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BACKGROUND: Tumour-promoting inflammation is a “hallmark” of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. METHODS: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis -Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,162 cancer cases and up to 824,556 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant ( P < 5.0 x 10 (-8) ) cis -acting SNPs (i.e. in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r (2) < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P -value (“ q -value”) < 0.05 was used as a threshold to define “strong evidence” to support associations and 0.05 ≤ q -value < 0.20 to define “suggestive evidence”. A colocalisation posterior probability (PPH (4) ) > 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. RESULTS: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR 1.19, 95% CI 1.10-1.29, q -value=0.033, PPH (4) =84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR 1.42, 95% CI 1.20-1.69, q -value=0.055, PPH (4) =73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR 0.66, 95% CI 0.53-0.81, q -value=0.067, PPH (4) =81.8%), macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR 1.14, 95% CI 1.05-1.23, q -value=0.072, PPH (4) =76.1%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR 0.92, 95% CI 0.88-0.97, q -value=0.15), PPH (4) =85.6%). For 22 of 30 cancer outcomes examined, there was little evidence ( q -value ≥ 0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. CONCLUSION: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 5 circulating inflammatory markers in risk of 5 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated.

Additional file 1: Table S1. Beta estimates for genome-wide significant SNPs for early/adult life body size in UK Biobank (overall, men, women). Table S2. Summary information on colorectal cancer risk for the SNPs used in the analysis. Table S3. Number of cancer cases by sex and subsite. Table S4. Sample size and power calculations for each phenotype and group in the Mendelian randomization study of early and adult life body size and risk of colorectal cancer. Table S5. Beta estimates for early/adult life body size in UK Biobank for the SNPs included in the MVMR analysis (overall, men, women). Table S6. STROBE-MR checklist of recommended items to address in reports of Mendelian randomization studies. Table S7. Univariable Mendelian randomization estimates between early and adult body size and colorectal cancer risk. Table S8. Fearly life body size, Fadult body size and Qa in the multivariable MR between early, adult body size and colorectal cancer. Table S9. Multivariable MR Egger analysis to assess the effect of both predicted early life and adult body size on colorectal cancer.

Additional file 2. Funding, acknowledgements. Funding – Information on consortia funding. Acknowledgements – Information on consortia acknowledgements.

Importance: Premature death from all causes and cardiovascular disease (CVD) causes is higher among persons with diabetes. Objective: To investigate the association between time spent cycling and all-cause and CVD mortality among persons with diabetes, as well as to evaluate the association between change in time spent cycling and risk of all-cause and CVD mortality. Design, setting, and participants: This prospective cohort study included 7459 adults with diabetes from the European Prospective Investigation into Cancer and Nutrition study. Questionnaires regarding medical history, sociodemographic, and lifestyle information were administered in 10 Western European countries from 1992 through 2000 (baseline examination) and at a second examination 5 years after baseline. A total of 5423 participants with diabetes completed both examinations. The final updated primary analysis was conducted on November 13, 2020. Exposures: The primary exposure was self-reported time spent cycling per week at the baseline examination. The secondary exposure was change in cycling status from baseline to the second examination. Main outcomes and measures: The primary and secondary outcomes were all-cause and CVD mortality, respectively, adjusted for other physical activity modalities, diabetes duration, and sociodemographic and lifestyle factors. Results: Of the 7459 adults with diabetes included in the analysis, the mean (SD) age was 55.9 (7.7) years, and 3924 (52.6%) were female. During 110 944 person-years of follow-up, 1673 deaths from all causes were registered. Compared with the reference group of people who reported no cycling at baseline (0 min/wk), the multivariable-adjusted hazard ratios for all-cause mortality were 0.78 (95% CI, 0.61-0.99), 0.76 (95% CI, 0.65-0.88), 0.68 (95% CI, 0.57-0.82), and 0.76 (95% CI, 0.63-0.91) for cycling 1 to 59, 60 to 149, 150 to 299, and 300 or more min/wk, respectively. In an analysis of change in time spent cycling with 57 802 person-years of follow-up, a total of 975 deaths from all causes were recorded. Compared with people who reported no cycling at both examinations, the multivariable-adjusted hazard ratios for all-cause mortality were 0.90 (95% CI, 0.71-1.14) in those who cycled and then stopped, 0.65 (95% CI, 0.46-0.92) in initial noncyclists who started cycling, and 0.65 (95% CI, 0.53-0.80) for people who reported cycling at both examinations. Similar results were observed for CVD mortality. Conclusion and relevance: In this cohort study, cycling was associated with lower all-cause and CVD mortality risk among people with diabetes independent of practicing other types of physical activity. Participants who took up cycling between the baseline and second examination had a considerably lower risk of both all-cause and CVD mortality compared with consistent noncyclists.

Objective To examine the association between serum concentrations of total cholesterol, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol, triglycerides, apolipoprotein A-I (apoA), apolipoprotein B and the incidence of colorectal cancer (CRC). Design Nested case-control study. Setting The study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC), a cohort of more than 520 000 participants from 10 western European countries. Participants 1238 cases of incident CRC, which developed after enrolment into the cohort, were matched with 1238 controls for age, sex, centre, follow-up time, time of blood collection and fasting status. Main outcome measures Serum concentrations were quantitatively determined by colorimetric and turbidimetric methods. Dietary and lifestyle data were obtained from questionnaires. Conditional logistic regression models were used to estimate incidence rate ratios (RRs) and 95% CIs which were adjusted for height, weight, smoking habits, physical activity, education, consumption of fruit, vegetables, meat, fish, alcohol, fibre and energy. Results After adjustments, the concentrations of HDL and apoA were inversely associated with the risk of colon cancer (RR for 1 SD increase of 16.6 mg/dl in HDL and 32.0 mg/dl in apoA of 0.78 (95% CI 0.68 to 0.89) and 0.82 (95% CI 0.72 to 0.94), respectively). No association was observed with the risk of rectal cancer. Additional adjustment for biomarkers of systemic inflammation, insulin resistance and oxidative stress or exclusion of the first 2 years of follow-up did not influence the association between HDL and risk of colon cancer. Conclusions These findings show that high concentrations of serum HDL are associated with a decreased risk of colon cancer. The mechanism behind this association needs further elucidation.

Additional file 2: Figure S1. Scatter plot of SNP-BMI and SNP-CRC associations. Figure S2. Scatter plot of SNP-BMI and SNP-CRC associations (female specific). Figure S3. Scatter plot of SNP-BMI and SNP-CRC associations (male specific). Figure S4. Scatter plot of SNP-BMI and SNP-colon cancer associations. Figure S5. Scatter plot of SNP-BMI and SNP-proximal colon cancer associations. Figure S6. Scatter plot of SNP-BMI and SNP-distal colon cancer associations. Figure S7. Scatter plot of SNP-BMI and SNP-rectal cancer associations. Figure S8. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of BMI on CRC. Figure S9. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of BMI on CRC (female specific). Figure S10. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of BMI on CRC (male specific). Figure S11. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of BMI on colon cancer. Figure S12. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of BMI on proximal colon cancer. Figure S13. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of BMI on distal colon cancer. Figure S14. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of BMI on rectal cancer. Figure S15. Leave-one-out plot showing the association between BMI and CRC, following SNP-by-SNP removal from the model. Figure S16. Leave-one-out plot showing the association between BMI and CRC (femalespecific), following SNP-by-SNP removal from the model. Figure S17. Leave-one-out plot showing the association between BMI and CRC (malespecific), following SNP-by-SNP removal from the model. Figure S18. Leave-one-out plot showing the association between BMI and colon cancer, following SNP-by-SNP removal from the model. Figure S19. Leave-one-out plot showing the association between BMI and proximal colon cancer, following SNP-by-SNP removal from the model. Figure S20. Leave-one-out plot showing the association between BMI and distal colon cancer, following SNP-by-SNP removal from the model. Figure S21. Leave-one-out plot showing the association between BMI and rectal cancer, following SNP-by-SNP removal from the model. Figure S22. Scatter plot of SNP-WHR and SNP-CRC associations. Figure S23. Scatter plot of SNP-WHR and SNP-CRC associations (female specific). Figure S24. Scatter plot of SNP-WHR and SNP-CRC associations (male specific). Figure S25. Scatter plot of SNP-WHR and SNP-colon cancer associations. Figure S26. Scatter plot of SNP-WHR and SNP-proximal colon cancer associations. Figure S27. Scatter plot of SNP-WHR and SNP-distal colon cancer associations. Figure S28. Scatter plot of SNP-WHR and SNP-rectal cancer associations. Figure S29. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of WHR on CRC. Figure S30. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of WHR on CRC (female specific). Figure S31. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of WHR on CRC (male specific). Figure S32. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of WHR on colon cancer. Figure S33. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of WHR on proximal colon cancer. Figure S34. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of WHR on distal colon cancer. Figure S35. Forest plot showing individual SNP (black) and combined MR estimates (red; Egger and IVW) for the effect of WHR on rectal cancer. Figure S36. Leave-one-out plot showing the association between WHR and CRC, following SNP-by-SNP removal from the model. Figure S37. Leave-one-out plot showing the association between WHR and CRC, following SNP-by-SNP removal from the model (female specific). Figure S38. Leave-one-out plot showing the association between WHR and CRC, following SNP-by-SNP removal from the model (male specific). Figure S39. Leave-one-out plot showing the association between WHR and colon cancer, following SNP-by-SNP removal from the model. Figure S40. Leave-one-out plot showing the association between WHR and proximal colon cancer, following SNP-by-SNP removal from the model. Figure S41. Leave-one-out plot showing the association between WHR and distal colon cancer, following SNP-by-SNP removal from the model. Figure S42. Leave-one-out plot showing the association between WHR and rectal cancer, following SNP-by-SNP removal from the model. Figure S43. Effects of BMI and WHR on circulating metabolite levels (NMR-detected metabolites, 1 of 5), based on two-sample MR (IVW models) in summary GWAS consortia data. Figure S44. Effects of BMI and WHR on circulating metabolite levels (NMR-detected metabolites, 2 of 5), based on two-sample MR (IVW models) in summary GWAS consortia data. Figure S45. Effects of BMI and WHR on circulating metabolite levels (NMR-detected metabolites, 3 of 5), based on two-sample MR (IVW models) in summary GWAS consortia data. Figure S46. Effects of BMI and WHR on circulating metabolite levels (NMR-detected metabolites, 4 of 5), based on two-sample MR (IVW models) in summary GWAS consortia data. Figure S47. Effects of BMI and WHR on circulating metabolite levels (NMR-detected metabolites, 5 of 5), based on two-sample MR (IVW models) in summary GWAS consortia data. Figure S48. Power curves for MR analyses, based on samples sizes for colorectal cancer in the present study (black), Thrift et al., 2015 (blue) and Jarvis et al., 2016 (purple). Upper and lower power curves describe genetic instruments explaining 5% and 0.3% of variance respectively for each study.

Background: Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear., Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis -Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,162 cancer cases and up to 824,556 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant ( P < 5.0 x 10 -8 ) cis -acting SNPs (i.e. in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r 2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P -value (" q -value") < 0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q -value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH 4 ) > 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes., Results: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR 1.19, 95% CI 1.10-1.29, q -value=0.033, PPH 4 =84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR 1.42, 95% CI 1.20-1.69, q -value=0.055, PPH 4 =73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR 0.66, 95% CI 0.53-0.81, q -value=0.067, PPH 4 =81.8%), macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR 1.14, 95% CI 1.05-1.23, q -value=0.072, PPH 4 =76.1%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR 0.92, 95% CI 0.88-0.97, q -value=0.15), PPH 4 =85.6%). For 22 of 30 cancer outcomes examined, there was little evidence ( q -value ≥ 0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk., Conclusion: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 5 circulating inflammatory markers in risk of 5 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated.