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.

Document Type

Thesis

Publication Date

2015-01-01

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