Identification of Two Novel Genome-Wide Significant Single Nucleotide Polymorphisms, associated with Barrett’s Oesophagus, determined by further Replication of a Genome-Wide Association Study

Abstract

Barrett's oesophagus (BE) is a common premalignant condition to oesophageal adenocarcinoma (EAC). A previous genome-wide association study (GWAS) identified BE susceptibility Single Nucleotide Polymorphisms (SNPs) on chromosome 6p21, within the HLA region, and16q23, where the closest protein-coding gene was FOXF1. The replication study outlined in this thesis aimed to identify possible additional variants that did not reach genome-wide significance in the GWAS, in up to 10,158 BE patients and 21,062 controls. Meta-analysis of the data identified two further BE susceptibility SNPs: rs3072 (2p24.1; OR=1.14; 95%CI 1.09-1.18; P=1.8×10−11); and rs2701108 (12q24.21; OR=0.90; 95%CI 0.86-0.93; P=7.5×10−9). The two closest protein-coding genes, and most likely functional targets, are the bone morphogenetic protein pathway ligand GDF7 (rs3072) and TBX5 (rs2701108). A second GWAS of combined BE and EAC cases was recently published, analysing a total of 922,031 SNPs, where 87 of 94 associated SNPs with P<1×10−4 were selected for further replication, identified four SNPs (three loci) with BE/EAC risk in CRTC1 and BARX1 and within 100kb of FOXP1. Our data supported three of the BE/EAC associated SNPs and meta-analysis of all 87 SNPs detected a further susceptibility locus, rs3784262, near ALDH1A2 (OR=0.90, 95%CI 0.87-0.93, P=3.72×10−9). Overall, two novel BE susceptibility loci have been identified and data has been provided to support three previously identified BE/EAC SNPs and one additional BE/EAC locus. To date, genes implicated in BE susceptibility appear to encode transcription factors involved in thoracic, diaphragmatic and oesophageal development or inflammatory response proteins.