Abstract
Leptin, a peptide hormone produced primarily by the adipocytes, is hypothesized to play a role in the pathogenesis of colorectal cancer (CRC). Soluble leptin receptor (sOB-R) may regulate leptin's physiologic functions; however its relation to CRC risk is unknown. This study explored the association of leptin and sOB-R with risk of CRC in a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 1,129 incident CRC cases (713 colon, 416 rectal) were matched within risk sets to 1,129 controls. Conditional logistic regression was used to calculate relative risks (RR) and 95% confidence intervals (CI). After multivariable adjustment including body mass index (BMI), waist circumference, and baseline leptin concentrations, sOB-R was strongly inversely associated with CRC (RR comparing the highest quintile vs. the lowest, 0.55; 95% CI, 0.40-0.76; P(trend) = 0.0004) and colon cancer (RR, 0.42; 95% CI, 0.28-0.63, P(trend) = 0.0001); whereas no association was seen for rectal cancer (RR adjusted for BMI and waist circumference, 0.83; 95% CI, 0.48-1.44, P(trend) = 0.38). In contrast, leptin was not associated with risk of CRC (RR adjusted for BMI and waist circumference, 0.85; 95% CI, 0.56-1.29, P(trend) = 0.23). Additional adjustments for circulating metabolic biomarkers did not attenuate these results. These novel findings suggest a strong inverse association between circulating sOB-R and CRC risk, independent of obesity measures, leptin concentrations, and other metabolic biomarkers. Further research is needed to confirm the potentially important role of sOB-R in CRC pathogenesis.
Highlights
Leptin is a 16 kDa protein encoded by the ob gene mostly produced by white adipose tissue that is secreted into the circulation
When the associations were explored by cancer site, individuals in the 4th quintile had a higher risk of colon cancer compared with those in the lowest quintile, the trend across quintiles was not statistically significant (RR, 1.79; 95% confidence intervals (CI), 1.19–2.69; Ptrend 1⁄4 0.46; Pnonlinearity 1⁄4 0.04)
Adjustment for body mass index (BMI) and waist circumference (WC) strongly attenuated the association with colon cancer (RR for the highest vs. the lowest quintile, 0.93; 95% CI, 0.54–1.60; Ptrend 1⁄4 0.27; Table 3)
Summary
Leptin is a 16 kDa protein encoded by the ob gene mostly produced by white adipose tissue that is secreted into the circulation. In 2 Scandinavian nested case-control studies [10, 11], leptin was associated with risk for colon cancer in men, but not in women; whereas an association in women was reported in the Japan Collaborative Cohort Study [12] and in the Women's Health Initiative cohort of postmenopausal women [13] Most of these studies were of relatively small sample size and did not fully account for major determinants of serum leptin levels, including lifestyle factors [14], body fat distribution [7, 15], as well as other metabolic markers [16,17,18,19]. Leptin actions may be modulated by other regulatory biologic factors It is well established, that the effects of leptin are mediated by membrane protein receptors, which circulate in soluble form in plasma [20,21,22]. To date no epidemiologic study investigated the association between sOB-R and CRC, as well as the joint effects of sOB-R and leptin on CRC
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