds ratio = 1.24, 95% confidence interval = 1.16-1.32 and P < 0.0001), compared to those with zero to four NUGs. Subsequent expression quantitative trait loci (eQTL) analysis further revealed that these SNPs were associated with significantly altered mRNA expression levels either in 373 normal lymphoblastoid cell lines (TP53 SNP rs9895829, P < 0.05) or in whole blood cells of 369 normal donors from the genotype-tissue expression project (GTEx) database [RPTOR SNP rs60268947 and rs28434589, both in high linkage disequilibrium (r2 > 0.9) withRPTOR rs62068300, P < 0.001]. Collectively, our findings suggest that these novel SNPs in the LKB1-AMPK pathway genes may modify susceptibility to PanC, possibly by influencing gene expression.Item Open Access Novel genetic variants in genes of the Fc gamma receptor-mediated phagocytosis pathway predict non-small cell lung cancer survival.(Translational lung cancer research, 2020-06) Qian, Danwen; Liu, Hongliang; Zhao, Lingling; Wang, Xiaomeng; Luo, Sheng; Moorman, Patricia G; Patz, Edward F; Su, Li; Shen, Sipeng; Christiani, David C; Wei, QingyiBackground:Both antibody-dependent cellular cytotoxicity and phagocytosis activate innate immunity, and the Fc gamma receptor (FCGR)-mediated phagocytosis is an integral part of the process. We assessed associations between single-nucleotide polymorphisms (SNPs) in FCGR-related genes and survival of patients with non-small cell lung cancer (NSCLC). Methods:We evaluated associations between 24,734 (SNPs) in 97 FCGR-related genes and survival of 1,185 patients with NSCLC using a published genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the results in another independent dataset of 894 NSCLC patients. Results:In the single-locus analysis with Bayesian false discovery probability (BFDP) for multiple testing correction, we found 1,084 SNPs to be significantly associated overall survival (OS) (P<0.050 and BFDP ≤0.80), of which two independent SNPs (PLCG2 rs9673682 T>G and PLPP1 rs115613985 T>A) were further validated in another GWAS dataset of 894 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study, with combined allelic hazards ratios for OS of 0.87 [95% confidence interval (CI): 0.81-0.94 and P=5.90×10-4] and 1.18 (95% CI: 1.08-1.29 and 1.32×10-4, respectively). Expression quantitative trait loci analysis showed that the rs9673682 G allele was significantly correlated with increased mRNA expression levels of PLCG2 in 373 transformed lymphoblastoid cell-lines (P=7.20×10-5). Additional evidence from differential expression analysis further supported a tumor-suppressive effect of PLCG2 on OS of patients with lung cancer, with lower mRNA expression levels in both lung squamous carcinoma and adenocarcinoma than in adjacent normal tissues. Conclusions:Genetic variants in PLCG2 of the FCGR-mediated phagocytosis pathway may be promising predictors of NSCLC survival, possibly through modulating gene expression, but additional investigation of the molecular mechanisms of PLPP1 rs115613985 is warranted.