General obesity (high body mass index, BMI) affects circulating proteins. Obesity-related outcomes, however, differ by body shape but waist and hip circumferences cannot distinguish abdominal from general obesity. We therefore used the allometric body shape index (ABSI), waist-to-hip index (WHI) and hip index (HI), which factor out general obesity. We examined in linear regression models associations with 7289 protein markers (SomaScan) in 4037 EPIC cohort participants. One fifth of 2256 proteins associated with BMI were additionally independently associated with allometric abdominal obesity (418 with ABSI, 479 with WHI, same direction as BMI), and 38 proteins were associated with HI (predominantly opposite direction to BMI). Traditional body shape indices resembled BMI. Highest ranked proteins for ABSI and WHI were adiponectin (negative) and GHR (positive), for HI were TIMP4 and CD300LG (positive), whereas for BMI were leptin and FABP3 (positive). Only protein-coding genes for ABSI and WHI highlighted pathways of epithelial mesenchymal transition, xenobiotic metabolism and coagulation and genes upregulated in the liver, while protein-coding genes for BMI were upregulated in adipose tissue. Thus, allometric abdominal obesity and HI showed distinct proteomic profiles from general obesity, reflecting distinct pathophysiological mechanisms. Distinguishing abdominal from general obesity could help develop treatments targeting fat distribution.

Dicarbonyls are reactive precursors of advanced glycation end-products. They are formed during food processing, and endogenously in humans during glycolysis and lipid peroxidation. Higher plasma dicarbonyls, particularly methylglyoxal (MGO), promote insulin resistance and type 2 diabetes, but the association between dietary dicarbonyls intake and type 2 diabetes is unknown. This study examined the associations between dietary dicarbonyls and type 2 diabetes incidence. 11,995 incident type 2 diabetes cases and a sub-cohort of 15,797 controls from the prospective multi-center European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct cohort were included. Intakes of three major dicarbonyls MGO, glyoxal [GO], and 3-deoxyglucosone [3-DG] were estimated at baseline using dietary questionnaires. Type 2 diabetes risk according to dietary dicarbonyl intake was estimated by multivariable-adjusted hazard ratios from Prentice-weighted Cox-regression analyses. Higher intakes of MGO (sample-specific mean intake 3.4 ± 1.3 mg/d) and 3-DG (13.8 ± 10.5) were associated with lower incidence of type 2 diabetes (HR 0.92 [95

BACKGROUND:Excessive adiposity increases disease risk, however, the metabolic processes underlying these associations remain incompletely understood. METHODS:We compared metabolic signatures (MSs) of adiposity indices (non-allometric: body fat %, waist circumference, hip circumference, waist-to-hip ratio, body mass index; allometric: a body shape index [ABSI], hip index [HI], waist-to-HI ratio) by sex and examined their cross-sectional associations with 29 clinical biomarkers in 151,526 UK Biobank participants. MSs performance was validated in an independent cohort. FINDINGS:In females, MSs mainly consisted of lipoprotein particle concentrations, apolipoproteins, fatty acids and inflammation-linked glycoprotein acetyls, whereas in males lipoproteins rich in cholesteryl esters and aromatic/branched-chain amino acids predominated. The highest percentages of common metabolites were observed between non-allometric adiposity indices (median: 42.4%; range: 9%-56%). MSs were independently associated with over 25 biomarkers with differences observed by sex and adiposity index, and these associations were stronger compared to the respective phenotypic associations. INTERPRETATION:MSABSI was found to be more atherogenic, whereas MSHI was more favourable for health. This study highlights i) that different regions of adipose tissue undergo distinct metabolic processes overall and by sex, each having unique impact on health, and ii) the importance of considering metabolic factors beyond simple adiposity indices in assessing health risk. FUNDING:This work was supported by Cancer Research UK (grant number C18281/A29019).

BACKGROUND:Hyperthyroidism has been associated with increased risk of breast cancer and in vitro studies have shown that thyroid hormones may influence breast tumorigenesis. We aimed to study associations between prediagnostic circulating thyroid hormone concentrations and breast cancer risk. METHODS:We evaluated associations between breast cancer risk and circulating concentrations of thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), fT3/fT4 ratio, and anti-thyroid peroxidase antibody (TPO-Ab) positivity, in plasma samples from 1518 invasive breast cancer cases (diagnosed between 2 and 14 years after blood collection) and 1518 matched controls from a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort using validated immunoassays. Conditional logistic regression models were used to evaluate associations with breast cancer, with adjustment for established breast cancer risk factors. FINDINGS:In fully adjusted models, fT3 (ORper standard deviation (SD) (95% CI) = 1.16 (1.05-1.29)) and fT4 (ORper SD = 1.11 (1.01-1.22)) concentrations were positively associated with breast cancer risk. For fT3, the association was stronger for HER2-positive tumours (HER2+: ORper SD = 1.59 (1.20-2.11); HER2-: ORper SD = 1.10 (0.98-1.23)) compared to other tumour types (P-heterogeneity = 0.01). TSH concentrations, fT3/fT4 ratio, and TPO-Ab positivity were not associated with breast cancer risk. INTERPRETATION:In this large-scale study, higher prediagnostic circulating fT3 and fT4 concentrations were associated with increased breast cancer risk, particularly for HER2-positive tumours. Confirming these findings is critical to achieving a better understanding of the associations between thyroid function and breast cancer risk, which may inform personalised prevention. FUNDING:This work was funded by the French National Cancer Institute (grant number 2018-118).

Effects (pure direct effect, total indirect effect, and total effect) estimated as function of time to event (years), considering site-specific cancer occurrence as outcome, RelativeIndex of Inequality Tertiles (RIIT) as exposure, age, and country (and sex) as confounders, site-specific lifestyle-behavioural factors as mediators.

Supplementary Table from Metabolically Defined Body Size Phenotypes and Risk of Endometrial Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Excessive adiposity increases disease risk, yet the exact underlying mechanisms remain unknown. We compared sex-specific metabolic signatures (MSs) of adiposity indices (non-allometric: body fat %, waist circumference, hip circumference, waist-to-hip ratio, body mass index; allometric: a body shape index, hip index, waist-to-hip-index ratio) and examined their associations with 29 clinical biomarkers in 151,526 UK Biobank participants. MSs performance was validated in an independent cohort. In females, MSs mainly consisted of lipoprotein particle concentrations, apolipoproteins, fatty acids and inflammation-linked glycoprotein acetyls, whereas in males lipoproteins rich in cholesteryl esters and aromatic/branched-chain amino acids predominated. The highest percentages of common metabolites were observed between non-allometric adiposity indices (median: 42.4%; range: 9%-56%). MSs were independently associated with over 25 biomarkers with differences observed by sex and adiposity index, and these associations were stronger compared to the respective phenotypic associations. MSABSI was found to be more atherogenic, whereas MSHI was more favourable for health. This study highlights i) that different regions of adipose tissue undergo distinct metabolic processes overall and by sex, each having unique impact on health, and ii) the importance of considering metabolic factors beyond simple adiposity indices in assessing health risk. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by Cancer Research UK (grant number C18281/A29019). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). RMM is supported by a Cancer Research UK 25 (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is also supported by the NIHR Bristol Biomedical Research Centre which is funded by the NIHR (BRC-1215-20011) and is a partnership between University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. Department of Health and Social Care disclaimer: The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Both UK Biobank and Epirus Health study underwent ethical review and were approved by the Northwest Multi-Centre Research Ethics Committee and the Research Ethics Committee of the University of Ioannina, respectively. This research has been conducted using the UK Biobank Resource under Application Number 79696. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data used in this work derived from UK Biobank Resource under Application Number 79696

Supplementary Table from Circulating Sex Hormone Levels and Colon Cancer Risk in Men: A Nested Case–Control Study and Meta-Analysis

Substantial evidence links higher adiposity to prostate cancer development. The relationship between adiposity and outcomes after a prostate cancer diagnosis, however, is unclear. This study aimed to investigate the association between adiposity measured close to prostate cancer diagnosis and all-cause and prostate cancer-specific mortality in a prospective cohort study. Cox regression analyses estimated HRs and 95% confidence intervals (CI) for mortality in 3,760 men in the UK Biobank who had first primary prostate cancer and complete data on body mass index (BMI), waist circumference, hip circumference, waist-to-hip ratio (measured up to 2 years before or up to 5 years after diagnosis), and on covariates (diagnosis age and year, smoking, Townsend deprivation index, exercise, sedentary activities, and alcohol). The waist-to-height ratio and body fat percentage (assessed by bioelectrical impedance) were also evaluated as adiposity measures. Each 5-U increment in pre- or post-diagnosis BMI (N = 3,760) was associated with a 30% (95% CI, 1.18-1.44) higher rate of all-cause mortality (deaths = 680), a 33% (95% CI, 1.15-1.52) higher rate of prostate cancer-specific mortality (deaths = 331), and a 28% (95% CI, 1.12-1.47) higher rate of non-prostate cancer mortality (deaths = 347). Positive associations of similar magnitude were observed for separate analyses by pre- and post-diagnosis BMI and for waist and hip circumference, waist-to-hip ratio, waist-to-height ratio, and body fat percentage. Obesity assessed close to prostate cancer diagnosis is associated with higher mortality. More studies are needed to strengthen the evidence and clarify the mechanisms behind the observed associations.Significance: Patients with prostate cancer might improve their chances of survival by avoiding obesity.

Background/Objectives: Worldwide, men experience a higher incidence of pancreatic cancer (PC) than women. Methods: To increase understanding of the underlying reasons for this sex-related difference, we analysed general and sex-related risk factors for PC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (women/men No. = 293,682/136,728; 717/577 PC-cases). Results: Cox proportional hazards models showed a 1.31-fold higher risk of developing PC for men compared to women (HR, 95% CI 1.15–1.49) after adjustment for age, smoking history, BMI, diabetes, and alcohol consumption. Associations of PC with established risk factors did not differ between men and women, with the exception of a greater risk of PC among women with greater attained body height, meat consumption and cigarettes smoked (1.12 (1.05–1.19) per 5 cm, 1.18 (1.02–1.36) per 100 g/d, 1.42 (1.27–1.59) per 10/d; respectively). Among child-bearing women, long cumulative duration of breastfeeding was inversely associated with risk of PC (HR 0.74, 95% CI 0.61–0.89) for >5.7 months of breastfeeding (median) relative to ≤5.7 months and among HRT users, cumulative duration of HRT use was inversely associated with PC risk (HR 0.71, 95% CI 0.53–0.95, >2.4 versus ≤2.4 years). Further reproductive and hormonal factors, such as age at menarche, number of full-term pregnancies, age at menopause, or use of oral contraceptives, were not significantly associated with PC risk. Conclusions: Pooled analyses of large cohort studies are needed to confirm these results, and detailed data on the type and intensity of HRT are required to better evaluate its effect.

Kidney cancer is related to obesity and inflammation and platelets are involved in thrombo-inflammation, but the prospective associations of individual leucocyte subtypes and platelet parameters with kidney cancer risk are unclear. Using data from the UK Biobank cohort and multivariable Cox proportional hazards models, we obtained hazard ratios (HR per one standard deviation increase) with 95

Descriptive analyses according to sex and country, Analyses to verify mediation assumptions. Supplementary Table S1 Descriptive analyses of the male EPIC population in terms of demographic, clinical, and risk/protective factors for cancer, according to the Relative Index of Inequality Tertiles (RIIT). Supplementary Table S2 Descriptive analyses of the female EPIC population in terms of demographic, clinical, and risk/protective factors for cancer, according to the Relative Index of Inequality Tertiles (RIIT). Supplementary Table S3 Descriptive analyses of the EPIC population in terms of demographic, clinical, and lifestyle risk/protective factors for cancer, according to sex and country. Supplementary Table S4 Multinomial logistic, logistic, and linear regressions results in terms of Odds Ratios (OR) or linear coefficient (beta) showing the association between the Relative Index of Inequality Tertiles (RIIT) and putative mediators. Supplementary Table S5 Cox Proportional-Hazard models showing the Hazard Ratio (HR) for the site-specific putative mediators on the incidence of the tumour at the relative site.

BACKGROUND:Obesity and diabetes are positively associated with pancreatic cancer risk. It is unclear, however, whether fat or fat-free mass plays a role in these relationships, whether abdominal obesity is more important than general obesity or whether the associations with anthropometric indices and diabetes are independent of each other. METHODS:We used multivariable Cox proportional hazards models to examine the prospective associations of body composition (allometric fat-mass index (AFI) and allometric lean-mass index (ALI), based on bioelectrical impedance, uncorrelated with each other and with height), waist size (allometric waist-to-hip index (WHI), uncorrelated with weight and height) and diabetes with pancreatic cancer risk in UK Biobank. We tested heterogeneity by sex, age and follow-up time with the augmentation method (p_het). RESULTS:During a mean follow-up of 10.4 years, 999 pancreatic cancer cases were ascertained in 427,939 participants. AFI was positively associated with pancreatic cancer risk in participants overall, independent of ALI, WHI, diabetes and covariates (hazard ratio HR = 1.102; 95% confidence interval CI = 1.033-1.176 per 1 standard deviation (SD) increase), more strongly in women aged under 55 years at recruitment (HR = 1.457; 95% CI = 1.181-1.797; p_het = 0.007) and in men only for follow-up 6 years or longer (HR = 1.159; 95% CI = 1.037-1.295; p_het = 0.075). ALI was positively associated with pancreatic cancer risk in participants overall (HR = 1.072; 95% CI = 1.005-1.145), more specifically in men (HR = 1.132; 95% CI = 1.035-1.238; p_het = 0.091). A positive association of WHI with pancreatic cancer risk was observed only in unadjusted models but was lost after adjustment for smoking status and diabetes. Independent of anthropometric indices, diabetes was associated positively with pancreatic cancer risk in participants overall (HR = 1.688; 95% CI = 1.365-2.087), but in women only for follow-up under 6 years (HR = 2.467; 95% CI = 1.477-4.121; p_het = 0.042). CONCLUSIONS:General obesity (reflected in AFI and ALI) and diabetes but not abdominal obesity were associated positively with pancreatic cancer risk, independent of each other and covariates.

Introduction Observational studies have shown that more educated people are at lower risk of developing type 2 diabetes (T2D). However, robust study designs are needed to investigate the likelihood that such a relationship is causal. This study used genetic instruments for education to estimate the effect of education on T2D using the Mendelian randomisation (MR) approach.Methods Analyses have been conducted in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study (more than 20 000 individuals), a case-cohort study of T2D nested in the EPIC cohort. Education was measured as Years of Education and Relative Index of Inequality. Prentice-weighted Cox models were performed to estimate the association between education and T2D. One-sample MR analyses investigated whether genetic predisposition towards longer education was associated with risk of T2D and investigated potential mediators of the association.Results MR estimates indicated a risk reduction of about 15% for each year of longer education on the risk of developing T2D, confirming the protective role estimated by observational models (HR 0.96, 95% CI 0.95 to 0.96). MR analyses on putative mediators showed a significant role of education on body mass index, alcohol consumption, adherence to the Mediterranean diet and smoking habits.Conclusion The results supported the hypothesis that higher education is a protective factor for the risk of developing T2D. Based on its position in the causal chain, education may be antecedent of other known risk factors for T2D including unhealthy behaviours. These findings reinforce evidence obtained through observational study designs and bridge the gap between correlation and causation.

Sarcopenia is characterised by low grip strength, muscle quantity or quality, and physical performance. This study investigated the associations of sarcopenia and its components with cancer incidence. A prospective cohort study was conducted utilising data from the UK Biobank. Sarcopenia and its components were defined according to the European Working Group on Sarcopenia in Older People criteria (EWGSOP2 2019). Cox proportional hazard models adjusted for sociodemographic, lifestyle, and health‐related factors were performed. Overall, 63,379 out of 414,094 study participants had an incident diagnosis of cancer during a median follow‐up of 11.7 years. In total, 32,286 participants had probable sarcopenia and 934 confirmed/severe sarcopenia at recruitment. Combined probable, confirmed, and severe sarcopenia was associated with a higher risk of liver (hazard ratio [HR] = 1.65, 95% confidence interval [CI]: 1.17–2.33), haematological (HR = 1.22, 95% CI: 1.01–1.46), and colorectal cancer (HR = 1.21, 95% CI: 1.04–1.41) in males, but not in females. The components of sarcopenia were associated with a higher risk of several cancers, including low grip strength (with liver, haematological and colorectal cancer in males), low muscle mass index (oesophageal in females and oral cancer in males), and slow walking pace (liver and lung in males, lung and overall cancer in females). Compared to participants with non‐sarcopenic obesity, those with sarcopenic obesity had a higher risk of colorectal cancer in males (HR = 1.31, 95% CI: 1.03–1.68). Our study suggests that sarcopenia, sarcopenia components, and sarcopenic obesity can be associated with risk for several cancers, mainly of the gastrointestinal tract and in males. Thus, early identification of sarcopenia components may benefit cancer prevention.

BackgroundInflammation influences tumour progression and cancer prognosis, but its role preceding breast cancer (BC) and its prognostic implications remain inconclusive. MethodsWe studied pre-diagnostic plasma inflammatory biomarkers in 1538 women with BC from the EPIC study. Cox proportional hazards models assessed their relationship with all-cause and BC-specific mortality, adjusting for tumour characteristics and lifestyle factors. ResultsOver a 7-year follow-up after diagnosis, 229 women died, 163 from BC. Elevated IL-6 levels were associated with increased all-cause mortality risk (HR1-SD 1.25, 95% CI 1.07-1.47). Among postmenopausal, IL-6 was associated with higher all-cause (HR1-SD 1.41, 95% CI 1.18-1.69) and BC-specific mortality (HR1-SD 1.31, 95% CI 1.03-1.66), (PHeterogeneity (pre/postmenopausal) < 0.05 for both), while IL-10 and TNF alpha were associated with all-cause mortality only (HR1-SD 1.19, 95% CI 1.02-1.40 and HR1-SD 1.28, 95% CI 1.06-1.56). Among ER+PR+, IL-10 was associated with all-cause and BC-specific mortality (HR1-SD 1.35, 95% CI 1.10-1.65 and HR1-SD 1.42 95% CI 1.08-1.86), while TNF-alpha was associated with all-cause mortality in HER2- (HR1-SD 1.31, 95% CI 1.07-1.61). An inflammatory score predicted higher all-cause mortality, especially in postmenopausal women (HR1-SD 1.30, 95% CI 1.07-1.58). ConclusionsHigher pre-diagnosis IL-6 levels suggest poorer long-term survival among BC survivors. In postmenopausal survivors, elevated IL-6, IL-10, and TNF alpha and inflammatory scores seem to predict all-cause mortality.

Thyroid cancer (TC) is substantially more common in women than in men, pointing to a possible role of sex steroid hormones. We investigated the association between circulating sex steroid hormones, sex hormone binding globulin (SHBG) and the risk of differentiated TC in men and women within the European Prospective Investigation into Cancer and nutrition (EPIC) cohort. During follow-up, we identified 333 first primary incident cases of differentiated TC (152 in pre/peri-menopausal women, 111 in post-menopausal women, and 70 in men) and 706 cancer-free controls. Women taking exogenous hormones at blood donation were excluded. Plasma concentrations of testosterone, androstenedione, dehydroepiandrosterone, estradiol, estrone and progesterone (in pre-menopausal women only) were performed using liquid chromatography/mass spectrometry method. SHBG concentrations were measured by immunoassay. Odds ratios (ORs) were estimated using conditional logistic regression models adjusted for possible confounders. No significant associations were observed in men and postmenopausal women, while a borderline significant increase in differentiated TC risk was observed with increasing testosterone (adjusted OR T3 vs T1: 1.68, 95% CI: 0.96-2.92, ptrend = .06) and androstenedione concentrations in pre/perimenopausal women (adjusted OR T3 vs T1: 1.78, 95% CI: 0.96-3.30, ptrend = .06, respectively). A borderline decrease in risk was observed for the highest progesterone/estradiol ratio (adjusted OR T3 vs T1: 0.54, 95% CI: 0.28-1.05, ptrend = .07). Overall, our results do not support a major role of circulating sex steroids in the etiology of differentiated TC in post-menopausal women and men but may suggest an involvement of altered sex steroid production in pre-menopausal women.

Abstract Background Obesity and diabetes are associated inversely with low‐grade prostate cancer risk and affect steroid hormone synthesis but whether they modify each other's impact on prostate cancer risk remains unknown. Methods We examined the independent associations of diabetes, body mass index (BMI), ‘a body shape index’ (ABSI), hip index (HI), circulating testosterone, sex hormone binding globulin (SHBG) (per one standard deviation increase) and oestradiol ≥175 pmol/L with total prostate cancer risk using multivariable Cox proportional hazards models for UK Biobank men. We evaluated multiplicative interactions (pMI) and additive interactions (relative excess risk from interaction (pRERI), attributable proportion (pAR), synergy index (pSI)) with obese (BMI ≥30 kg/m2) and diabetes. Results During a mean follow‐up of 10.3 years, 9417 incident prostate cancers were diagnosed in 195,813 men. Diabetes and BMI were associated more strongly inversely with prostate cancer risk when occurring together (pMI = 0.0003, pRERI = 0.032, pAP = 0.020, pSI = 0.002). ABSI was associated positively in obese men (HR = 1.081; 95% CI = 1.030–1.135) and men with diabetes (HR = 1.114; 95% CI = 1.021–1.216). The inverse associations with obesity and diabetes were attenuated for high‐ABSI ≥79.8 (pMI = 0.022, pRERI = 0.008, pAP = 0.005, pSI <0.0001 obesity; pMI = 0.017, pRERI = 0.047, pAP = 0.025, pSI = 0.0005 diabetes). HI was associated inversely in men overall (HR = 0.967; 95% CI = 0.947–0.988). Free testosterone (FT) was associated most strongly positively in normal weight men (HR = 1.098; 95% CI = 1.045–1.153) and men with diabetes (HR = 1.189; 95% CI = 1.081–1.308). Oestradiol was associated inversely in obese men (HR = 0.805; 95% CI = 0.682–0.951). The inverse association with obesity was stronger for high‐FT ≥243 pmol/L (pRERI = 0.040, pAP = 0.031, pSI = 0.002) and high‐oestradiol (pRERI = 0.030, pAP = 0.012, pSI <0.0001). The inverse association with diabetes was attenuated for high‐FT (pMI = 0.008, pRERI = 0.015, pAP = 0.009, pSI = 0.0006). SHBG was associated inversely in men overall (HR = 0.918; 95% CI = 0.895–0.941), more strongly for high‐HI ≥49.1 (pMI = 0.024). Conclusions Obesity and diabetes showed synergistic inverse associations with prostate cancer risk, likely involving testosterone reduction for diabetes and oestrogen generation for obesity, which were attenuated for high‐ABSI. HI and SHBG showed synergistic inverse associations with prostate cancer risk.

The allometric body shape index (ABSI) and hip index (HI), as well as multi-trait body shape phenotypes, have not yet been compared in their associations with inflammatory markers. The aim of this study was to examine the relationship between novel and traditional anthropometric indexes with inflammation using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank cohorts. Participants from EPIC (n = 17,943, 69.1

BACKGROUND:Traditional body-shape indices such as Waist Circumference (WC), Hip Circumference (HC), and Waist-to-Hip Ratio (WHR) are associated with colorectal cancer (CRC) risk, but are correlated with Body Mass Index (BMI), and adjustment for BMI introduces a strong correlation with height. Thus, new allometric indices have been developed, namely A Body Shape Index (ABSI), Hip Index (HI), and Waist-to-Hip Index (WHI), which are uncorrelated with weight and height; these have also been associated with CRC risk in observational studies, but information from Mendelian randomization (MR) studies is missing. METHODS:We used two-sample MR to examine potential causal cancer site- and sex-specific associations of the genetically-predicted allometric body-shape indices with CRC risk, and compared them with BMI-adjusted traditional body-shape indices, and BMI. Data were obtained from UK Biobank and the GIANT consortium, and from GECCO, CORECT and CCFR consortia. RESULTS:WHI was positively associated with CRC in men (OR per SD: 1.20, 95% CI: 1.03-1.39) and in women (1.15, 1.06-1.24), and similarly for colon and rectal cancer. ABSI was positively associated with colon and rectal cancer in men (1.27, 1.03-1.57; and 1.40, 1.10-1.77, respectively), and with colon cancer in women (1.20, 1.07-1.35). There was little evidence for association between HI and colon or rectal cancer. The BMI-adjusted WHR and HC showed similar associations to WHI and HI, whereas WC showed similar associations to ABSI only in women. CONCLUSIONS:This large MR study provides strong evidence for a potential causal positive association of the allometric indices ABSI and WHI with CRC in both sexes, thus establishing the association between abdominal fat and CRC without the limitations of the traditional waist size indices and independently of BMI. Among the BMI-adjusted traditional indices, WHR and HC provided equivalent associations with WHI and HI, while differences were observed between WC and ABSI.