A Nested Case-Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Background Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown. Methods and Findings The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m.sup.2 ), (2) metabolically healthy/overweight (BMI [greater than or equal to] 25 kg/m.sup.2 ), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m.sup.2 ), and (4) metabolically unhealthy/overweight (BMI [greater than or equal to] 25 kg/m.sup.2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [[greater than or equal to]80 cm for women and [greater than or equal to]94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of Conclusions These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.
Author(s): Neil Murphy 1,*, Amanda J. Cross 1, Mustapha Abubakar 2, Mazda Jenab 3, Krasimira Aleksandrova 4, Marie-Christine Boutron-Ruault 5,6,7, Laure Dossus 5,6,7, Antoine Racine 5,6,7, Tilman Kühn 8, Verena [...]