---
title: "Age- and sex-specific links between metabolic syndrome and colorectal cancer risk in UK Biobank"
id: "british-journal-of-cancer-0-age-and-sex-dependent-associations-of-metabolic-syndrome-with-colorectal-cancer"
canonical_url: "https://medichelpline.com/clinical-feed/british-journal-of-cancer-0-age-and-sex-dependent-associations-of-metabolic-syndrome-with-colorectal-cancer"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "British Journal of Cancer"
source_url: "https://www.nature.com/articles/s41416-026-03564-1"
published_at: "2026-07-30T09:25:41.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Age- and sex-specific links between metabolic syndrome and colorectal cancer risk in UK Biobank
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/british-journal-of-cancer-0-age-and-sex-dependent-associations-of-metabolic-syndrome-with-colorectal-cancer
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** British Journal of Cancer
- **Source URL:** [Original Journal Publication](https://www.nature.com/articles/s41416-026-03564-1)
- **Published At:** 2026-07-30T09:25:41.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This prospective cohort analysis of UK Biobank data evaluated associations between **metabolic syndrome (MetS)** and incident **colorectal cancer (CRC)** across age- and sex-specific subgroups. - The study included 379,173 participants aged 40–69 years at baseline, with 4,971 incident CRC cases identified over a median follow-up of 11.8 years. - MetS was defined by established criteria requiring ≥3 of five metabolic abnormalities: elevated waist circumference, hypertriglyceridemia, hyperglycaemia (HbA1c ≥42 mmol/mol or antidiabetic medication), elevated blood pressure (or antihypertensive use), and low HDL-C (or lipid-modifying medications). - Participants were jointly stratified by sex and age (<60 vs ≥60 years) to examine heterogeneity in associations. - Overall, MetS showed the strongest association with CRC risk in younger males (HR 1.31, 95% CI 1.15–1.50). MetS was also significantly associated with CRC in older males (HR 1.18, 95% CI 1.07–1.30) and older females (HR 1.18, 95% CI 1.05–1.33), but not in younger females (HR 1.05, 95% CI 0.89–1.25). - In older males, CRC risk increased with greater numbers of metabolic abnormalities (noted for 3, 4, and 5 abnormalities vs none); this gradient was not observed in females of the same age group according to the source. - Apart from younger females, **elevated waist circumference** was the only individual MetS component that was consistently associated with higher CRC risk. - The authors conclude that the MetS–CRC association is strongly age- and sex-dependent in White populations represented in the UK Biobank, with highest risk in young and middle-aged males, supporting risk-stratified prevention and further research into sex- and age-specific mechanisms. - Study methods included multivariable Cox proportional hazards models, exclusion of participants with prior cancer (except non-melanoma skin cancer) or missing MetS data, covariate adjustment for demographic, lifestyle, dietary, screening, family history and medication variables, and outcome ascertainment through cancer registries and hospital records.
## Clinical Analysis & Structured Key Points
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[articles](https://www.nature.com/bjc/articles?type=article) 4. article Age- and sex-dependent associations of metabolic syndrome with colorectal cancer in the UK Biobank [ Download PDF ](https://www.nature.com/articles/s41416-026-03564-1.pdf) [ Download PDF ](https://www.nature.com/articles/s41416-026-03564-1.pdf) * Article * [Open access](https://www.springernature.com/gp/open-science/about/the-fundamentals-of-open-access-and-open-research) * Published: 30 July 2026 Epidemiology # Age- and sex-dependent associations of metabolic syndrome with colorectal cancer in the UK Biobank * [Zilin Luo](https://www.nature.com/articles/s41416-026-03564-1#auth-Zilin-Luo-Aff1-Aff2) [ORCID: orcid.org/0000-0001-5071-1423](https://orcid.org/0000-0001-5071-1423)[1](https://www.nature.com/articles/s41416-026-03564-1#Aff1),[2](https://www.nature.com/articles/s41416-026-03564-1#Aff2), * [Fatemeh Safizadeh](https://www.nature.com/articles/s41416-026-03564-1#auth-Fatemeh-Safizadeh-Aff1-Aff3-Aff4) [ORCID: orcid.org/0000-0002-3293-9499](https://orcid.org/0000-0002-3293-9499)[1](https://www.nature.com/articles/s41416-026-03564-1#Aff1),[3](https://www.nature.com/articles/s41416-026-03564-1#Aff3),[4](https://www.nature.com/articles/s41416-026-03564-1#Aff4), * [Marko Mandic](https://www.nature.com/articles/s41416-026-03564-1#auth-Marko-Mandic-Aff1-Aff3-Aff4) [ORCID: orcid.org/0000-0002-7372-8284](https://orcid.org/0000-0002-7372-8284)[1](https://www.nature.com/articles/s41416-026-03564-1#Aff1),[3](https://www.nature.com/articles/s41416-026-03564-1#Aff3),[4](https://www.nature.com/articles/s41416-026-03564-1#Aff4), * [Michael Hoffmeister](https://www.nature.com/articles/s41416-026-03564-1#auth-Michael-Hoffmeister-Aff1) [ORCID: orcid.org/0000-0002-8307-3197](https://orcid.org/0000-0002-8307-3197)[1](https://www.nature.com/articles/s41416-026-03564-1#Aff1) & * … * [Hermann Brenner](https://www.nature.com/articles/s41416-026-03564-1#auth-Hermann-Brenner-Aff4) [ORCID: orcid.org/0000-0002-6129-1572](https://orcid.org/0000-0002-6129-1572)[4](https://www.nature.com/articles/s41416-026-03564-1#Aff4) Show authors [_British Journal of Cancer_](https://www.nature.com/bjc) (2026) [Cite this article](https://www.nature.com/articles/s41416-026-03564-1#citeas) [ Save article ](https://www.nature.com/articles/s41416-026-03564-1/save-research?_csrf=ClEJiqqYm45HUw6s7XQF9JNs_c-gdJh4) [ View saved research ](https://www.nature.com/saved-research) ## Abstract ### Background The concurrent rise in metabolic syndrome (MetS) and the changing age profile of colorectal cancer (CRC) necessitates clarifying the heterogeneity in their association across demographic groups. This study aimed to define the precise age- and sex-specific associations between MetS and CRC risk, addressing a key gap to inform targeted prevention paradigms. ### Methods In this cohort study, we analysed data from UK Biobank participants aged 40–69 years (recruited 2006–2010). Participants were stratified by age (<60 or ≥60 years) and sex into four groups. Multivariable Cox proportional hazards models were used to assess the associations of MetS, the number of metabolic abnormalities, and each component with CRC incidence. ### Results Among 379,173 participants, 4971 developed CRC during a median follow-up of 11.8 years. MetS was most strongly associated with CRC in younger males (hazard ratio [HR] 1.31, 95% CI 1.15–1.50), significantly in older adults of both males (HR 1.18, 95% CI 1.07–1.30) and females (HR 1.18, 95% CI 1.05–1.33), but not in younger females (HR 1.05, 95% CI 0.89–1.25). Older males but not females showed increasing risks when having 3, 4, and 5 abnormalities compared to none, respectively. Beyond younger females, elevated waist circumference was the sole component consistently linked to higher risk. ### Conclusions The association between MetS and CRC is strongly dependent on age and sex in White populations, with the highest risk concentrated in young and middle-aged males. These findings directly support risk-stratified prevention and provide crucial clues for investigating the underlying sex- and age-specific biological mechanisms. ## Introduction Colorectal cancer (CRC) ranked as the third most commonly diagnosed cancer and the second leading cause of cancer-related mortality globally in 2022 [[1](https://www.nature.com/articles/s41416-026-03564-1#ref-CR1 "Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–63.")]. A particularly alarming trend is the rapidly increasing incidence of CRC in younger populations [[2](https://www.nature.com/articles/s41416-026-03564-1#ref-CR2 "Akimoto N, Ugai T, Zhong R, Hamada T, Fujiyoshi K, Giannakis M, et al. Rising incidence of early-onset colorectal cancer - a call to action. Nat Rev Clin Oncol. 2021;18:230–43.")]. Despite extensive research, the factors driving this changing age profile of CRC remain incompletely understood. Metabolic syndrome (MetS), a cluster of interrelated metabolic abnormalities including central obesity, hypertriglyceridemia, hypertension, hyperglycaemia, and dyslipidemia [[3](https://www.nature.com/articles/s41416-026-03564-1#ref-CR3 "Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640–5.")], is a well-established risk factor for CRC [[4](https://www.nature.com/articles/s41416-026-03564-1#ref-CR4 "Han F, Wu G, Zhang S, Zhang J, Zhao Y, Xu J. The association of metabolic syndrome and its components with the incidence and survival of colorectal cancer: a systematic review and meta-analysis. Int J Biol Sci. 2021;17:487–97.")]. Emerging evidence has linked MetS to CRC risk specifically in younger populations. A nested case-control study from the US reported a 25% higher risk of early-onset CRC (diagnosed before age 50) among individuals with MetS, with females showing a more pronounced 32% increased risk compared to males’ 19% elevated risk [[5](https://www.nature.com/articles/s41416-026-03564-1#ref-CR5 "Chen H, Zheng X, Zong X, Li Z, Li N, Hur J, et al. Metabolic syndrome, metabolic comorbid conditions and risk of early-onset colorectal cancer. Gut. 2021;70:1147–54.")]. Similarly, a large South Korean prospective cohort study with a median 9-year follow-up, involving over 5.7 million adults aged 20–49, demonstrated that MetS was associated with significantly elevated CRC risk, showing hazard ratios ranging from 1.14 to 1.29 depending on tumour location [[6](https://www.nature.com/articles/s41416-026-03564-1#ref-CR6 "Jin EH, Han K, Lee DH, Shin CM, Lim JH, Choi YJ, et al. Association between metabolic syndrome and the risk of colorectal cancer diagnosed before age 50 years according to tumor location. Gastroenterology. 2022;163:637–48.e2.")]. While existing studies have examined MetS-related CRC risk through either sex or age stratification, few investigations have employed joint stratification by both factors. Consequently, the potential interaction between sex-specific biological mechanisms and age-dependent susceptibility in MetS-associated carcinogenesis remains poorly understood. This gap is especially important given the biological, hormonal, and behavioural differences across different ages and between males and females. Understanding how these factors interact is vital for improving individualised risk prediction and tailoring CRC screening strategies. Therefore, this study aims to evaluate the association between MetS and CRC risk across sex-specific and age-specific subgroups, leveraging the rich prospective cohort data from the UK Biobank. ## Methods ### Study design and population This study was based on a large-scale, population-based prospective cohort derived from the UK Biobank, which recruited over 500,000 participants aged 40–69 years between 2006 and 2010. The details have been previously documented [[7](https://www.nature.com/articles/s41416-026-03564-1#ref-CR7 "Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;12:e1001779.")]. In brief, participants were enroled from 22 assessment centres across England, Scotland, and Wales and underwent comprehensive baseline assessments, including questionnaires, physical measurements, and biological sample collection. Longitudinal follow-up of participants was conducted through linkage with electronic health records, enabling continuous tracking of various health outcomes including cancer incidence. Ethical approval for the UK Biobank study was obtained from the North West Multi-Centre Research Ethics Committee (11/NW/0382). All participants provided written informed consent prior to enrolment. Individuals with a prior cancer diagnosis (except for non-melanoma skin cancer) or missing data on MetS components were excluded from the current analysis. This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline [[8](https://www.nature.com/articles/s41416-026-03564-1#ref-CR8 "Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. Strengthening the Reporting of Observational Studies in Epidemiology \(STROBE\) statement: guidelines for reporting observational studies. Bmj. 2007;335:806–8.")]. ### Assessment of MetS MetS was defined according to established criteria [[3](https://www.nature.com/articles/s41416-026-03564-1#ref-CR3 "Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640–5.")], incorporating five metabolic abnormalities: elevated waist circumference (≥102 cm in males and ≥88 cm in females for European populations), hypertriglyceridemia (≥1.7 mmol/L), hyperglycaemia (glycated haemoglobin (HbA1c) ≥ 42 mmol/mol, or antidiabetic medication use), elevated blood pressure (systolic ≥130 mmHg, diastolic ≥85 mmHg, or antihypertensive medication use), and low HDL-C (<1.03 mmol/L in males, <1.29 mmol/L in females, or lipid-modifying medications) (Table [S1](https://www.nature.com/articles/s41416-026-03564-1#MOESM1)). For hyperglycaemia, because the UK Biobank study did not require fasting before blood glucose measurement, we used the more stable indicator of HbA1c, with a cutoff of ≥42 mmol/mol to define impaired glucose regulation [[9](https://www.nature.com/articles/s41416-026-03564-1#ref-CR9 "John WG. Use of HbA1c in the diagnosis of diabetes mellitus in the UK. The implementation of World Health Organization guidance 2011. Diabet Med. 2012;29:1350–7."), [10](https://www.nature.com/articles/s41416-026-03564-1#ref-CR10 "Li M, Cao SM, Dimou N, Wu L, Li JB, Yang J. Association of metabolic syndrome with risk of lung cancer: a population-based prospective cohort study. Chest. 2024;165:213–23.")]. Lipid-modifying medications can influence multiple aspects of the lipid profile, including HDL-C and triglycerides [[11](https://www.nature.com/articles/s41416-026-03564-1#ref-CR11 "Ascaso J, Gonzalez Santos P, Hernandez Mijares A, Mangas Rojas A, Masana L, Millan J, et al. Management of dyslipidemia in the metabolic syndrome: recommendations of the Spanish HDL-Forum. Am J Cardiovasc Drugs. 2007;7:39–58.")]. To mitigate potential redundancy in classification, these medications were categorised under the reduced HDL-C group. The use of these medications was determined through Anatomical Therapeutic Chemical (ATC) codes, referencing an extensive review of prior studies that defined MetS using ATC classifications [[10](https://www.nature.com/articles/s41416-026-03564-1#ref-CR10 "Li M, Cao SM, Dimou N, Wu L, Li JB, Yang J. Association of metabolic syndrome with risk of lung cancer: a population-based prospective cohort study. Chest. 2024;165:213–23."), [12](https://www.nature.com/articles/s41416-026-03564-1#ref-CR12 "Yuan F, Wen W, Jia G, Long J, Shu XO, Zheng W. Serum lipid profiles and cholesterol-lowering medication use in relation to subsequent risk of colorectal cancer in the UK biobank cohort. Cancer Epidemiol Biomarkers Prev. 2023;32:524–30."),[13](https://www.nature.com/articles/s41416-026-03564-1#ref-CR13 "Mendonça FM, de Sousa FR, Barbosa AL, Martins SC, Araújo RL, Soares R, et al. Metabolic syndrome and risk of cancer: which link? Metabolism. 2015;64:182–9."),[14](https://www.nature.com/articles/s41416-026-03564-1#ref-CR14 "Chandler PD, Song Y, Lin J, Zhang S, Sesso HD, Mora S, et al. Lipid biomarkers and long-term risk of cancer in the Women’s Health Study. Am J Clin Nutr. 2016;103:1397–407.")]. A diagnosis of MetS was assigned when at least three of these criteria were met. ### Outcomes Incident CRC cases were identified through linkage to national cancer registries and hospitals, using International Classification of Diseases, 10th Revision (ICD-10) codes C18–C20. Follow-up data for cancer incidence were accessible through national cancer registries until July 31, 2019, for England, December 31, 2016, for Wales, and October 31, 2015, for Scotland. CRC cases diagnosed beyond these respective registry censoring dates were captured through hospital episode statistics, which remained available until September 30, 2021, for England and July 31, 2021, for Scotland. In Wales, complete diagnostic records were only obtainable up to March 31, 2016, preceding the registry data cutoff date. ### Covariates During baseline evaluations, comprehensive covariate data were collected through standardised protocols. Demographic variables included age (continuous variable), self-reported ethnicity (categorical: White, Other), and socioeconomic status measured by the Townsend deprivation index (continuous). Educational attainment was classified as an ordinal categorical variable (higher academic/professional, lower academic/vocational, no formal qualifications). Lifestyle factors comprised smoking status (categorical: never, former, current), alcohol consumption frequency (categorical: never, special occasions only, 1–3 times/month, 1–2 times/week, 3–4 times/week, daily or almost daily), and physical activity levels (categorical: low, moderate, high based on international physical activity questionnaire (IPAQ) [[15](https://www.nature.com/articles/s41416-026-03564-1#ref-CR15 "Craig CL, Marshall AL, Sjöström M, Bauman AE, Booth ML, Ainsworth BE, et al. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc. 2003;35:1381–95.")]. Dietary variables included daily fruit intake (continuous, pieces/day) and vegetable consumption (continuous, tablespoons/day), along with red/processed meat intake (categorical: never, less than once a week, once a week, ≥2 times a week). Medical covariates were all categorical: CRC screening history (binary), family history of CRC in first-degree relatives (binary), and regular use of non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin (binary). ### Statistical analysis In the UK Biobank, incident early-onset CRC cases were too few for meaningful analysis [[16](https://www.nature.com/articles/s41416-026-03564-1#ref-CR16 "Gausman V, Liang PS, O’Connell K, Kantor ED, Du M. Evaluation of early-life factors and early-onset colorectal can
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