title: Pathway analysis of genome-wide association study on serum prostate-specific antigen levels.
abstract: The wide application of prostate-specific antigen (PSA) has contributed to the early diagnosis and improved management of prostate cancer (PCa). Accumulating evidence has suggested the involvement of genetic components in regulating serum PSA levels, and several single nucleotide polymorphisms (SNPs) have been identified by genome-wide association studies (GWASs). However, the GWASs' results have the limited power to identify the causal variants and pathways. After the quality control filters, a total of 330,540 genotyped SNPs from one GWAS with 657 PCa-free Caucasian males were included for the identify candidate causal SNPs and pathways (ICSNPathway) analysis. In addition, the genotype-phenotype association analysis has been conducted with the data from HapMap database. Overall, a total of four SNPs in three genes and six pathways were identified by ICSNPathway analysis, which in total provided three hypothetical mechanisms. First, CYP26B1 rs2241057 polymorphism (nonsynonymous coding) which leads to a Leu-to-Ser amino acid shift at position 264, was implicated in the pathways including meiosis, proximal/distal pattern formation, and M phase of meiotic cell cycle. Second, CLIC5 rs3734207 and rs11752816 polymorphisms (regulatory region) to the 2 iron, 2 sulfur cluster binding pathway through regulating expression levels of CLIC5 mRNA. Third, rs4819522 polymorphism (nonsynonymous coding) leads to a Thr-to-Met transition at position 350 of TBX1 and involves in the pathways about gland and endocrine system development. In summary, our results demonstrated four candidate SNPs in three genes (CYP26B1 rs2241057, CISD1 rs2251039, rs2590370, and TBX1 rs4819522 polymorphisms), which were involved in six potential pathways to influence serum PSA levels.
authors.affiliation: Department of Urology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China.
authors.forename: Yu-Zheng
authors.initials: YZ
authors.lastname: Ge
authors.affiliation: Department of Urology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Urology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China.
authors.forename: Lu-Wei
authors.initials: LW
authors.lastname: Xu
authors.affiliation: Department of Urology, The First Hospital of Nanchang, Nanchang University, 128 Xiangshan North Road, Nanchang 330008, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Yu
authors.affiliation: Department of Urology, Xuzhou Third People's Hospital, Jiangsu University, 131 Huancheng Road, Xuzhou 221005, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Urology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xin
authors.affiliation: Department of Urology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Urology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China.
authors.forename: Si-Jia
authors.initials: SJ
authors.lastname: Tan
authors.affiliation: Department of Urology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Song
authors.affiliation: Department of Urology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Wu
authors.affiliation: Department of Urology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China.
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Li
authors.affiliation: Department of Urology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China.
authors.forename: Jia-Geng
authors.initials: JG
authors.lastname: Zhu
authors.affiliation: Department of Urology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China. Electronic address: urojiarp@126.com.
authors.forename: Rui-Peng
authors.initials: RP
authors.lastname: Jia
mesh_terms: D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D060148:HapMap Project; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017430:Prostate-Specific Antigen / Q000097:blood* / Q000235:genetics*; D000072516:Retinoic Acid 4-Hydroxylase; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D044465:White People
chemical_list: C525595:CISD1 protein, human; C411466:CLIC5 protein, human; D018118:Chloride Channels; D008840:Microfilament Proteins; D024101:Mitochondrial Proteins; D020825:T-Box Domain Proteins; C108625:TBX1 protein, human; D003577:Cytochrome P-450 Enzyme System; C000607079:CYP26B1 protein, human; D000072516:Retinoic Acid 4-Hydroxylase; D017430:Prostate-Specific Antigen
keywords: Genome-wide association study; Pathway analysis; Prostate-specific antigen