A polymorphic variant of the insulin-like growth factor type I receptor gene modifies risk of obesity for esophageal adenocarcinoma.
BACKGROUND
To investigate potential biologic mechanisms underlying the association between obesity and risk for esophageal adenocarcinoma (EADC), we studied the frequency of a common polymorphism of the insulin-like growth factor I receptor (IGF-IR) gene in patients with either gastroesophageal reflux disease (GERD), premalignant Barrett esophagus (BE) and or invasive EADC.


METHODS
Using a well characterized series of 431 individuals enrolled in a case-control study, we studied the frequency of the IGF-IR gene polymorphism, G1013A.


RESULTS
On multivariate analysis controlling for age and gender, in comparison to asymptomatic controls, obese individuals with the polymorphic A-variant (G/A, A/A) were found to have significantly increased risk for EADC (OR 4.81; 95%CI 1.09-21.15), whereas obese individuals with the G/G variant were not at statistically significant increased risk (OR 2.69; 95%CI 0.41-17.62). Similarly, compared to asymptomatic controls, only obese individuals with the A-variant (G/A, A/A) were at increased risk for BE (OR 3.11; 95%CI 1.12-8.63), while obese individuals with the G/G variant were not at increased risk for BE (OR 2.91; 95%CI 0.69-12.15).


CONCLUSIONS
We conclude that the common IGF-IR gene polymorphism G1013A modulates the risk of obesity for EADC, an effect most likely mediated by altered the receptor function by influencing gene transcription or mRNA stability. These findings further implicate the insulin-like growth factor axis in the molecular pathogenesis of EADC, and represent a plausible mechanistic link underlying the association between obesity and malignancy.
MacDonald
Kimberley
K
Department of Pathology (Division of Molecular Pathology and Molecular Genetics), Dalhousie University, NS, Canada.
Porter
Geoffrey A
GA
Guernsey
Duane L
DL
Zhao
Ronghua
R
Casson
Alan G
AG
D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D001471:Barrett Esophagus / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D016022:Case-Control Studies; D004938:Esophageal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005764:Gastroesophageal Reflux / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015999:Multivariate Analysis; D009765:Obesity / Q000150:complications* / Q000235:genetics*; D011110:Polymorphism, Genetic; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D012307:Risk Factors
D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1