Leptin and leptin receptor genotypes and colon cancer: gene-gene and gene-lifestyle interactions.
Leptin may play an important role in colorectal cancer because of its role in energy balance, insulin and inflammation. We evaluated the LEP rs2167270 (19 G > A) and rs7799039 (-2548 G > A) polymorphisms and the leptin receptor, LEPR rs6588147 (located in intron 2), polymorphism with risk of developing colon cancer in a study of 1,567 cases and 1,965 controls. We evaluated the effects of the polymorphisms with body mass index (BMI), recent use of aspirin/NSAIDs and genetic variations in genes related to insulin signaling pathways including insulin-like growth factor 1 (IGF1), insulin-like growth factor binding protein 3 (IGFBP3), and insulin-related substrates 1 and 2 (IRS1, IRS2) and the vitamin D receptor (VDR). We observed a slight reduction in colon cancer risk with the AA LEP rs2167270 genotype (OR 0.79 95% CI 0.64, 0.98) and although not reaching statistical significance, with the combined GG LEP rs2167270 and GG LEPR rs6588147 (OR 0.70, 95% CI 0.49, 1.02) genotypes. BMI did not interact with any of these polymorphisms to alter colon cancer risk. However, recent aspirin/NSAID use significantly interacted with both LEP polymorphisms. Likewise, variants of IGF1 and IRS2 interacted with the LEP rs2167270 polymorphism. VDR polymorphisms interacted with all LEP and LEPR polymorphisms. These data support an association between LEP and colon cancer. They also suggest that the mechanisms linking leptin to colon cancer may be independent of energy balance.
Department of Medicine, University of Utah, Salt Lake City, UT, USA. marty.slattery@hsc.utah.edu
Martha L
ML
Slattery
Roger K
RK
Wolff
Jennifer
J
Herrick
Bette J
BJ
Caan
John D
JD
Potter
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D001241:Aspirin / Q000008:administration & dosage; D015992:Body Mass Index; D016022:Case-Control Studies; D003110:Colonic Neoplasms / Q000209:etiology* / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D020738:Leptin / Q000235:genetics*; D008019:Life Style; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D054411:Receptors, Leptin / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D000894:Anti-Inflammatory Agents, Non-Steroidal; C515497:IGFBP3 protein, human; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D010750:Phosphoproteins; D054411:Receptors, Leptin; D007334:Insulin-Like Growth Factor I; D001241:Aspirin