Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study

Abstract

Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

Visceral Adiposity and Cancer: Role in Pathogenesis and Prognosis

“…Gender difference was nevertheless significant only in colorectal cancer. This finding is supported by a Mendelian randomization study [7] on the association between BMI and colorectal cancer incidence: risk was 22% higher among men per 4.2 kg/m 2 increase in BMI and 9% higher among women per 5.2 kg/m 2 . In 2016, the International Agency for Research on Cancer (IARC) Working Group added hepatocellular carcinoma, meningioma, gastric cardia and ovarian cancers to the aforementioned obesity-associated tumors [8].…”

GWAS of allometric body-shape indices in UK Biobank identifies loci suggesting associations with morphogenesis, organogenesis, adrenal cell renewal and cancer

“…A question, therefore, emerges whether excess abdominal fat mediates the development of cancers associated with abdominal obesity 39 , or abdominal obesity and cancer are parallel outcomes with shared genetic predisposition. Although studies exploring a causal relationship between body shape and cancer are limited, Mendelian randomisation based on traditional body-shape indices has already provided evidence for causal positive associations of WHR or WHR adj BMI with colorectal cancer 40 , 41 and renal cell carcinoma 42 but an inverse association with breast cancer 43 .…”

Sex Differences in the Incidence of Obesity-Related Gastrointestinal Cancer

“…In addition, a Mendelian randomization study revealed that higher BMI was associated with increased CRC risk only in men, whereas a higher WHR was more closely correlated with CRC risk in women than in men [ 122 ]. WC, not BMI, was also positively related to CRC risk in postmenopausal women, which might be associated with VAT accumulation [ 123 ].…”