Biology subjects

Kazmi, N.

Publications and source records attributed to Kazmi, N..

4 recordsLinked to original sources

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↗

bioRxiv2019

Identifying epigenetic biomarkers of established prognostic factors and survival in a clinical cohort of individuals with oropharyngeal cancer

Smoking status, alcohol consumption and HPV infection (acquired through sexual activity) are the predominant risk factors for oropharyngeal cancer and are thought to alter the prognosis of the disease. Here, we conduct epigenome-wide association studies (EWAS) of these factors and [~]3-year survival using Illumina Methylation EPIC blood DNA methylation profiles from 409 individuals in the Head and Neck 5000 (HN5000) study. CpG site associations below our multiple-testing threshold (PBonferroni < 0.05) with both a prognostic factor and with survival were observed in four gene regions: SPEG (smoking), GFI1 (smoking), PPT2 (smoking), and KHD3CL (alcohol consumption). These were further analysed using 2-step Mendelian randomization to assess whether methylation may be a causal mediator of cancer survival. Evidence for mediation was observed only in the SPEG gene region, showing an association with decreased survival (mortality HR: 1.28, 95% CI: 1.14 to 1.43, P: 2.12x10-05). Replication in data from independent datasets, and from HN5000 participants with longer follow-up times is needed to confirm these findings.

epidemiology↗

bioRxiv2019

Appraising causal relationships of dietary, nutritional and physical-activity exposures with overall and aggressive prostate cancer: two-sample Mendelian randomization study based on 79,148 prostate cancer cases and 61,106 controls

BackgroundProstate cancer is the second most common male cancer worldwide, but there is substantial geographical variation suggesting a potential role for modifiable risk factors in prostate carcinogenesis.\n\nMethodsWe identified previously reported prostate cancer risk factors from the World Cancer Research Funds (WCRF) systematic appraisal of the global evidence (2018). We assessed whether each identified risk factor was causally associated with risk of overall (79,148 cases and 61,106 controls) or aggressive (15,167 cases and 58,308 controls) prostate cancer using Mendelian randomization (MR) based on genome wide association study (GWAS) summary statistics from the PRACTICAL and GAME-ON/ELLIPSE consortia. We assessed evidence for replication in UK Biobank (7,844 prostate cancer cases and 204,001 controls).\n\nFindingsWCRF identified 57 potential risk factors, of which 22 could be instrumented for MR analyses using single nucleotide polymorphisms (SNPs). In MR analyses for overall prostate cancer, we identified evidence compatible with causality for the following risk factors (odds ratio [OR] per standard deviation increase; 95% confidence interval): accelerometer-measured physical-activity, OR=0.49 (0.33-0.72; p=0.0003); serum iron, OR=0.92 (0.86-0.98; p=0.007); body mass index (BMI), OR=0.90 (0.84-0.97; p=0.003); and mono-unsaturated fat, OR=1.11 (1.02-1.20; p=0.02). Findings in our replication analyses in UK Biobank were compatible with our main analyses (albeit with wide confidence intervals). In MR analysis, height was positively associated with aggressive prostate cancer risk: OR=1.07 (1.01-1.15; p=0.03).\n\nInterpretationThe results for physical-activity, serum iron, BMI, mono-unsaturated fat and height are compatible with causality for prostate cancer but more research is needed to rule out violations of MR assumptions for some risk factors. The results suggest that interventions aimed at increasing physical activity may reduce prostate cancer risk, but the direction of effects of BMI, and iron are at odds with their effects on other diseases, so the overall public health impact of intervening on these need to be considered.\n\nFundingWorld Cancer Research Fund International (2015/1421), Cancer Research UK program grant (C18281/A19169), National Institute for Health Research, Bristol Biomedical Research Centre, and Victorian Cancer Agency (MCRF18005).

epidemiology↗