Dataset Information

Observational and genetic associations between cardiorespiratory fitness and cancer: a UK Biobank and international consortia study.

ABSTRACT:

Background

The association of fitness with cancer risk is not clear.

Methods

We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method.

Results

After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O₂⋅min^-1⋅kg^-1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR = 0.81, 95% CI: 0.73-0.89), colorectal (0.94, 0.90-0.99), and breast cancer (0.96, 0.92-0.99). In MR analyses, a 0.5 SD increase in genetically predicted O₂⋅min^-1⋅kg^-1 fat-free mass was associated with a lower risk of breast cancer (OR = 0.92, 95% CI: 0.86-0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated.

Discussion

Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention.

SUBMITTER: Watts EL

PROVIDER: S-EPMC10781786 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Publications

Observational and genetic associations between cardiorespiratory fitness and cancer: a UK Biobank and international consortia study.

Watts Eleanor L EL Gonzales Tomas I TI Strain Tessa T Saint-Maurice Pedro F PF Bishop D Timothy DT Chanock Stephen J SJ Johansson Mattias M Keku Temitope O TO Le Marchand Loic L Moreno Victor V Newcomb Polly A PA Newton Christina C CC Pai Rish K RK Purdue Mark P MP Ulrich Cornelia M CM Smith-Byrne Karl K Van Guelpen Bethany B Day Felix R FR Wijndaele Katrien K Wareham Nicholas J NJ Matthews Charles E CE Moore Steven C SC Brage Soren S

British journal of cancer 20231206 1

<h4>Background</h4>The association of fitness with cancer risk is not clear.<h4>Methods</h4>We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the i ...[more]

PMID: 38057395

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Project description:BackgroundSmoking is a well-established cause of lung cancer and there is strong evidence that smoking also increases the risk of several other cancers. Alcohol consumption has been inconsistently associated with cancer risk in observational studies. This mendelian randomisation (MR) study sought to investigate associations in support of a causal relationship between smoking and alcohol consumption and 19 site-specific cancers.Methods and findingsWe used summary-level data for genetic variants associated with smoking initiation (ever smoked regularly) and alcohol consumption, and the corresponding associations with lung, breast, ovarian, and prostate cancer from genome-wide association studies consortia, including participants of European ancestry. We additionally estimated genetic associations with 19 site-specific cancers among 367,643 individuals of European descent in UK Biobank who were 37 to 73 years of age when recruited from 2006 to 2010. Associations were considered statistically significant at a Bonferroni corrected p-value below 0.0013. Genetic predisposition to smoking initiation was associated with statistically significant higher odds of lung cancer in the International Lung Cancer Consortium (odds ratio [OR] 1.80; 95% confidence interval [CI] 1.59-2.03; p = 2.26 × 10-21) and UK Biobank (OR 2.26; 95% CI 1.92-2.65; p = 1.17 × 10-22). Additionally, genetic predisposition to smoking was associated with statistically significant higher odds of cancer of the oesophagus (OR 1.83; 95% CI 1.34-2.49; p = 1.31 × 10-4), cervix (OR 1.55; 95% CI 1.27-1.88; p = 1.24 × 10-5), and bladder (OR 1.40; 95% CI 1.92-2.65; p = 9.40 × 10-5) and with statistically nonsignificant higher odds of head and neck (OR 1.40; 95% CI 1.13-1.74; p = 0.002) and stomach cancer (OR 1.46; 95% CI 1.05-2.03; p = 0.024). In contrast, there was an inverse association between genetic predisposition to smoking and prostate cancer in the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (OR 0.90; 95% CI 0.83-0.98; p = 0.011) and in UK Biobank (OR 0.90; 95% CI 0.80-1.02; p = 0.104), but the associations did not reach statistical significance. We found no statistically significant association between genetically predicted alcohol consumption and overall cancer (n = 75,037 cases; OR 0.95; 95% CI 0.84-1.07; p = 0.376). Genetically predicted alcohol consumption was statistically significantly associated with lung cancer in the International Lung Cancer Consortium (OR 1.94; 95% CI 1.41-2.68; p = 4.68 × 10-5) but not in UK Biobank (OR 1.12; 95% CI 0.65-1.93; p = 0.686). There was no statistically significant association between alcohol consumption and any other site-specific cancer. The main limitation of this study is that precision was low in some analyses, particularly for analyses of alcohol consumption and site-specific cancers.ConclusionsOur findings support the well-established relationship between smoking and lung cancer and suggest that smoking may also be a risk factor for cancer of the head and neck, oesophagus, stomach, cervix, and bladder. We found no evidence supporting a relationship between alcohol consumption and overall or site-specific cancer risk.

Project description:BackgroundObservational studies have shown inverse associations among fitness, physical activity, and cardiovascular disease. However, little is known about these associations in individuals with elevated genetic susceptibility for these diseases.MethodsWe estimated associations of grip strength, objective and subjective physical activity, and cardiorespiratory fitness with cardiovascular events and all-cause death in a large cohort of 502 635 individuals from the UK Biobank (median follow-up, 6.1 years; interquartile range, 5.4-6.8 years). Then we further examined these associations in individuals with different genetic burden by stratifying individuals based on their genetic risk scores for coronary heart disease and atrial fibrillation. We compared disease risk among individuals in different tertiles of fitness, physical activity, and genetic risk using lowest tertiles as reference.ResultsGrip strength, physical activity, and cardiorespiratory fitness showed inverse associations with incident cardiovascular events (coronary heart disease: hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.77-0.81; HR, 0.95; 95% CI, 0.93-0.97; and HR, 0.68; 95% CI, 0.63-0.74, per SD change, respectively; atrial fibrillation: HR, 0.75; 95% CI, 0.73-0.76; HR, 0.93; 95% CI, 0.91-0.95; and HR, 0.60; 95% CI, 0.56-0.65, per SD change, respectively). Higher grip strength and cardiorespiratory fitness were associated with lower risk of incident coronary heart disease and atrial fibrillation in each genetic risk score group (Ptrend <0.001 in each genetic risk category). In particular, high levels of cardiorespiratory fitness were associated with 49% lower risk for coronary heart disease (HR, 0.51; 95% CI, 0.38-0.69) and 60% lower risk for atrial fibrillation (HR, 0.40; 95%, CI 0.30-0.55) among individuals at high genetic risk for these diseases.ConclusionsFitness and physical activity demonstrated inverse associations with incident cardiovascular disease in the general population, as well as in individuals with elevated genetic risk for these diseases.

Project description:BackgroundBrain iron deposition has been linked to several neurodegenerative conditions and reported in alcohol dependence. Whether iron accumulation occurs in moderate drinkers is unknown. Our objectives were to investigate evidence in support of causal relationships between alcohol consumption and brain iron levels and to examine whether higher brain iron represents a potential pathway to alcohol-related cognitive deficits.Methods and findingsObservational associations between brain iron markers and alcohol consumption (n = 20,729 UK Biobank participants) were compared with associations with genetically predicted alcohol intake and alcohol use disorder from 2-sample mendelian randomization (MR). Alcohol intake was self-reported via a touchscreen questionnaire at baseline (2006 to 2010). Participants with complete data were included. Multiorgan susceptibility-weighted magnetic resonance imaging (9.60 ± 1.10 years after baseline) was used to ascertain iron content of each brain region (quantitative susceptibility mapping (QSM) and T2*) and liver tissues (T2*), a marker of systemic iron. Main outcomes were susceptibility (χ) and T2*, measures used as indices of iron deposition. Brain regions of interest included putamen, caudate, hippocampi, thalami, and substantia nigra. Potential pathways to alcohol-related iron brain accumulation through elevated systemic iron stores (liver) were explored in causal mediation analysis. Cognition was assessed at the scan and in online follow-up (5.82 ± 0.86 years after baseline). Executive function was assessed with the trail-making test, fluid intelligence with puzzle tasks, and reaction time by a task based on the "Snap" card game. Mean age was 54.8 ± 7.4 years and 48.6% were female. Weekly alcohol consumption was 17.7 ± 15.9 units and never drinkers comprised 2.7% of the sample. Alcohol consumption was associated with markers of higher iron (χ) in putamen (β = 0.08 standard deviation (SD) [95% confidence interval (CI) 0.06 to 0.09], p < 0.001), caudate (β = 0.05 [0.04 to 0.07], p < 0.001), and substantia nigra (β = 0.03 [0.02 to 0.05], p < 0.001) and lower iron in the thalami (β = -0.06 [-0.07 to -0.04], p < 0.001). Quintile-based analyses found these associations in those consuming >7 units (56 g) alcohol weekly. MR analyses provided weak evidence these relationships are causal. Genetically predicted alcoholic drinks weekly positively associated with putamen and hippocampus susceptibility; however, these associations did not survive multiple testing corrections. Weak evidence for a causal relationship between genetically predicted alcohol use disorder and higher putamen susceptibility was observed; however, this was not robust to multiple comparisons correction. Genetically predicted alcohol use disorder was associated with serum iron and transferrin saturation. Elevated liver iron was observed at just >11 units (88 g) alcohol weekly c.f. <7 units (56 g). Systemic iron levels partially mediated associations of alcohol intake with brain iron. Markers of higher basal ganglia iron associated with slower executive function, lower fluid intelligence, and slower reaction times. The main limitations of the study include that χ and T2* can reflect changes in myelin as well as iron, alcohol use was self-reported, and MR estimates can be influenced by genetic pleiotropy.ConclusionsTo the best of our knowledge, this study represents the largest investigation of moderate alcohol consumption and iron homeostasis to date. Alcohol consumption above 7 units weekly associated with higher brain iron. Iron accumulation represents a potential mechanism for alcohol-related cognitive decline.

Dataset Information

Observational and genetic associations between cardiorespiratory fitness and cancer: a UK Biobank and international consortia study.

Background

Methods

Results

Discussion

Publications

Observational and genetic associations between cardiorespiratory fitness and cancer: a UK Biobank and international consortia study.

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