A population-based study of IGF axis polymorphisms and the esophageal inflammation, metaplasia, adenocarcinoma sequence.
OBJECTIVE
Insulin-like growth factor (IGF) axis plays a key role in cell development, proliferation, and survival and is implicated in the etiology of several cancers. Few studies have examined the relationship between genetic variation of this axis and esophageal adenocarcinoma (EAC) or its precursors.


METHODS
In a population-based case-control study, we investigated the association of common polymorphisms of IGF-1, IGF-2, IGF-1 receptor, IGF binding protein-3, growth hormones (GH) 1 and GH2, and GH receptor with reflux esophagitis (RE), Barrett esophagus (BE), and EAC. Two hundred and thirty RE, 224 BE, 227 EAC cases, and 260 controls were studied. Gene polymorphisms were identified using publicly available online resources; 102 IGF axis tag and putatively functional single-nucleotide polymorphisms (SNPs) were analyzed using MassARRAY iPLEX and Taqman assays. Results were analyzed using Haploview.


RESULTS
Three polymorphisms were disease-associated. IGF1 SNP rs6214 was associated with BE (adjusted P = .039). Using GG genotype as reference, odds ratio for BE in AA (wild-type) was 0.43 (95% confidence interval [CI], 0.24-0.75). GH receptor SNP rs6898743 was associated with EAC (adjusted P = .0112). With GG as reference, odds ratio for EAC in CC (wild-type) genotype was 0.42 (95% CI, 0.23-0.76). IGF1 (CA)(17) 185-bp allele was associated with RE (adjusted P = .0116). Using IGF1(non17) as reference, odds ratio for RE in IGF1(17) carriers was 7.29 (95% CI, 1.57-46.7).


CONCLUSIONS
In this study, 3 polymorphisms of IGF genes were associated with EAC or its precursors. These polymorphisms may be markers of disease risk; independent validation of our findings is required. These results suggest the IGF pathway is involved in EAC development.
McElholm
Adrian R
AR
Cancer Epidemiology and Prevention Research Group, Centre for Public Health, Queens University of Belfast, Belfast, United Kingdom. amcelholm@hotmail.com
McKnight
Amy-Jane
AJ
Patterson
Chris C
CC
Johnston
Brian T
BT
Hardie
Laura J
LJ
Murray
Liam J
LJ
D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000209:etiology / Q000235:genetics*; D004941:Esophagitis / Q000209:etiology / Q000235:genetics*; D004947:Esophagus / Q000473:pathology*; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008297:Male; D008679:Metaplasia; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
D007334:Insulin-Like Growth Factor I