title: Polymorphic rs9471643 and rs6458238 upregulate PGC transcription and protein expression in overdominant or dominant models.
abstract: The pepsinogen C (PGC) gene encodes a major differentiation biomarker for gastric mucosa and has two single nucleotide polymorphisms, rs9471643 G>C and rs6458238 G>A, within its 5' upstream region that are involved in gastric carcinogenesis. However, in what genetic models the two polymorphisms modulate disease risk and how they relate to gastric carcinogenesis needs further study. We fitted the most appropriate genetic models to the PGC polymorphisms and validated their robustness; then with knowledge of the genetic model, we investigated the influence of functional variant alleles or genotypes on gene expression in vitro and in vivo. We confirmed that rs9471643 CG genotype was stably associated with reduced gastric cancer risk in complete overdominant model. This favorable CG genotype was also associated with reduced atrophic gastritis risk in subjects carrying rs6458238 AG/AA genotype. The G>C transition at rs9471643 enhanced promoter activity and transcription factor binding ability, and the CG genotype was consistently associated with elevated levels of PGC mRNA, in situ protein and serum protein in complete overdominant model based-analyses. Additionally, rs6458238 AG/AA genotype was associated with reduced atrophic gastritis risk in dominant model. Its favorable A allele was related to higher promoter activity and lower transcription factor binding ability, and the AG/AA genotype showed association with elevated levels of serum PGC protein in dominant model based-analyses. Our results suggest that rs9471643 CG and rs6458238 AG/AA genotypes have important roles in up-regulating PGC expression, which may partially explain why individuals with these favorable genotypes have decreased risks of getting gastric cancer.
authors: Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Control in Liaoning Province, Shenyang, China.|Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors: Caiyun
authors: C
authors: He
authors: Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Control in Liaoning Province, Shenyang, China.
authors: Qian
authors: Q
authors: Xu
authors: Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Control in Liaoning Province, Shenyang, China.|Department of Epidemiology, Rollins School of Public Health, Emory University, GA.
authors: Huakang
authors: H
authors: Tu
authors: Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Control in Liaoning Province, Shenyang, China.
authors: Liping
authors: L
authors: Sun
authors: Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Control in Liaoning Province, Shenyang, China.
authors: Yuehua
authors: Y
authors: Gong
authors: Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Control in Liaoning Province, Shenyang, China.
authors: Jingwei
authors: J
authors: Liu
authors: Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Control in Liaoning Province, Shenyang, China.
authors: Yuan
authors: Y
authors: Yuan
mesh_terms: D044466:Asian People / Q000235:genetics; D045744:Cell Line, Tumor; D005757:Gastritis, Atrophic / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D020115:Pepsinogen C / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D020115:Pepsinogen C
keywords: gastric cancer; gene expression; genetic model; molecular function; pepsinogen C/PGC