A Multiple Interaction Analysis Reveals ADRB3 as a Potential Candidate for Gallbladder Cancer Predisposition via a Complex Interaction with Other Candidate Gene Variations.

Rajani Rai,Balraj Mittal,Sanjeev Misra,Ashok Kumar,Jong Kim

doi:10.3390/ijms161226077

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.

Highlights

Gallbladder cancer (GBC) is infrequent, it is very aggressive, and the most common biliary tract cancer worldwide with marked geographical, racial and gender-specific orientations [1,2]
We found no effect of genome-wide association study (GWAS) reported SNPs on GBC risk
We found ADRB3 as the main SNPs associated with increased GBC susceptibility

Summary

Introduction

Gallbladder cancer (GBC) is infrequent, it is very aggressive, and the most common biliary tract cancer worldwide with marked geographical, racial and gender-specific orientations [1,2]. The etiology of GBC is multifactorial with gallstone and chronic inflammation as the root of disease [3,4]. Due to the absence of specific symptoms and late presentation, more than 90% of GBC patients are diagnosed at an advanced stage with little treatment alternatives [5]. Despite recent advancements, the molecular basis of GBC is poorly understood and it still remains a diagnostic and therapeutic challenge for clinicians [7]. There is always a need to develop novel biomarker for its early diagnosis, and to enhance our understanding of inter-individual variability in vulnerability of GBC

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