Leptin gene variants and colorectal cancer risk: Sex-specific associations

Abstract

BackgroundHigh levels of serum leptin and low levels of serum adiponectin are strongly correlated with obesity, a well-established risk factor for colorectal cancer (CRC). Growing evidence suggests that dysregulation of leptin and adiponectin levels may play an etiological role in colorectal carcinogenesis. We evaluated 20 candidate variants in 4 genes previously shown to alter serum leptin and adiponectin levels for associations with obesity (BMI>30 kg/m2) and CRC risk.MethodsWe analyzed 6,246 CRC cases and 7,714 population-based controls from 11 studies within the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations of each variant with obesity or CRC were evaluated using multivariate logistic regression models stratified by sex and adjusted for age, a study variable, and the first three principal components of genetic ancestry. Gene-specific False Discovery Rate (FDR)-adjusted p-values <0.05 denoted statistical significance.ResultsTwo variants in the leptin gene showed statistically significant associations with CRC among women: LEP rs2167270 (OR = 1.13, 95% CI: 1.06–1.21) and LEP rs4731426 (OR = 1.09, 95% CI: 1.02–1.17). These associations remained significant after adjustment for obesity, suggesting that leptin SNPs may influence CRC risk independent of obesity. We observed statistically significant interactions of the leptin variants with hormone replacement therapy (HRT) for CRC risk; these variant associations were strengthened when analyses were restricted to post-menopausal women with low estrogen exposure, as estimated by ‘never use’ of HRT and/or non-obese BMI. No variants were associated with CRC among men.ConclusionsLeptin gene variants may exhibit sex-specific associations with CRC risk. Endogenous and exogenous estrogen exposure may modify the association between these variants, leptin levels, and CRC risk.

Circulating Leptin, Adiponectin, and Tumor Necrosis Factor-Alpha in Patients Undergoing Surgery Due to Colorectal Cancer

“…These data corroborate a report by Saetang et al [51], who found that low serum ADP concentration was significantly associated with the development of colorectal adenoma and early-stage colorectal carcinoma; however, in the invasive CRC group in that study, blood ADP concentration was similar to that observed in the control group. An increase in blood ADP concentration with CRC staging may suggest the appropriate response of anti-neoplasmatic ADPrelated organism activities [2,12,16,21,30,[34][35][36][37][38][39][40][41][42], which, unfortunately, were ineffective in the control of cancer growth. This suggestion is supported by the obser-vation that patients with stage II CRC had a higher ratio of ADP to TNF-alpha compared to stages I and III patients, as this accords with the existing data [30] and may be interpreted as patients with localized CRC (stages II, III, and II + III) still having a better balance between anti-(ADP) and pro-(TNF-alpha) cancerogenic adipocytokines.…”

“…LEP, along with ghrelin, mainly plays a role in the regulation of appetite and energy expenditure through decreasing orexigenic and increasing anorexigenic neuropeptide release from the hypothalamus and is recognized as a serum biomarker of total body fat mass (FM) [20]. However, in vitro, LEP also promotes colonic cell growth, proliferation, survival (antiapoptosis), immune response, migration, and angiogenesis [2,[20][21][22][23][24][25][26][27][28][29][30][31]. In a recent meta-analysis by Yang et al [17], the role of LEP as an independent factor in carcinogenesis was confirmed through associations found between LEP rs2167270 and LEP rs4731426 single-nucleotide polymorphisms, and the risk of CRC remained significant in women after adjusting for obesity [30].…”

“…ADP is secreted through abdominal fat tissue in 2 isoforms: high-molecular weight and non-high-molecular weight; however, it is frequently determined as total ADP [16,33]. ADP exerts anti-diabetic, anti-atherosclerotic, and anti-inflammatory effects [2,8,12,16,21,30,33] and directly modulates several intracellular signaling pathways involved in colorectal carcinogenesis [8,16,[32][33][34][35][36][37]. ADP single-nucleotide polymorphisms (ADIPOQ rs2241766 T>G, rs1501299 G>T, rs266729 C>G) [38,39], low blood ADP concentration [37][38][39][40][41], and reduced ADP receptor (Adipo-R1/-R2) expression are considered risk factors for CRC [42].…”

“…Moreover, a low postoperative/preoperative ADP ratio is recognized as a risk factor for postoperative infection in patients undergoing surgery due to gastric and CRC [12], and, therefore, some functional foods (soy genistein extract, lychee-derived low-molecular-weight polyphenol, olive extract, and turmeric) have been proposed to promote ADP secretion and thus inhibit cancer occurrence and recurrence [40]. On the other hand, prediagnostic low plasma ADP concentration is associated with increased CRC-specific and overall mortality [43], although Chun et al [30] suggest that dysregulation between high LEP and low ADP secretion (i.e., a low ADP-to-LEP ratio) is more important in colorectal carcinogenesis.…”

Energy Restriction and Colorectal Cancer: A Call for Additional Research

“…Increased blood leptin is associated with increased risk of developing breast [117] or thyroid [118] cancer. Interestingly, certain polymorphisms in the leptin gene have been associated with increased CRC in women [119]. However, no changes in serum leptin were found in CRC patients [120], and in fact, increased expression of leptin and leptin receptor in CRC samples was associated with better prognosis [121].…”