Pre-Diagnostic Circulating Resistin Concentrations Are Not Associated with Colorectal Cancer Risk in the European Prospective Investigation into Cancer and Nutrition Study

Abstract

Resistin is a polypeptide implicated in inflammatory processes, and as such could be linked to colorectal carcinogenesis. In case-control studies, higher resistin levels have been found in colorectal cancer (CRC) patients compared to healthy individuals. However, evidence for the association between pre-diagnostic resistin and CRC risk is scarce. We investigated pre-diagnostic resistin concentrations and CRC risk within the European Prospective Investigation into Cancer and Nutrition using a nested case-control study among 1293 incident CRC-diagnosed cases and 1293 incidence density-matched controls. Conditional logistic regression models controlled for matching factors (age, sex, study center, fasting status, and women-related factors in women) and potential confounders (education, dietary and lifestyle factors, body mass index (BMI), BMI-adjusted waist circumference residuals) were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for CRC. Higher circulating resistin concentrations were not associated with CRC (RR per doubling resistin, 1.11; 95% CI 0.94–1.30; p = 0.22). There were also no associations with CRC subgroups defined by tumor subsite or sex. However, resistin was marginally associated with a higher CRC risk among participants followed-up maximally two years, but not among those followed-up after more than two years. We observed no substantial correlation between baseline circulating resistin concentrations and adiposity measures (BMI, waist circumference), adipokines (adiponectin, leptin), or metabolic and inflammatory biomarkers (C-reactive protein, C-peptide, high-density lipoprotein cholesterol, reactive oxygen metabolites) among controls. In this large-scale prospective cohort, there was little evidence of an association between baseline circulating resistin concentrations and CRC risk in European men and women.

Pre‐diagnostic circulating resistin concentrations and mortality among individuals with colorectal cancer: Results from the European Prospective Investigation into Cancer and Nutrition study

“…Although case-control studies suggest that persons with CRC have higher resistin concentrations than controls, 16 we have previously found in a prospective study that in persons free of cancer at baseline resistin is not significantly associated with risk of incident CRC. 17 Findings from that prospective study are consistent with a previous case-cohort study within the Women's Health Initiative study, 18 and our recent Mendelian Randomization study. 19 Together with the results from the present analysis, evidence suggests that circulating resistin concentrations are neither related to risk of CRC nor mortality among persons with CRC.…”

“…14,36 However, in a previous study using EPIC data, we found no significant correlation between pre-diagnostic resistin and BMI (correlation coefficient = À0.02, P = .52), 17 but a weakly significant positive correlation with CRP concentrations in control participants (correlation coefficient = 0.12, P < .01). 17 The findings were consistent with several population-based studies that showed a significant but comparatively weak positive association between resistin and BMI in humans (modest absolute value of correlation coefficients). [37][38][39] The null or least significant correlation between resistin and BMI as well as CRP might partially help explain the lack of association between resistin and CRC mortality in our study.…”

“…8 While some studies found higher resistin concentrations in patients with CRC as compared to controls, 16 findings from prospective studies, including our recent study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, suggest that pre-diagnostic resistin concentrations are not associated with risk of CRC. 17,18 In a recent Mendelian randomization study with substantial statistical power to detect even weak associations, we found no association between genetically predicted levels of resistin and CRC risk. 19 However, this does not preclude the possibility that resistin may have an effect on CRC cancer progression and mortality, because inflammation [3][4][5][6] and angiogenesis, 7 in which resistin is involved, may contribute to advanced stages of the disease.…”

“…Obesity is also characterized by chronic low‐grade systemic inflammation (CLGSI), 15 and by the infiltration of inflammatory cells into adipose tissues 8 . While some studies found higher resistin concentrations in patients with CRC as compared to controls, 16 findings from prospective studies, including our recent study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, suggest that pre‐diagnostic resistin concentrations are not associated with risk of CRC 17,18 . In a recent Mendelian randomization study with substantial statistical power to detect even weak associations, we found no association between genetically predicted levels of resistin and CRC risk 19 .…”

“…With a standard deviation of 0.52 for log‐transformed resistin concentrations, 17 a sample size of 1343 participants, CRC‐specific mortality of 0.35, a 5% probability of type I error and 80% power, the minimum detectable HR per doubling of resistin levels is 1.28, which represents the smallest effect size in the hazard ratio that our study can statistically distinguish from the null hypothesis. Further information on the rationales of model covariate selection, the implementation of multiple imputation and assessment of the proportional hazard assumption is provided in Data S1.…”