ORCID Profile
0000-0002-1932-7463
Current Organisation
University of Oxford
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Publisher: American Association for Cancer Research (AACR)
Date: 20-04-2021
DOI: 10.1158/1055-9965.EPI-20-1690
Abstract: Epidemiologic studies evaluating associations between sex steroid hormones and colorectal cancer risk have yielded inconsistent results. To elucidate the role of circulating levels of testosterone, and sex hormone-binding globulin (SHBG) in colorectal cancer risk, we conducted observational and Mendelian randomization (MR) analyses. The observational analyses included 333,530 participants enrolled in the UK Biobank with testosterone and SHBG measured. HRs and 95% confidence intervals (CI) were estimated using multivariable Cox proportional hazards models. For MR analyses, genetic variants robustly associated with hormone levels were identified and their association with colorectal cancer (42,866 cases/42,752 controls) was examined using two-s le MR. In the observational analysis, there was little evidence that circulating levels of total testosterone were associated with colorectal cancer risk the MR analyses showed a greater risk for women (OR per 1-SD = 1.09 95% CI, 1.01–1.17), although pleiotropy may have biased this result. Higher SHBG concentrations were associated with greater colorectal cancer risk for women (HR per 1-SD = 1.16 95% CI, 1.05–1.29), but was unsupported by the MR analysis. There was little evidence of associations between free testosterone and colorectal cancer in observational and MR analyses. Circulating concentrations of sex hormones are unlikely to be causally associated with colorectal cancer. Additional experimental studies are required to better understand the possible role of androgens in colorectal cancer development. Our results from large-scale analyses provide little evidence for sex hormone pathways playing a causal role in colorectal cancer development. See related commentary by Hang and Shen, p. 1302
Publisher: Springer Science and Business Media LLC
Date: 11-03-2022
DOI: 10.1007/S10552-022-01562-1
Abstract: Dietary factors are assumed to play an important role in cancer risk, apparent in consensus recommendations for cancer prevention that promote nutritional changes. However, the evidence in this field has been generated predominantly through observational studies, which may result in biased effect estimates because of confounding, exposure misclassification, and reverse causality. With major geographical differences and rapid changes in cancer incidence over time, it is crucial to establish which of the observational associations reflect causality and to identify novel risk factors as these may be modified to prevent the onset of cancer and reduce its progression. Mendelian randomization (MR) uses the special properties of germline genetic variation to strengthen causal inference regarding potentially modifiable exposures and disease risk. MR can be implemented through instrumental variable (IV) analysis and, when robustly performed, is generally less prone to confounding, reverse causation and measurement error than conventional observational methods and has different sources of bias (discussed in detail below). It is increasingly used to facilitate causal inference in epidemiology and provides an opportunity to explore the effects of nutritional exposures on cancer incidence and progression in a cost-effective and timely manner. Here, we introduce the concept of MR and discuss its current application in understanding the impact of nutritional factors (e.g., any measure of diet and nutritional intake, circulating biomarkers, patterns, preference or behaviour) on cancer aetiology and, thus, opportunities for MR to contribute to the development of nutritional recommendations and policies for cancer prevention. We provide applied ex les of MR studies examining the role of nutritional factors in cancer to illustrate how this method can be used to help prioritise or deprioritise the evaluation of specific nutritional factors as intervention targets in randomised controlled trials. We describe possible biases when using MR, and methodological developments aimed at investigating and potentially overcoming these biases when present. Lastly, we consider the use of MR in identifying causally relevant nutritional risk factors for various cancers in different regions across the world, given notable geographical differences in some cancers. We also discuss how MR results could be translated into further research and policy. We conclude that findings from MR studies, which corroborate those from other well-conducted studies with different and orthogonal biases, are poised to substantially improve our understanding of nutritional influences on cancer. For such corroboration, there is a requirement for an interdisciplinary and collaborative approach to investigate risk factors for cancer incidence and progression.
Publisher: Public Library of Science (PLoS)
Date: 12-01-2021
DOI: 10.1371/JOURNAL.PMED.1003487
Abstract: Higher levels of physical activity (PA) are associated with a lower risk of cardiovascular disease (CVD). However, uncertainty exists on whether the inverse relationship between PA and incidence of CVD is greater at the highest levels of PA. Past studies have mostly relied on self-reported evidence from questionnaire-based PA, which is crude and cannot capture all PA undertaken. We investigated the association between accelerometer-measured moderate, vigorous, and total PA and incident CVD. We obtained accelerometer-measured moderate-intensity and vigorous-intensity physical activities and total volume of PA, over a 7-day period in 2013–2015, for 90,211 participants without prior or concurrent CVD in the UK Biobank cohort. Participants in the lowest category of total PA smoked more, had higher body mass index and C-reactive protein, and were diagnosed with hypertension. PA was associated with 3,617 incident CVD cases during 440,004 person-years of follow-up (median (interquartile range [IQR]): 5.2 (1.2) years) using Cox regression models. We found a linear dose–response relationship for PA, whether measured as moderate-intensity, vigorous-intensity, or as total volume, with risk of incident of CVD. Hazard ratios (HRs) and 95% confidence intervals for increasing quarters of the PA distribution relative to the lowest fourth were for moderate-intensity PA: 0.71 (0.65, 0.77), 0.59 (0.54, 0.65), and 0.46 (0.41, 0.51) for vigorous-intensity PA: 0.70 (0.64, 0.77), 0.54 (0.49,0.59), and 0.41 (0.37,0.46) and for total volume of PA: 0.73 (0.67, 0.79), 0.63 (0.57, 0.69), and 0.47 (0.43, 0.52). We took account of potential confounders but unmeasured confounding remains a possibility, and while removal of early deaths did not affect the estimated HRs, we cannot completely dismiss the likelihood that reverse causality has contributed to the findings. Another possible limitation of this work is the quantification of PA intensity-levels based on methods validated in relatively small studies. In this study, we found no evidence of a threshold for the inverse association between objectively measured moderate, vigorous, and total PA with CVD. Our findings suggest that PA is not only associated with lower risk for of CVD, but the greatest benefit is seen for those who are active at the highest level.
Publisher: Public Library of Science (PLoS)
Date: 20-09-2021
DOI: 10.1371/JOURNAL.PMED.1003786
Abstract: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI). We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood s les from up to 1,305 kidney cancer case–control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10 −8 ). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10 −5 ), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some—but not all—metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., −0.17 SD change [ß BMI ] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10 −5 ). BMI was also associated with increased levels of glutamate (ß BMI : 0.12, p = 1.5 × 10 −3 ). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds. This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI—the principal modifiable risk factor of kidney cancer.
Publisher: BMJ
Date: 06-09-2021
DOI: 10.1136/BJSPORTS-2021-104050
Abstract: To improve classification of movement behaviours in free-living accelerometer data using machine-learning methods, and to investigate the association between machine-learned movement behaviours and risk of incident cardiovascular disease (CVD) in adults. Using free-living data from 152 participants, we developed a machine-learning model to classify movement behaviours (moderate-to-vigorous physical activity behaviours (MVPA), light physical activity behaviours, sedentary behaviour, sleep) in wrist-worn accelerometer data. Participants in UK Biobank, a prospective cohort, were asked to wear an accelerometer for 7 days, and we applied our machine-learning model to classify their movement behaviours. Using compositional data analysis Cox regression, we investigated how reallocating time between movement behaviours was associated with CVD incidence. In leave-one-participant-out analysis, our machine-learning method classified free-living movement behaviours with mean accuracy 88% (95% CI 87% to 89%) and Cohen’s kappa 0.80 (95% CI 0.79 to 0.82). Among 87 498 UK Biobank participants, there were 4105 incident CVD events. Reallocating time from any behaviour to MVPA, or reallocating time from sedentary behaviour to any behaviour, was associated with lower CVD risk. For an average in idual, reallocating 20 min/day to MVPA from all other behaviours proportionally was associated with 9% (95% CI 7% to 10%) lower risk, while reallocating 1 hour/day to sedentary behaviour from all other behaviours proportionally was associated with 5% (95% CI 3% to 7%) higher risk. Machine-learning methods classified movement behaviours accurately in free-living accelerometer data. Reallocating time from other behaviours to MVPA, and from sedentary behaviour to other behaviours, was associated with lower risk of incident CVD, and should be promoted by interventions and guidelines.
Publisher: American Medical Association (AMA)
Date: 11-10-2018
Publisher: MDPI AG
Date: 15-03-0003
Abstract: Bilirubin, an endogenous antioxidant, may play a protective role in cancer development. We applied two-s le Mendelian randomization to investigate whether genetically raised bilirubin levels are causally associated with the risk of ten cancers (pancreas, kidney, endometrium, ovary, breast, prostate, lung, Hodgkin’s lymphoma, melanoma, and neuroblastoma). The number of cases and their matched controls of European descent ranged from 122,977 and 105,974 for breast cancer to 1200 and 6417 for Hodgkin’s lymphoma, respectively. A total of 115 single-nucleotide polymorphisms (SNPs) associated (p 5 × 10−8) with circulating total bilirubin, extracted from a genome-wide association study in the UK Biobank, were used as instrumental variables. One SNP (rs6431625) in the promoter region of the uridine-diphosphoglucuronate glucuronosyltransferase1A1 (UGT1A1) gene explained 16.9% and the remaining 114 SNPs (non-UGT1A1 SNPs) explained 3.1% of phenotypic variance in circulating bilirubin levels. A one-standarddeviation increment in circulating bilirubin (≈ 4.4 µmol/L), predicted by non-UGT1A1 SNPs, was inversely associated with risk of squamous cell lung cancer and Hodgkin’s lymphoma (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.73–0.99, P 0.04 and OR 0.64, 95% CI 0.42–0.99, p 0.04, respectively), which was confirmed after removing potential pleiotropic SNPs. In contrast, a positive association was observed with the risk of breast cancer after removing potential pleiotropic SNPs (OR 1.12, 95% CI 1.04–1.20, p 0.002). There was little evidence for robust associations with the other seven cancers investigated. Genetically raised bilirubin levels were inversely associated with risk of squamous cell lung cancer as well as Hodgkin’s lymphoma and positively associated with risk of breast cancer. Further studies are required to investigate the utility of bilirubin as a low-cost clinical marker to improve risk prediction for certain cancers.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.JSAMS.2018.10.008
Abstract: To describe the cross-sectional association between musculoskeletal pain at multiple sites and physical work capacity (PWC) and objectively measured physical activity (PA). Observational study. Data from a subs le of the UK Biobank were utilised (n=9856 mean age 58.5 years, mean body mass index 30.2kg/m Increase in number of painful sites was associated with lower PWC, moderate and vigorous PA and increased low intensity PA in a dose-response relationship (all p-values for trend ≤0.001) before and after adjustment for confounders. In site specific analyses, hip pain was associated with an increased low intensity PA (β 52.8min/week, 95% CI 2.3-103.2) and reduced moderate PA (β -50.1min/week, 95% CI -98.5 to -1.8). Knee pain was only associated with vigorous PA (β -5.7min/week, 95% CI -10.0 to -1.3). Pain at neck/shoulder pain and back were not independently associated with PWC and PA. Greater number of painful sites is consistently associated with poorer PWC, increased low intensity PA and reduced moderate to vigorous PA. Clinicians should address the critical role of being physically active in managing chronic musculoskeletal pain and interventions targeting musculoskeletal pain may be needed to increase PA levels.
Publisher: Oxford University Press (OUP)
Date: 19-04-2022
DOI: 10.1093/JNCI/DJAC061
Abstract: It is unclear if body weight in early life affects cancer risk independently of adult body weight. To investigate this question for 6 obesity-related cancers, we performed univariable and multivariable analyses using 1) Mendelian randomization (MR) analysis and 2) longitudinal analyses in prospective cohorts. Both the MR and longitudinal analyses indicated that larger early life body size was associated with higher risk of endometrial (odds ratioMR = 1.61, 95% confidence interval = 1.23 to 2.11) and kidney (odds ratioMR = 1.40, 95% confidence interval = 1.09 to 1.80) cancer. These associations were attenuated after accounting for adult body size in both the MR and cohort analyses. Early life body mass index (BMI) was not consistently associated with the other investigated cancers. The lack of clear independent risk associations suggests that early life BMI influences endometrial and kidney cancer risk mainly through pathways that are common with adult BMI.
Publisher: Cold Spring Harbor Laboratory
Date: 22-09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 15-07-2022
DOI: 10.1158/1055-9965.EPI-21-1033
Abstract: Tobacco exposure causes 8 of 10 lung cancers, and identifying additional risk factors is challenging due to confounding introduced by smoking in traditional observational studies. We used Mendelian randomization (MR) to screen 207 metabolites for their role in lung cancer predisposition using independent genome-wide association studies (GWAS) of blood metabolite levels (n = 7,824) and lung cancer risk (n = 29,266 cases/56,450 controls). A nested case–control study (656 cases and 1,296 matched controls) was subsequently performed using prediagnostic blood s les to validate MR association with lung cancer incidence data from population-based cohorts (EPIC and NSHDS). An MR-based scan of 207 circulating metabolites for lung cancer risk identified that blood isovalerylcarnitine (IVC) was associated with a decreased odds of lung cancer after accounting for multiple testing (log10-OR = 0.43 95% CI, 0.29–0.63). Molar measurement of IVC in prediagnostic blood found similar results (log10-OR = 0.39 95% CI, 0.21–0.72). Results were consistent across lung cancer subtypes. Independent lines of evidence support an inverse association of elevated circulating IVC with lung cancer risk through a novel methodologic approach that integrates genetic and traditional epidemiology to efficiently identify novel cancer biomarkers. Our results find compelling evidence in favor of a protective role for a circulating metabolite, IVC, in lung cancer etiology. From the treatment of a Mendelian disease, isovaleric acidemia, we know that circulating IVC is modifiable through a restricted protein diet or glycine and L-carnatine supplementation. IVC may represent a modifiable and inversely associated biomarker for lung cancer.
Publisher: Cold Spring Harbor Laboratory
Date: 16-08-2023
DOI: 10.1101/2023.08.14.23294084
Abstract: Circulating proteins are integral to many biological processes. We aimed to assess differences in the plasma proteome between people of different dietary groups defined by degree of animal food consumption. The UK Biobank recruited middle-aged adults (mostly 40 to 69 years) throughout the UK between 2006-2010. Relative concentrations of 1463 plasma proteins were quantified using the Olink Proximity Extension Assay on blood s les from 49,326 participants, who were also asked to report their ethnicity and consumption of red and processed meat, poultry, fish, dairy and eggs. We defined six diet groups among the white British participants (23,116 regular meat eaters, 23,323 low meat eaters, 484 poultry eaters, 1074 fish eaters, 722 vegetarians, and 54 vegans), and two diet groups among the British Indians (390 meat eaters and 163 vegetarians). We used multivariable-adjusted linear regressions to assess differences in protein concentrations between diet groups, with correction for multiple testing. We observed significant differences in many plasma proteins by diet group (683 proteins in white British participants, 1 in British Indians), in particular many proteins that are majority expressed in the digestive system. Of the biggest differences, compared with regular meat eaters, the non-meat eaters had significantly higher FGF21 (e.g. +0.40 SD in vegetarians), GUCA2A (+0.33), FOLR1 (+0.32), IGFBP2 (+0.31) and DSG2 (+0.30) all groups except the vegans had lower HAVCR1 (-0.38 in vegetarians). The observed differences were generally similar in direction in both ethnicities. In this first comprehensive assessment of plasma proteins by diet group, we identified many differences in proteins between groups defined by animal food consumption this variation in protein levels suggests differences in various biological activities, including gastrointestinal tract and kidney function, which may relate to differences in future disease risk.
Publisher: Elsevier BV
Date: 11-2021
Publisher: Cold Spring Harbor Laboratory
Date: 29-06-2023
DOI: 10.1101/2023.06.20.23291538
Abstract: International differences in the incidence of many cancer types indicate the existence of carcinogen exposures which make a substantial contribution to cancer burden, vary geographically, and have underlying agents thus far unidentified by conventional epidemiology 1 . This pertains to clear cell renal cell carcinomas (ccRCC), for which obesity, hypertension, and tobacco smoking are risk factors but do not explain its geographical variation in incidence 2 . Some carcinogens generate somatic mutations and past exposures can be inferred from the patterns of mutations found in cancer genomes. Therefore, we sequenced the whole genomes of 962 ccRCC from 11 countries of varying incidence. Somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures likely caused by extracts of Aristolochia plants were present in most cases and rare elsewhere. In Japan, a mutational signature of unknown cause was found in % cases and % elsewhere. Another mutational signature of unknown cause was ubiquitous and associated with kidney cancer incidence rates (p-value × 10 −18 ), with higher numbers of mutations in countries with higher risk. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension suggesting non-mutagenic mechanisms of action underlying these risk factors. The results indicate the existence of multiple, widespread, geographically variable mutagenic exposures to known and unknown agents, which may contribute to the incidence of kidney cancer.
Publisher: Springer Science and Business Media LLC
Date: 18-10-2021
DOI: 10.1038/S41588-021-00928-6
Abstract: Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. Mutational profiles were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining differences in ESCC incidence. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures single-base substitution (SBS)2 and SBS13 were present in 88% and 91% of cases, respectively, and accounted for 25% of the mutation burden on average, indicating that APOBEC activation is a crucial step in ESCC tumor development.
Publisher: Cold Spring Harbor Laboratory
Date: 30-04-2021
DOI: 10.1101/2021.04.26.21254132
Abstract: Germline genetic variants are involved in lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated genes involved in smoking propensity and DNA repair but further work is required to identify additional LC susceptibility variants and to investigate LC disease development dynamics. We have undertaken a family history-based genome-wide association (GWAx) study of LC, analysing 48,843 European cases with a parent/sibling with LC compared to 195,387 controls from the UK Biobank. This was meta-analysed with previously described LC GWAS results. We performed Polygenic Risk Scores (PRS) analyses and further evaluated the PRS influence on the somatic environment in exome (N=736) and genome sequencing (N=61) profiled cohorts. Eight novel loci were identified including DNA repair genes ( CHEK1, MDM4 ), metabolic genes ( CYP1A1 ) and variants that were also associated with smoking propensity, such as both subunits of the neuronal α4β2 nicotinic acetylcholine receptor ( CHRNA4 and CHRNB2) . PRS analysis demonstrated that variants related to eQTLs and/or smoking propensity are enriched for susceptibility variants, including variants below genome-wide significant threshold. PRS of LC variants related to smoking propensity were associated with somatic mutation burden in two case cohorts, with in iduals with higher polygenic genetic risk having increased numbers of somatic mutations in their lung tumours. This study has expanded the number of susceptibility loci linked with LC and provided insights into the molecular mechanisms by which these susceptibility variants contribute to the development of lung cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 27-09-2023
Publisher: Cold Spring Harbor Laboratory
Date: 05-08-2023
DOI: 10.1101/2023.07.28.23293330
Abstract: Proteins are essential for the development and progression of cancer and for the human body’s defense against tumor onset. The availability of a large panel of protein measurements and whole exome sequence data in the UK Biobank has enabled the simultaneous examination of plasma protein associations with risk across multiple cancer sites and their potential role in cancer etiology. We investigated the associations of plasma proteins with incidence of 19 cancers and 9 cancer subsites in up to 44,645 middle-aged adults in the UK Biobank, who had measurements of 1,463 plasma proteins generated using Olink Explore Proximity Extension Assay in baseline blood s les (2006-2010). Using multivariable-adjusted Cox regression, we estimated the risk of each protein with each cancer overall and by time-to-diagnosis after correction for multiple-testing. Identified protein-cancer associations were further assessed in an analysis of cancer risk using cis -pQTL and exome-wide protein genetic scores (exGS) in all UK Biobank participants (n=337,543). We identified 371 proteins associated with the risk of at least one incident cancer, represented by a total of 621 protein-cancer associations. These proteins were associated with cancers of the blood (201 proteins), liver (131), kidney (51), lung (28), esophagus (22), colorectum (15), stomach (8), breast (5), prostate (3), endometrium (3), ovary (2), bladder (1), head and neck (1), and brain (1). 100 of these 621 protein-cancer associations persisted for cases diagnosed more than seven years after blood draw. Of these 621 associations, there was further support from cis -pQTL analyses for the etiological role of TNFRSF14 in risk of non-Hodgkin lymphoma (NHL), and from whole exome protein score (exGS) analyses for 28 other protein-cancer associations, including SRP14 and risk of leukemia. Proteins with directionally concordant evidence from long time-to-diagnosis analyses and from both cis -pQTL and exGS analyses were SFTPA2 for lung cancer, TNFRSF1B and CD74 for NHL, and ADAM8 for leukemia. For the first time using an integrated multi-omics and cross-cancer approach, we have comprehensively assessed the plasma proteome in relation to cancer risk and identified multiple novel etiological candidates. Differences in the levels of many circulating proteins were detectable more than seven years before cancer diagnosis while some of these are likely to be markers of early cancer processes that may inform risk stratification, and/or risk factors, concordant evidence from genetic analyses suggests that some may have a role in cancer development.
Publisher: Oxford University Press (OUP)
Date: 02-05-2022
DOI: 10.1093/JNCI/DJAC087
Abstract: Germline genetic variation contributes to lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated susceptibility loci involved in smoking behaviors and DNA repair genes, but further work is required to identify susceptibility variants. To identify LC susceptibility loci, a family history-based genome-wide association by proxy (GWAx) of LC (48 843 European proxy LC patients, 195 387 controls) was combined with a previous LC GWAS (29 266 patients, 56 450 controls) by meta-analysis. Colocalization was used to explore candidate genes and overlap with existing traits at discovered susceptibility loci. Polygenic risk scores (PRS) were tested within an independent validation cohort (1 666 LC patients vs 6 664 controls) using variants selected from the LC susceptibility loci and a novel selection approach using published GWAS summary statistics. Finally, the effects of the LC PRS on somatic mutational burden were explored in patients whose tumor resections have been profiled by exome (n = 685) and genome sequencing (n = 61). Statistical tests were 2-sided. The GWAx–GWAS meta-analysis identified 8 novel LC loci. Colocalization implicated DNA repair genes (CHEK1), metabolic genes (CYP1A1), and smoking propensity genes (CHRNA4 and CHRNB2). PRS analysis demonstrated that these variants, as well as subgenome-wide significant variants related to expression quantitative trait loci and/or smoking propensity, assisted in LC genetic risk prediction (odds ratio = 1.37, 95% confidence interval = 1.29 to 1.45 P & .001). Patients with higher genetic PRS loads of smoking-related variants tended to have higher mutation burdens in their lung tumors. This study has expanded the number of LC susceptibility loci and provided insights into the molecular mechanisms by which these susceptibility variants contribute to LC development.
Publisher: Oxford University Press (OUP)
Date: 05-02-2019
DOI: 10.1093/IJE/DYY294
Abstract: Physical inactivity is associated with an increased risk of major chronic diseases, although uncertainty exists about which chronic diseases, themselves, might contribute to physical inactivity. The objective of this study was to compare the physical activity of those with chronic diseases to healthy in iduals using an objective measure of physical activity. We conducted a cross-sectional analysis of data from 96 706 participants aged 40 years or older from the UK Biobank prospective cohort study (2006–10). Diagnoses were identified through ICD 9 and 10 coding within hospital admission records and a cancer registry linked to UK Biobank participants. We extracted summary physical activity information from participants who wore a wrist-worn triaxial accelerometer for 7 days. Statistical analyses included computation of adjusted geometric means and means using general linear models. Participants with chronic disease undertook 9% or 61 minutes (95% confidence interval: 57.8–64.8) less moderate activity and 11% or 3 minutes (95% confidence interval: 2.7–3.3) less vigorous activity per week than in iduals without chronic disease. Participants in every chronic-disease subgroup undertook less physical activity than those without chronic disease. Sixty-seven diagnoses within these subgroups were associated with lower moderate activity. The cross-sectional association of physical activity with chronic disease is broad. Given the substantial health benefits of being physically active, clinicians and policymakers should be aware that their patients with any chronic disease are at greater health risk from other diseases than anticipated because of their physical inactivity.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Karl Smith-Byrne.