Leptin and leptin receptor genotypes and colon cancer: Gene–gene and gene–lifestyle interactions

Abstract

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 (22548 G > A) poly-morphisms 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 poly-morphisms. 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. ' 2007 Wiley-Liss, Inc. Leptin is a 16 kDa glycolprotein product of the leptin gene (LEP), which is expressed almost exclusively (>95%) by adipo-cytes. 1 Initial interest in leptin focused on its role in obesity but it is rapidly becoming evident that its physiological properties extend beyond those associated with energy homeostasis. In addition to regulation of energy balance, leptin, has been associated with reproductive factors, inflammatory response, insulin signal-ing, bone remodeling and neuroendocrine function. 2 The leptin receptor , a class I pro-inflammatory cytokine, is a member of the cytokine receptor family that includes IL-6. The leptin receptor plays a key role in how leptin functions. When leptin binds to the leptin receptor, Janus kinase (JAK2), a tyrosine kinase is activated to initiate downstream signaling of suppressors of cytokine signal-ing 1 and 3 (SOCS) and signal transducer and activator of transcription -3 (STAT). 2-4 Of particular importance for cancer is the influence of leptin on SOCS which in turn limits insulin signaling; SOCS3 has been shown to limit leptin signaling. Studies have shown that leptin also can stimulate expression of the inflamma-tory marker CRP (C-reactive protein). 5 There is growing evidence that nuclear hormone receptors regulate the action of leptin and other class I cytokines. 6 However, data also suggest that hormone receptors, such as the vitamin D receptor , might play an important role in regulating leptin; vitamin D 3 has been shown to inhibit leptin secretion in human adipose tissue. 7 Leptin has been ...

Link between insulin and metabolic disorders in cancer: does leptin play a key role?

“…Due to its mitogen effect, a condition of hyperleptinemia could favour the development of malignancies. In close agreement with this hypothesis, several lines of evidence support the role of leptin in the neoplastic processes [6][7][8][9]. Moreover, this is further supported by some genetic evidences showing a correlation between serum leptin levels, leptin receptor polymorphisms, and the risk of breast cancer [10,11].…”

Genetic variation in adipokine genes and risk of colorectal cancer

“…In addition to the report about the relationship between the RETN SNP C-420G and the risk of CRC (17), only one study has addressed the question of an association between genetic variation in the adipokine genes and the risk of CRC (51). In that study, a decreased risk for the AA genotype carriers of the SNP rs2167270 in the 5 0 -UTR of the LEP gene was observed.…”

Metabolic syndrome and risk of subsequent colorectal cancer

“…Of particular importance for cancer is the influence of leptin on suppressors of cytokine signaling 1 and 3 which in turn limits insulin signaling [49] . Although data directly linking leptin to colon cancer are limited, some studies have shown increased risk of colon and colorectal cancer with high serum leptin levels.…”