Explaining the link between adiposity and colorectal cancer risk in men and postmenopausal women in the UK Biobank: A sequential causal mediation analysis

S. Ghazaleh Dashti, Vivian Viallon, Julie A. Simpson, Amalia Karahalios, Margarita Moreno-Betancur, Dallas R. English, Marc J. Gunter, Neil Murphy

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Abstract

Mechanisms underlying adiposity–colorectal cancer (CRC) association are incompletely understood. Using UK Biobank data, we investigated the role of C-reactive protein (CRP), hemoglobin-A1c (HbA1c) and (jointly) sex hormone-binding globulin (SHBG) and testosterone, in explaining this association. Total effect of obesity versus normal-weight (based on waist circumference, body mass index, waist–hip ratio) on CRC risk was decomposed into natural direct (NDE) and indirect (NIE) effects using sequential mediation analysis. After a median follow-up of 7.1 years, 2070 incident CRC cases (men = 1,280; postmenopausal women = 790) were recorded. For men, the adjusted risk ratio (RR) for waist circumference (≥102 vs. ≤94 cm) was 1.37 (95% confidence interval [CI], 1.19–1.58). The RRsNIE were 1.08 (95% CI: 1.01–1.16) through all biomarkers, 1.06 (95% CI: 1.01–1.11) through pathways influenced by CRP, 0.99 (95% CI: 0.97–1.01) through HbA1c beyond (the potential influence of) CRP and 1.03 (95% CI: 0.99–1.08) through SHBG and testosterone combined beyond CRP and HbA1c. The RRNDE was 1.26 (95% CI: 1.09–1.47). For women, the RR for waist circumference (≥88 vs. ≤80 cm) was 1.27 (95% CI: 1.07–1.50). The RRsNIE were 1.08 (95% CI: 0.94–1.22) through all biomarkers, 1.08 (95% CI: 0.99–1.17) through CRP, 1.00 (95% CI: 0.98–1.02) through HbA1c beyond CRP and 1.00 (95% CI: 0.92–1.09) through SHBG and testosterone combined beyond CRP and HbA1c. The RRNDE was 1.18 (95% CI: 0.96–1.45). For men and women, pathways influenced by CRP explained a small proportion of the adiposity-CRC association. Testosterone and SHBG also explained a small proportion of this association in men. These results suggest that pathways marked by these obesity-related factors may not explain a large proportion of the adiposity-CRC association.

Original languageEnglish
Pages (from-to)1881-1894
Number of pages14
JournalInternational Journal of Cancer
Volume147
Issue number7
DOIs
Publication statusPublished - 1 Oct 2020

Keywords

  • adiposity
  • C-reactive protein
  • causal mediation analysis
  • colorectal cancer
  • hemoglobin-A1c
  • inflammation
  • insulin resistance
  • sex-hormone-binding globulin
  • sex-steroid hormones
  • testosterone

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