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.
Date of Award | 2015 |
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Original language | English |
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Awarding Institution | |
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Supervisor | Elaine Green (Other Supervisor) |
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- Barrett's Oesophagus
- Cancer
- Genetics
- Genome-Wide Association Study
- Single Nucleotide Polymorphisms
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
Chegwidden, L. (Author). 2015
Student thesis: PhD