Biology subjects

Tsilidis, K. K.

Publications and source records attributed to Tsilidis, K. K..

3 recordsLinked to original sources

bioRxiv2019

Insulin-like growth factor-1 (IGF-1), insulin-like growth factor-binding protein-3 (IGFBP-3) and breast cancer risk: observational and Mendelian randomization analyses

BackgroundEpidemiological evidence supports a positive association between circulating insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk, but both the magnitude and causality of this relationship are uncertain. We conducted observational analyses with adjustment for regression dilution bias, and Mendelian randomization (MR) analyses to allow causal inference.\n\nPatients and methodsWe investigated the associations between circulating IGF-1 concentrations and incident breast cancer risk in 206,263 women in the UK Biobank. Multivariable hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. HRs were corrected for regression dilution using repeat IGF-1 measures available in a subsample of 6,711 women. For the MR analyses, genetic variants associated with circulating IGF-1 and IGFBP-3 levels were identified and their association with breast cancer was examined with two-sample MR methods using genome-wide data from 122,977 cases and 105,974 controls.\n\nResultsIn the UK Biobank, after a median follow-up of 7.1 years, 4,360 incident breast cancer cases occurred. In the multivariable-adjusted models corrected for regression dilution, higher IGF-1 concentrations were associated with a greater risk of breast cancer (HR per 5 nmol/L increment of IGF-1=1.11, 95%CI=1.07-1.16). Similar positive associations were found by follow-up time, menopausal status, body mass index, and other risk factors. In the MR analyses, a 5 nmol/L increment in genetically-predicted IGF-1 concentration was associated with greater breast cancer risk (odds ratio [OR]=1.05, 95%CI=1.01-1.10; Pvalue=0.02), with a similar effect estimate for estrogen positive (ER+) tumors, but no effect found for estrogen negative (ER-) tumors. Genetically-predicted IGFBP-3 concentrations were not associated with breast cancer risk (OR per 1-SD increment=1.00, 95%CI=0.97-1.04; Pvalue=0.98).\n\nConclusionOur results support a probable causal relationship between circulating IGF-1 concentrations and breast cancer, suggesting that interventions targeting the IGF pathway may be beneficial in preventing breast tumorigenesis.\n\nDisclaimerWhere authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization.

genetics↗

bioRxiv2019

Mendelian randomisation study exploring the associations of serum folate with pan and site-specific cancers

BackgroundEpidemiological studies report evidence for an association between folate and the risk of several common cancers. However, both protective and harmful effects have been reported, and effects may differ by cancer site. Using Mendelian randomisation (MR), we investigated the causal relationships of genetically predicted serum folate with pan-cancer risk (all cancers excluding non-melanoma skin cancers); breast, prostate, ovarian, lung, and colorectal cancers; and malignant melanoma. MethodsWe conducted a two-sample MR analysis, using genetic instruments for serum folate to appraise the possible causal role on risk of pan-cancer and six site-specific cancers using summary statistics available from large consortia and the population-based cohort study UK Biobank (UKBB). ResultsThere was little evidence that genetically elevated serum folate was causally associated with risk of pan-cancer or six site-specific cancers. Meta-analysis showed odds ratios (OR) per SD increase in log serum folate of 0.93 (95% CI 0.78-1.11) for breast cancer, 0.87 (95% CI 0.71-1.06) for prostate cancer, 0.84 (95% CI 0.59-1.20) for ovarian cancer, and 0.87 (95% CI 0.57-1.32) for lung cancer. The OR for colorectal cancer was 1.18 (95% CI 0.64-2.18) in large consortia analysis, while ORs for pan-cancers and malignant melanoma in UKBB were 0.88 (95% CI 0.73-1.06) and 0.56 (95% CI 0.29-1.08) respectively. The results were powered to detect modest effect sizes (>90% power ( 0.05) to detect ORs 1.2 (0.8) for the GWAS consortia) and were consistent between the two statistical approaches used (inverse variance weighted (IVW) and likelihood-based). ConclusionsThere is little evidence that genetically elevated serum folate may affect the risk of pan-cancer and six site-specific cancers. However, we may still be underpowered to detect clinically relevant but smaller magnitude effects. Our results provide some evidence that increasing levels of circulating folate through widespread supplementation or deregulation of fortification of foods with folic acid is unlikely to lead to moderate unintended population-wide increase in cancer risk. Key MessagesO_LIObservational studies have identified associations between folate (both intake and circulating levels) and risk of developing site-specific cancers. However, these studies are liable to biases such as confounding, measurement error, and reverse causation. C_LIO_LIUsing Mendelian randomisation, we appraised the causal relationships between genetically influenced serum folate levels and pan-cancer risk (all cancers excluding non-melanoma skin cancers); breast, prostate, ovarian, lung, and colorectal cancers; and malignant melanoma. C_LIO_LIOverall findings suggest that there is little evidence for the causal associations between genetically influenced serum folate and risk of pan-cancer and six site-specific cancers. C_LIO_LIWe provide some evidence that increasing levels of circulating folate through widespread supplementation or deregulation of fortification of foods with folic acid is unlikely to lead to moderate unintended population-wide increase in cancer risk. C_LI

genomics↗

bioRxiv2019

Physical activity and risks of breast and colorectal cancer: A Mendelian randomization analysis

Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomization analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.59, 95% confidence interval [CI]: 0.42 to 0.84, P-value=0.003) and colorectal cancer (OR: 0.66, 95% CI: 0.53 to 0.82, P-value=2*E-4). We found similar magnitude inverse associations by breast cancer subtype and by colorectal cancer anatomical site. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.\n\nDisclaimerWhere authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization.

genetics↗