Gaoxiang Ma1,2,3, Hanting Liu1,2, Mulong Du1,2,4, Gang Zhang1,2, Yadi Lin1,2, Yuqiu Ge1,2, Meilin Wang1,2, Guangfu Jin5, Qinghong Zhao6, Haiyan Chu1,2, Weida Gong7, Zhengdong Zhang1,2. 1. Department of Environmental Genomics, Center for Global Health, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. 2. Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China. 3. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China. 4. Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. 5. Department of Epidemiology and Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. 6. Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China. 7. Department of General Surgery, Yixing Cancer Hospital, Yixing, China.
Abstract
BACKGROUND: Previous genome-wide association studies (GWASs) have identified that several single nucleotide polymorphisms (SNPs) are implicated in gastric cancer (GC) risk. However, the multiple statistical comparisons of GWASs may reject some true biological positives with subthreshold P values. METHODS: This study annotated the genomic locations of all CpG islands in the genome using the Encyclopedia of DNA Elements (ENCODE). The SNPs in the regions were then genotyped using the Illumina 660W Quad chip. The effects of the prominent variations on GC risk were further confirmed in the other independent cohorts. RESULTS: SNP rs2990245, which is located in the promoter of pseudogene GBAP1, was associated with GC risk using GWASs data. An additional cohort of 1275 GC patients and 1424 controls validated that individuals with the CC genotype had a 62% decreased risk of GC compared with those who carried the TT genotype (P = 2.01E-04) in the codominant model. The significant association was observed in the additive, dominant, and recessive models. A meta-analysis combining the results from the GWASs and replication studies revealed that rs2990245 was significantly associated with decreased GC risk (P = 5.59E-12). Importantly, rs2990245 can regulate the expression of GBAP1 by influencing the methylation status of the GBAP1 promoter. GBAP1 can act as a competing endogenous RNA by binding competitively with micro-RNA-212-3p and then promoting GBA expression. CONCLUSION: rs2990245 is significantly associated with a decreased risk of GC. Pseudogene GBAP1 contributes to the development and progression of GC by sequestering the miR-212-3p from binding to GBA.
BACKGROUND: Previous genome-wide association studies (GWASs) have identified that several single nucleotide polymorphisms (SNPs) are implicated in gastric cancer (GC) risk. However, the multiple statistical comparisons of GWASs may reject some true biological positives with subthreshold P values. METHODS: This study annotated the genomic locations of all CpG islands in the genome using the Encyclopedia of DNA Elements (ENCODE). The SNPs in the regions were then genotyped using the Illumina 660W Quad chip. The effects of the prominent variations on GC risk were further confirmed in the other independent cohorts. RESULTS: SNP rs2990245, which is located in the promoter of pseudogene GBAP1, was associated with GC risk using GWASs data. An additional cohort of 1275 GC patients and 1424 controls validated that individuals with the CC genotype had a 62% decreased risk of GC compared with those who carried the TT genotype (P = 2.01E-04) in the codominant model. The significant association was observed in the additive, dominant, and recessive models. A meta-analysis combining the results from the GWASs and replication studies revealed that rs2990245 was significantly associated with decreased GC risk (P = 5.59E-12). Importantly, rs2990245 can regulate the expression of GBAP1 by influencing the methylation status of the GBAP1 promoter. GBAP1 can act as a competing endogenous RNA by binding competitively with micro-RNA-212-3p and then promoting GBA expression. CONCLUSION:rs2990245 is significantly associated with a decreased risk of GC. Pseudogene GBAP1 contributes to the development and progression of GC by sequestering the miR-212-3p from binding to GBA.
Authors: Amanda Nazaré Cohen Lima de Castro; Marianne Rodrigues Fernandes; Darlen Cardoso de Carvalho; Tatiane Piedade de Souza; Juliana Carla Gomes Rodrigues; Roberta Borges Andrade; Antonio Andre Conde Modesto; Sidney Santos; Paulo Pimentel Assumpção; Ney Pereira Carneiro Dos Santos Journal: Am J Transl Res Date: 2020-10-15 Impact factor: 4.060