scholarly journals Impact of glycemic traits, type 2 diabetes and metformin use on breast and prostate cancer risk: a Mendelian randomization study

2019 ◽  
Vol 7 (1) ◽  
pp. e000872 ◽  
Author(s):  
Shiu Lun Au Yeung ◽  
Catherine Mary Schooling
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Type 2 Diabetes ◽  
Cancer Risk ◽  
Fasting Glucose ◽  
Prostate Cancer Risk ◽  
Immortal Time Bias ◽  
Log Odds ◽  
Breast And Prostate Cancer

ObjectivesObservational studies suggest glycemic traits and type 2 diabetes are positively associated, and metformin inversely associated with breast and prostate cancer risk. However, observational studies are susceptible to unmeasured confounding while studies of metformin use are also vulnerable to immortal time bias. The use of Mendelian randomization may reduce confounding due to random allocation of relevant genetic markers at birth, and may reduce immortal time bias (for metformin-related variants analysis) since the start of exposure is at birth.Research design and methodsWe identified strong genetic predictors of fasting glucose, glycated hemoglobin, and type 2 diabetes from the Meta-Analyses of Glucose and Insulin-related traits Consortium and Diabetes Genetics Replication And Meta-analysis Consortium (n=140 595 for glucose; n=123 665 for HbA1c; n=898 130 for type 2 diabetes) and of AMPK-instrumented HbA1c reduction as a proxy of metformin and applied them to large genome-wide association studies of breast cancer (Breast Cancer Association Consortium; BCAC) and prostate cancer (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome; PRACTICAL). We used inverse variance weighting to obtain estimates. Sensitivity analyses included use of MR-Egger, weighted median, exclusion of pleiotropic instruments, and validation using UK Biobank (breast cancer only).ResultsThere was no association of fasting glucose (OR 1.03 per mmol/L, 95% CI 0.85 to 1.25), HbA1c (OR 1.02 per %, 95% CI 0.73 to 1.45), or type 2 diabetes (OR 0.98 per log odds, 95% CI 0.95 to 1.01) with breast cancer in BCAC, with similar findings from UK Biobank. There was no association of fasting glucose (OR 0.93 per mmol/L, 95% CI 0.73 to 1.17), HbA1c (OR 0.90 per %, 95% CI 0.58 to 1.40) or type 2 diabetes (OR 1.02 per log odds, 95% CI 0.97 to 1.07) with prostate cancer in PRACTICAL. No strong evidence was observed for AMPK-instrumented HbA1c reduction on cancer risk.ConclusionGlycemic traits and type 2 diabetes unlikely cause breast and prostate cancer. Whether metformin can be repurposed for cancer prevention remains unclear.

scholarly journals Do sex hormones confound or mediate the effect of chronotype on breast and prostate cancer? A Mendelian randomization study.

2021 ◽  
Author(s):  
Bryony L Hayes ◽  
Timothy Robinson ◽  
Siddhartha P. Kar ◽  
Katherine S Ruth ◽  
Konstantinos K Tsilidis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Cancer Risk ◽  
Protective Effect ◽  
Sex Hormones ◽  
Prostate Cancer Risk ◽  
Total Testosterone ◽  
Testosterone Levels ◽  
Bioavailable Testosterone ◽  
Breast And Prostate Cancer

BACKGROUND Previous research has demonstrated that a morning-preference chronotype is protective against both breast and prostate cancer. Sex hormones have been implicated in relation to both chronotype and the development of both cancers. This study aims to assess whether sex hormones confound or mediate the effect of chronotype on breast and prostate cancer risk using a Mendelian Randomization (MR) framework. METHODS We obtained genetic variants strongly (p<5x10-8) associated with chronotype and sex hormones (total testosterone, bioavailable testosterone, sex hormone binding globulin (SHBG), and oestradiol from previously published genome-wide association studies (GWAS) that had been undertaken in UK Biobank and 23andMe (n=244,207 females and n=205,527 males). These variants were used to investigate causal relationships with risk of breast and prostate cancer using summary data from the largest available consortia in breast (nCases/nControls=133,384/ 113,789) and prostate cancer (nCases/nControls=79,148/61,106). This was achieved using a series of MR approaches: univariable, bidirectional and multivariable. Results Overall, we found evidence for a protective effect of genetically predicted tendency towards morning preference on both breast (OR=0.93, 95% CI:0.88, 1.00) and prostate (OR=0.90, 95% CI:0.83, 0.97) cancer risk. There was evidence that an increased tendency to morning preference reduces bioavailable testosterone levels in both females (mean SD difference=-0.08, 95% CI:-0.12, -0.05) and males (mean SD difference=-0.06, 95% CI:-0.09, -0.03), and reduces total testosterone levels in females (mean SD difference=-0.07, 95% CI:-0.10, -0.03). We also found evidence to support higher total and bioavailable testosterone increasing the risk of breast cancer (OR=1.15, 95% CI:1.07, 1.23, OR=1.10, 95% CI:1.01, 1.19 respectively) and higher bioavailable testosterone increasing prostate cancer risk (OR=1.22, 95% CI:1.08, 1.37). While findings from univariable and bidirectional MR analyses indicated that testosterone may lie on the causal pathway between chronotype and cancer risk, there was evidence for a bidirectional association between chronotype and testosterone in females, implicating testosterone as both a confounder and mediator of the chronotype effect on breast cancer risk. However, the effects of chronotype remained largely unchanged when accounting for testosterone in multivariable MR, suggesting that any confounding or mediating effect is likely to be minimal. Conclusions This study has extended previous findings regarding the protective effect of chronotype on breast cancer and found evidence to suggest that morning preference also reduces prostate cancer risk in men. While testosterone levels were found to be closely linked with both chronotype and cancer risk, there was inconsistent evidence for the role of testosterone in mediating the effect of morning preference chronotype on both breast and prostate cancer. Findings regarding the potential protective effect of chronotype on both breast and prostate cancer risk are clinically interesting. However, this may not serve as a direct target for intervention, since it is difficult to modify someone's morning/evening preference. Given this, further studies are needed to investigate the mechanisms underlying this effect and to identify other potential modifiable intermediates.

scholarly journals No Association of Type 2 Diabetes Risk Variants and Prostate Cancer Risk: the Multiethnic Cohort and PAGE: Table 1.

2011 ◽  
Vol 20 (9) ◽  
pp. 1979-1981 ◽  
Author(s):  
Kevin M. Waters ◽  
Lynne R. Wilkens ◽  
Kristine R. Monroe ◽  
Daniel O. Stram ◽  
Laurence N. Kolonel ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Type 2 Diabetes ◽  
Cancer Risk ◽  
Prostate Cancer Risk ◽  
Diabetes Risk ◽  
Risk Variants ◽  
Multiethnic Cohort ◽  
Page Table

scholarly journals Reduced risk of prostate cancer in a cohort of Lithuanian diabetes patients

2019 ◽  
Author(s):  
Marius Kincius ◽  
Patasius Ausvydas ◽  
Linkeviciute-Ulinskiene Donata ◽  
Rimantas Stukas ◽  
Zabuliene Lina ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Type 2 Diabetes ◽  
Cancer Risk ◽  
Lower Risk ◽  
Large Population ◽  
Prostate Cancer Risk ◽  
Cancer Case ◽  
Insurance Fund ◽  
Diabetes Patients

Abstract Background: The aim of this study was to determine whether type 2 diabetes mellitus and treatment with metformin is associated with prostate cancer risk. Methods: Male patients with diagnosis of type 2 diabetes during the period of 2000 – 2016 were identified in the National Health Insurance Fund database. The prostate cancer cases were identified by pooling these records from the national Cancer Registry. The calculation of prostate cancer stardardized incidence ratios (SIRs) was composed as a ratio of observed number of cancer case in people with diagnosis of diabetes to the expected number of cancer cases in the underlying general population. Results: Overall, 64,000 males diagnosed with diabetes in Lithuania between 2000 and 2016 were included in the final cohort. 2,754 prostate cancers were observed versus 3,111.26 expected within the period of observation entailing an SIR of 0.89 (95% CI: 0.85–0.92). Significantly lower risk of prostate cancer was found in diabetes patients in all age groups, there were no differences in prostate cancer risk by time since diagnosis of diabetes. Significantly lower risk of prostate cancer also was found in both metformin users and never-users’ groups, with higher risk reduction in metformin users (SIR 0.71, 95% CI: 0.68–0.75) than in diabetes patients never-users (SIR 0.88, 95% CI: 0.80–0.96). Conclusions: In this large population-based study we found a significantly decreased risk of prostate cancer among men with diabetes and metformin users. However, the risk of prostate cancer showed no clear trend with diabetes duration and cumulative metformin dose.

scholarly journals Circulating selenium and prostate cancer risk: a Mendelian randomization analysis

2017 ◽  
Author(s):  
James Yarmolinsky ◽  
Carolina Bonilla ◽  
Philip C Haycock ◽  
Ryan JQ Langdon ◽  
Luca A Lotta ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Type 2 Diabetes ◽  
Cancer Risk ◽  
Mendelian Randomization ◽  
Prostate Cancer Risk ◽  
Selenium Supplementation ◽  
High Grade ◽  
Mendelian Randomization Analysis ◽  
Randomization Analysis

AbstractIn the Selenium and Vitamin E Cancer Prevention Trial (SELECT), selenium supplementation (causing a median 114 μg/L increase in circulating selenium) did not lower overall prostate cancer risk, but increased risk of high-grade prostate cancer and type 2 diabetes. Mendelian randomization analysis uses genetic variants to proxy modifiable risk factors and can strengthen causal inference in observational studies. We constructed a genetic risk score comprising eleven single-nucleotide polymorphisms robustly (P<5x10−8) associated with circulating selenium in genome-wide association studies. In a Mendelian randomization analysis of 72,729 men in the PRACTICAL Consortium (44,825 cases, 27,904 controls), 114 μg/L higher genetically-elevated circulating selenium was not associated with prostate cancer (OR: 1.01; 95% CI: 0.89-1.13). Concordant with findings from SELECT, selenium was weakly associated with advanced (including high-grade) prostate cancer (OR: 1.21; 95% CI: 0.98-1.49) and type 2 diabetes (OR: 1.18; 95% CI: 0.97-1.43; in a type 2 diabetes GWAS meta-analysis with up to 49,266 cases, 249,906 controls). Mendelian randomization mirrored the outcome of selenium supplementation in SELECT and may offer an approach for the prioritization of interventions for follow-up in large-scale randomized controlled trials.

Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes

2007 ◽  
Vol 39 (8) ◽  
pp. 977-983 ◽  
Author(s):  
Julius Gudmundsson ◽  
Patrick Sulem ◽  
Valgerdur Steinthorsdottir ◽  
Jon T Bergthorsson ◽  
Gudmar Thorleifsson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Type 2 Diabetes ◽  
Cancer Risk ◽  
Prostate Cancer Risk ◽  
Chromosome 17 ◽  
The One
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