Medicine · Nov 13, 2026

Metabolic abnormalities and colorectal cancer: An integrated secondary analysis triangulating Mendelian randomization with global burden and temporal trends

By Gao Z, Peng K

Metabolic abnormalities are plausible and modifiable contributors to colorectal cancer (CRC), but genetic evidence and population-level burden data are often reported separately. This integrated secondary analysis triangulated Mendelian randomization (MR), Global Burden of Disease 2021 estimates, metabolic risk attribution, estimated annual percentage change analyses, geographic and Socio-demographic Index (SDI) comparisons, and observed age-standardized mortality trends to characterize the relationship between metabolic abnormalities and CRC from 1990 to 2021. Genetically predicted body mass index (BMI), diabetes, and familial combined hyperlipidemia (FCHL) were positively associated with CRC risk in inverse-variance weighted MR analyses, with the strongest association observed for BMI. The diabetes (odds ratio = 1.002, 95% confidence interval = 1.001–1.003) and FCHL (odds ratio = 1.0010, 95% confidence interval = 1.0003–1.0017) estimates were statistically significant but extremely close to the null, indicating minimal individual-level effect sizes on the genetic-liability scale and no basis for inferring clinically meaningful risk differences. Globally, CRC incident cases increased substantially from 916,584 in 1990 to 2,194,143 in 2021, while the age-standardized death rate declined from 15.56 to 12.40 per 100,000 population. China showed a particularly steep increase in incident cases and age-standardized incidence rate. Across SDI strata, CRC incidence rose in all strata except high-SDI settings, whereas diabetes incidence increased in every region and stratum. Low-middle SDI settings showed the clearest ecological co-burden, with rising CRC and diabetes burden occurring together. Age-specific analyses showed that CRC burden attributable to high BMI and high fasting plasma glucose increased sharply with age, with the highest attributable death and disability-adjusted life-year rates in the oldest age groups. Observed global CRC age-standardized death rates declined from 1990 to 2021 for both sexes combined, males, and females. These findings support metabolic health as an important and actionable component of CRC prevention, particularly in settings where CRC and diabetes burdens are rising in parallel. The population-level findings should be interpreted as ecological co-burden rather than proof of interaction, and the MR estimates reflect lifelong genetic liability rather than clinical relative risks. In particular, the diabetes and FCHL estimates should not be interpreted as clinically meaningful individual-level effects.

doi.org/10.1097/md.0000000000051519PubMed 43024327Populations