title: A Multiple Interaction Analysis Reveals ADRB3 as a Potential Candidate for Gallbladder Cancer Predisposition via a Complex Interaction with Other Candidate Gene Variations.
abstract: Gallbladder cancer is the most common and a highly aggressive biliary tract malignancy with a dismal outcome. The pathogenesis of the disease is multifactorial, comprising the combined effect of multiple genetic variations of mild consequence along with numerous dietary and environmental risk factors. Previously, we demonstrated the association of several candidate gene variations with GBC risk. In this study, we aimed to identify the combination of gene variants and their possible interactions contributing towards genetic susceptibility of GBC. Here, we performed Multifactor-Dimensionality Reduction (MDR) and Classification and Regression Tree Analysis (CRT) to investigate the gene-gene interactions and the combined effect of 14 SNPs in nine genes (DR4 (rs20576, rs6557634); FAS (rs2234767); FASL (rs763110); DCC (rs2229080, rs4078288, rs7504990, rs714); PSCA (rs2294008, rs2978974); ADRA2A (rs1801253); ADRB1 (rs1800544); ADRB3 (rs4994); CYP17 (rs2486758)) involved in various signaling pathways. Genotyping was accomplished by PCR-RFLP or Taqman allelic discrimination assays. SPSS software version 16.0 and MDR software version 2.0 were used for all the statistical analysis. Single locus investigation demonstrated significant association of DR4 (rs20576, rs6557634), DCC (rs714, rs2229080, rs4078288) and ADRB3 (rs4994) polymorphisms with GBC risk. MDR analysis revealed ADRB3 (rs4994) to be crucial candidate in GBC susceptibility that may act either alone (p < 0.0001, CVC = 10/10) or in combination with DCC (rs714 and rs2229080, p < 0.0001, CVC = 9/10). Our CRT results are in agreement with the above findings. Further, in-silico results of studied SNPs advocated their role in splicing, transcriptional and/or protein coding regulation. Overall, our result suggested complex interactions amongst the studied SNPs and ADRB3 rs4994 as candidate influencing GBC susceptibility.
authors.affiliation: School of Biotechnology, Yeungnam University, Gyeongsan, Gyeongbuk 712-749, Korea. rajaniraiims@gmail.com.|Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow-226014, India. rajaniraiims@gmail.com.
authors.forename: Rajani
authors.initials: R
authors.lastname: Rai
authors.affiliation: School of Biotechnology, Yeungnam University, Gyeongsan, Gyeongbuk 712-749, Korea. kimjj@ynu.ac.kr.
authors.forename: Jong Joo
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Department of Surgical Oncology, King George's Medical University (KGMU), Lucknow-226003, India. misralko@gmail.com.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Misra
authors.affiliation: Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow-226014, India. dr_ashokgupta@yahoo.com.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow-226014, India. balrajmittal@gmail.com.
authors.forename: Balraj
authors.initials: B
authors.lastname: Mittal
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D019295:Computational Biology / Q000379:methods; D004843:Epistasis, Genetic; D005260:Female; D005706:Gallbladder Neoplasms / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D058011:Multifactor Dimensionality Reduction; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics*; D012044:Regression Analysis; D012307:Risk Factors
chemical_list: D022702:Receptors, Adrenergic, beta-3
keywords: Classification and Regression Tree Analysis (CRT); Multifactor-Dimensionality Reduction (MDR); gallbladder cancer (GBC); genetic susceptibility; polymorphism