Publications
103 results found
Breeur M, Ferrari P, Dossus L, et al., 2022, Pan-cancer analysis of pre-diagnostic blood metabolite concentrations in the European Prospective Investigation into Cancer and Nutrition, BMC Medicine, Vol: 20, ISSN: 1741-7015
BACKGROUND: Epidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations. METHODS: We analysed targeted metabolomics data available for 5828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data-shared lasso penalty. RESULTS: Out of the 50 studied metabolites, (i) six were inversely associated with the risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2, and three clusters of phosphatidylcholines (PCs); (ii) three were positively associated with most cancer types: proline, decanoylcarnitine, and one cluster of PCs; and (iii) 10 were specifically associated with particular cancer types, including histidine that was inversely associated with colorectal cancer risk and one cluster of sphingomyelins that was inversely associated with risk of hepatocellular carcinoma and positively with endometrial cancer risk. CONCLUSIONS: These results could provide novel insights for the identification of pathways for cancer development, in particular those shared across different cancer types.
Clasen JL, Heath AK, Van Puyvelde H, et al., 2022, Biomarkers of the transsulfuration pathway and risk of renal cell carcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, International Journal of Cancer, Vol: 151, Pages: 708-716, ISSN: 0020-7136
Previous studies have suggested that components of one-carbon metabolism, particularly circulating vitamin B6, have an etiological role in renal cell carcinoma (RCC). Vitamin B6 is a cofactor in the transsulfuration pathway. We sought to holistically investigate the role of the transsulfuration pathway in RCC risk. We conducted a nested case-control study (455 RCC cases and 455 matched controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Plasma samples from the baseline visit were analyzed for metabolites of the transsulfuration pathway, including pyridoxal 5'-phosphate (PLP, the biologically active form of vitamin B6), homocysteine, serine, cystathionine, and cysteine, in addition to folate. Bayesian conditional logistic regression was used to estimate associations of metabolites with RCC risk as well as interactions with established RCC risk factors. Circulating PLP and cysteine were inversely associated with RCC risk, and these association were not attenuated after adjustment for other transsulfuration metabolites (odds ratio (OR) and 90% credible interval (CrI) per 1 SD increase in log concentration: 0.76 [0.66, 0.87]; 0.81 [0.66, 0.96], respectively). A comparison of joint metabolite profiles suggested substantially greater RCC risk for the profile representative of low overall transsulfuration function compared with high function (OR 2.70 [90% CrI 1.26, 5.70]). We found some statistical evidence of interactions of cysteine with body mass index, and PLP and homocysteine with smoking status, on their associations with RCC risk. In conclusion, we found evidence suggesting that the transsulfuration pathway may play a role in metabolic dysregulation leading to RCC development. This article is protected by copyright. All rights reserved.
Heath AK, Muller DC, van den Brandt PA, et al., 2022, Diet-wide association study of 92 foods and nutrients and lung cancer risk in the European Prospective Investigation into Cancer and Nutrition study and the Netherlands Cohort Study, International Journal of Cancer, Vol: 151, Pages: 1935-1946, ISSN: 0020-7136
Diet-wide association study of 92 foods and nutrients and lung cancer risk in the European Prospective Investigation into Cancer and Nutrition study and the Netherlands Cohort Study
Breeur M, Ferrari P, Dossus L, et al., 2022, Pan-cancer analysis of pre-diagnostic blood metabolite concentrations in the European Prospective Investigation into Cancer and Nutrition, Publisher: Cold Spring Harbor Laboratory
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Epidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We analyzed targeted metabolomics data available for 5,828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites, and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data shared lasso penalty.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Out of the 50 studied metabolites, <jats:italic>(i)</jats:italic> six were inversely associated with risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2 and three clusters of phosphatidylcholines (PCs); <jats:italic>(ii)</jats:italic> three were positively associated with most cancer types: proline, decanoylcarnitine and one cluster of PCs; and <jats:italic>(iii)</jats:italic> 10 were specifically associated with particular cancer types, including histidine that was inversely associate
Mariosa D, Smith-Byrne K, Richardson TG, et al., 2022, Body size at different ages and risk of six cancers: a Mendelian randomization and prospective cohort study, JNCI: Journal of the National Cancer Institute, Vol: 114, Pages: 1296-1300, ISSN: 0027-8874
It is unclear if body weight in early life affects cancer risk independently of adult body weight. To investigate this question for six obesity-related cancers, we performed univariable and multivariable analyses using i) Mendelian randomization (MR) analysis and ii) longitudinal analyses in prospective cohorts. Both the MR and longitudinal analyses indicated that larger body size at age 10 was associated with higher risk of endometrial (ORMR=1.61, 95%CI = 1.23–2.11) and kidney cancer (ORMR=1.40, 95%CI = 1.09–1.80). These associations were attenuated after accounting for adult body size in both the MR and cohort analyses. Early life 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.
Cairat M, Rinaldi S, Navionis A-S, et al., 2022, Circulating inflammatory biomarkers, adipokines and breast cancer risk-a case-control study nested within the EPIC cohort, BMC MEDICINE, Vol: 20, ISSN: 1741-7015
Papadimitriou N, Bouras E, van den Brandt PA, et al., 2022, A prospective diet-wide association study for risk of colorectal cancer in EPIC, Clinical Gastroenterology and Hepatology, Vol: 20, Pages: 864-873.e13, ISSN: 1542-3565
BACKGROUND & AIMS: Evidence regarding the association of dietary exposures with colorectal cancer (CRC) risk is not consistent with a few exceptions. Therefore, we conducted a diet-wide association study (DWAS) in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the associations between several dietary exposures with CRC risk. METHODS: The association of 92 food and nutrient intakes with CRC risk was assessed in 386,792 participants, 5,069 of whom developed incident CRC. Correction for multiple comparisons was performed using the false discovery rate, and emerging associations were examined in the Netherlands Cohort Study (NLCS). Multiplicative gene-nutrient interactions were also tested in EPIC based on known CRC-associated loci. RESULTS: In EPIC, alcohol, liquor/spirits, wine, beer/cider, soft drinks, and pork were positively associated with CRC, whereas milk, cheese, calcium, phosphorus, magnesium, potassium, riboflavin, vitamin B6, beta-carotene, fruit, fibre, non-white bread, banana, and total protein intakes were inversely associated. Of these 20 associations, 13 were replicated in NLCS, for which a meta-analysis was performed, namely alcohol (summary HR per 1 SD increment in intake: 1.07; 95%CI:1.04-1.09), liquor/spirits (1.04; 1.02-1.06), wine (1.04;1.02-1.07), beer/cider (1.06;1.04-1.08), milk (0.95;0.93-0.98), cheese (0.96;0.94-0.99), calcium (0.93;0.90-0.95), phosphorus (0.92;0.90-0.95), magnesium (0.95;0.92-0.98), potassium (0.96;0.94-0.99), riboflavin (0.94;0.92-0.97), beta-carotene (0.96;0.93-0.98), and total protein (0.94;0.92-0.97). None of the gene-nutrient interactions were significant after adjustment for multiple comparisons. CONCLUSIONS: Our findings confirm a positive association for alcohol and an inverse association for dairy products and calcium with CRC risk, and also suggest a lower risk at higher dietary intakes of phosphorus, magnesium, potassium, riboflavin, beta-carotene and total protein.
Alcala K, Mariosa D, Smith-Byrne K, et al., 2022, The relationship between blood pressure and risk of renal cell carcinoma, International Journal of Epidemiology, Vol: 51, Pages: 1317-1327, ISSN: 0300-5771
BackgroundThe relation between blood pressure and kidney cancer risk is well established but complex and different study designs have reported discrepant findings on the relative importance of diastolic blood pressure (DBP) and systolic blood pressure (SBP). In this study, we sought to describe the temporal relation between diastolic and SBP with renal cell carcinoma (RCC) risk in detail.MethodsOur study involved two prospective cohorts: the European Prospective Investigation into Cancer and Nutrition study and UK Biobank, including >700 000 participants and 1692 incident RCC cases. Risk analyses were conducted using flexible parametric survival models for DBP and SBP both separately as well as with mutuality adjustment and then adjustment for extended risk factors. We also carried out univariable and multivariable Mendelian randomization (MR) analyses (DBP: ninstruments = 251, SBP: ninstruments = 213) to complement the analyses of measured DBP and SBP.ResultsIn the univariable analysis, we observed clear positive associations with RCC risk for both diastolic and SBP when measured ≥5 years before diagnosis and suggestive evidence for a stronger risk association in the year leading up to diagnosis. In mutually adjusted analysis, the long-term risk association of DBP remained, with a hazard ratio (HR) per standard deviation increment 10 years before diagnosis (HR10y) of 1.20 (95% CI: 1.10–1.30), whereas the association of SBP was attenuated (HR10y: 1.00, 95% CI: 0.91–1.10). In the complementary multivariable MR analysis, we observed an odds ratio for a 1-SD increment (ORsd) of 1.34 (95% CI: 1.08–1.67) for genetically predicted DBP and 0.70 (95% CI: 0.56–0.88) for genetically predicted SBP.ConclusionThe results of this observational and MR study are consistent with an important role of DBP in RCC aetiology. The relation between SBP and RCC risk was less clear but does not appear to be independent o
Guida F, Tan VY, Corbin LJ, et al., 2021, The blood metabolome of incident kidney cancer: A case-control study nested within the MetKid consortium, PLoS Medicine, Vol: 18, ISSN: 1549-1277
BACKGROUND: 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). METHODS AND FINDINGS: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples 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 [ßBMI] 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 (&sz
Clasen J, Heath AK, Van Puyvelde H, et al., 2021, Vitamin B6 intake, its active form pyridoxal 5'phosphate, and markers of B6 activity and catabolism, IEA WORLD CONGRESS OF EPIDEMIOLOGY 2021, Publisher: Oxford University Press, Pages: 1-1, ISSN: 0300-5771
BackgroundSeveral biological pathways implicated in cancer risk rely on vitamin B6, which can be measured in its active form pyridoxal 5’-phosphate (PLP). Functional markers of B6 enzymatic activity have been proposed, including the homocysteine:cysteine ratio (Hcy:Cys, a marker of transsulfuration), 3-hydroxykynurenine ratio (HKr, a marker of tryptophan catabolism), and the 4-pyridoxic acid ratio (PAr, a marker of B6 catabolism). We investigated the extent to which these markers are associated with B6 intake.MethodsData from 4,750 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study were included. We estimated the expected percentage change in each of the markers (PLP, Hcy:Cys, HKr, and PAr) for a doubling in B6 intake using log-linear Bayesian hierarchical regression models with log-transformed intake and biomarker data.ResultsThe percent change (posterior mean [95% Credible Interval (CrI)]) for a doubling of B6 intake was 61.0 [51.2, 71.8] for PLP, -12.7 [-15.2, -9.9] for Hcy:Cys, -12.9 [-15.7, -9.9] for HKr, and 1.3 [-3.5, 6.2] for PAr.ConclusionsB6 intake is most strongly associated with PLP, but is also associated with functional markers of transsulfuration and tryptophan catabolism, in the direction of increased activity in these pathways. There is no evidence of a linear association between vitamin B6 intake and catabolism.Key messagesOur results show differing sensitivity of PLP, markers of tryptophan catabolism and transsulfuration, and vitamin B6 catabolism to B6 intake.
Heath A, Clasen J, Riboli E, et al., 2021, Investigation of the obesity paradox in kidney cancer: mystifying association or myth?, World Congress of Epidemiology 2021, Publisher: Oxford University Press, ISSN: 0300-5771
Hageman S, Pennells L, Ojeda F, et al., 2021, SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe, EUROPEAN HEART JOURNAL, Vol: 42, Pages: 2439-2454, ISSN: 0195-668X
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Clasen J, Heath A, Van Puyvelde H, et al., 2021, A comparison of complementary measures of vitamin B6 status, function, and metabolism in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, American Journal of Clinical Nutrition, Vol: 114, Pages: 338-347, ISSN: 0002-9165
BackgroundVitamin B6 insufficiency has been linked to increased risk of cancer and other chronic diseases. The circulating concentration of pyridoxal 5′-phosphate (PLP) is a commonly used measure of vitamin B6 status. Ratios of substrates indicating PLP coenzymatic function and metabolism may be useful complementary measures to further explore the role of vitamin B6 in health.ObjectivesWe explored the sensitivity of 5 outcomes, namely PLP concentration, homocysteine:cysteine (Hcy:Cys), cystathionine:cysteine (Cysta:Cys), the 3´-hydroxykynurenine ratio (HKr), and the 4-pyridoxic acid ratio (PAr) to vitamin B6 intake as well as personal and lifestyle characteristics.MedthodsDietary intake and biomarker data were collected from participants from 3 nested case-control studies within the European Prospective Investigation into Cancer and Nutrition (EPIC). Bayesian regression models assessed the associations of the 5 biomarker outcomes with vitamin B6 intake and personal and lifestyle covariates. Analogous models examined the relations of Hcy:Cys, Cysta:Cys, and HKr with PLP.ResultsIn total, 4608 participants were included in the analyses. Vitamin B6 intake was most strongly associated with PLP, moderately associated with Hcy:Cys, Cysta:Cys, and HKr, and not associated with PAr (fold change in marker given a doubling of vitamin B6 intake: PLP 1.60 [95% credible interval (CrI): 1.50, 1.71]; Hcy:Cys 0.87 [95% CrI: 0.84, 0.90]; Cysta:Cys 0.89 [95% CrI: 0.84, 0.94]; HKr 0.88 [95% CrI: 0.85, 0.91]; PAr 1.00 [95% CrI: 0.95, 1.05]). PAr was most sensitive to age, and HKr was least sensitive to BMI and alcohol intake. Sex and menopause status were strongly associated with all 5 markers.ConclusionsWe found that 5 different markers, capturing different aspects of vitamin B6–related biological processes, varied in their associations with vitamin B6 intake and personal and lifestyle predictors.
Van Puyvelde H, Papadimitriou N, Clasen J, et al., 2021, Dietary methyl-group donor intake and breast cancer risk in the European prospective investigation into cancer and nutrition (EPIC), Nutrients, Vol: 13, Pages: 1-15, ISSN: 2072-6643
(1) Background: Methyl-group donors (MGDs), including folate, choline, betaine, and methionine, may influence breast cancer (BC) risk through their role in one-carbon metabolism; (2) Methods: We studied the relationship between dietary intakes of MGDs and BC risk, adopting data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort; (3) Results: 318,686 pre- and postmenopausal women were followed between enrolment in 1992–2000 and December 2013–December 2015. Dietary MGD intakes were estimated at baseline through food-frequency questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary intake of MGDs, measured both as a calculated score based on their sum and individually, and BC risk. Subgroup analyses were performed by hormone receptor status, menopausal status, and level of alcohol intake. During a mean follow-up time of 14.1 years, 13,320 women with malignant BC were identified. No associations were found between dietary intakes of the MGD score or individual MGDs and BC risk. However, a potential U-shaped relationship was observed between dietary folate intake and overall BC risk, suggesting an inverse association for intakes up to 350 µg/day compared to a reference intake of 205 µg/day. No statistically significant differences in the associations were observed by hormone receptor status, menopausal status, or level of alcohol intake; (4) Conclusions: There was no strong evidence for an association between MGDs involved in one-carbon metabolism and BC risk. However, a potential U-shaped trend was suggested for dietary folate intake and BC risk. Further research is needed to clarify this association.
Heath A, Clasen J, Jayanth N, et al., 2021, Soft drink and juice consumption and renal cell carcinoma incidence and mortality in the European Prospective Investigation into Cancer and Nutrition, Cancer Epidemiology, Biomarkers and Prevention, Vol: 30, Pages: 1270-1274, ISSN: 1055-9965
Background: Renal cell carcinoma (RCC) accounts for more than 80% of kidney cancers in adults, and obesity is a known risk factor. Regular consumption of sweetened beverages has been linked to obesity and several chronic diseases, including some types of cancer. It is uncertain whether soft drink and juice consumption is associated with risk of RCC. We investigated the associations of soft drink and juice consumption with RCC incidence and mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC).Methods: A total of 389,220 EPIC participants with median age of 52 years at recruitment (1991–2000) were included. Cox regression yielded adjusted HRs and 95% confidence intervals (CI) for RCC incidence and mortality in relation to intakes of juices and total, sugar-sweetened, and artificially sweetened soft drinks.Results: A total of 888 incident RCCs and 356 RCC deaths were identified. In models including adjustment for body mass index and energy intake, there was no higher risk of incident RCC associated with consumption of juices (HR per 100 g/day increment = 1.03; 95% CI, 0.97–1.09), total soft drinks (HR = 1.01; 95% CI, 0.98–1.05), sugar-sweetened soft drinks (HR = 0.99; 95% CI, 0.94–1.05), or artificially sweetened soft drinks (HR = 1.02; 95% CI, 0.96–1.08). In these fully adjusted models, none of the beverages was associated with RCC mortality (HR, 95% CI per 100 g/day increment 1.06, 0.97–1.16; 1.03, 0.98–1.09; 0.97, 0.89–1.07; and 1.06, 0.99–1.14, respectively).Conclusions: Consumption of juices or soft drinks was not associated with RCC incidence or mortality after adjusting for obesity.
Christakoudi S, Pagoni P, Ferrari P, et al., 2021, Weight change in middle adulthood and risk of cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, International Journal of Cancer, Vol: 148, Pages: 1637-1651, ISSN: 0020-7136
Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241,323 participants (31% men), 20% lost and 32% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow-up after the second weight assessment, 20,960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio HR=1.14; 95% confidence interval: 1.05-1.23). Compared to stable weight (+/-0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR=1.41; 1.01-1.96), post-menopausal breast (HR=1.08, 1.00-1.16) and thyroid (HR=1.40; 1.04-1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organization categories) was positively associated with most obesity-related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the post-menopausal breast (HR=1.19; 1.06-1.33), ovary (HR=1.40; 1.04-1.91), corpus uteri (HR=1.42; 1.06-1.91), kidney (HR=1.80; 1.20-2.68) and pancreas in men (HR=1.81; 1.11-2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR=0.40; 0.23-0.69) and colon (HR=0.69; 0.52-0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood.
Singleton RK, Heath AK, Clasen JL, et al., 2021, Risk prediction for renal cell carcinoma: results from the European Prospective Investigation into Cancer and Nutrition (EPIC) prospective cohort study, Cancer Epidemiology, Biomarkers and Prevention, ISSN: 1055-9965
Thomas M, Sakoda LC, Hoffmeister M, et al., 2021, Response to Li and Hopper, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 108, Pages: 527-529, ISSN: 0002-9297
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Laskar RS, Li P, Ecsedi S, et al., 2021, Sexual dimorphism in cancer: insights from transcriptional signatures in kidney tissue and renal cell carcinoma, HUMAN MOLECULAR GENETICS, Vol: 30, Pages: 343-355, ISSN: 0964-6906
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Chadeau M, Bodinier B, Vermeulen R, et al., 2020, Education, biological ageing, all-cause and cause-specific mortality and morbidity: UK Biobank Cohort Study, EClinicalMedicine, Vol: 29-30, ISSN: 2589-5370
BackgroundSocioeconomic position as measured by education may be embodied and affect the functioning of key physiological systems. Links between social disadvantage, its biological imprint, and cause-specific mortality and morbidity have not been investigated in large populations, and yet may point towards areas for public health interventions beyond targeting individual behaviours.MethodsUsing data from 366,748 UK Biobank participants with 13 biomarker measurements, we calculated a Biological Health Score (BHS, ranging from 0 to 1) capturing the level of functioning of five physiological systems. Associations between BHS and incidence of cardiovascular disease (CVD) and cancer, and mortality from all, CVD, cancer, and external causes were examined. We explored the role of education in these associations. Mendelian randomisation using genetic evidence was used to triangulate these findings.FindingsAn increase in BHS of 0.1 was associated with all-cause (HR = 1.14 [1.12–1.16] and 1.09 [1.07–1.12] in men and women respectively), cancer (HR = 1.11 [1.09–1.14] and 1.07 [1.04–1.10]) and CVD (HR = 1.25 [1.20–1.31] and 1.21 [1.11–1.31]) mortality, CVD incidence (HR = 1.15 [1.13–1.16] and 1.17 [1.15–1.19]). These associations survived adjustment for education, lifestyle-behaviours, body mass index (BMI), co-morbidities and medical treatments. Mendelian randomisation further supported the link between the BHS and CVD incidence (HR = 1.31 [1.21–1.42]). The BHS contributed to CVD incidence prediction (age-adjusted C-statistic = 0.58), other than through education and health behaviours.InterpretationThe BHS captures features of the embodiment of education, health behaviours, and more proximal unknown factors which all complementarily contribute to all-cause, cancer and CVD morbidity and premature death.
Clasen J, Heath AK, Scelo G, et al., 2020, Components of one-carbon metabolism and renal cell carcinoma: A systematic review and meta-analysis, European Journal of Nutrition, Vol: 59, Pages: 3801-3813, ISSN: 0044-264X
PurposeLittle is known about the aetiology of renal cell carcinoma (RCC). Components of one-carbon (1C) metabolism, which are required for nucleotide synthesis and methylation reactions, may be related to risk of RCC but existing evidence is inconclusive. We conducted a systematic review and independent exposure-specific meta-analyses of dietary intake and circulating biomarkers of 1C metabolites and RCC risk.MethodsMedline and Embase databases were searched for observational studies investigating RCC or kidney cancer incidence or mortality in relation to components of 1C metabolism and 12 eligible articles were included in the meta-analyses. We used Bayesian meta-analyses to estimate summary relative risks (RRs) and 95% credible intervals (CrIs) comparing the highest versus lowest categories as well as the between-study heterogeneity.ResultsWe did not find convincing evidence of an association between any exposure (riboflavin, vitamin B6, folate, vitamin B12, methionine, homocysteine, choline, or betaine) and RCC risk. However, vitamin B6 biomarker status did have a protective (RR = 0.62) but imprecise (95% CrI 0.39–1.14) effect estimate and folate intake had a notable association as well (RR = 0.85, 95% CrI 0.71–1.01).ConclusionThere was a lack of precision due largely to the low number of studies. Further investigation is warranted, especially for folate and vitamin B6, which had consistent suggestive evidence of a protective effect for both dietary intake and biomarker status. A unique strength of this review is the use of Bayesian meta-analyses which allowed for robust estimation of between-study heterogeneity.
Sanikini H, Muller DC, Chadeau-Hyam M, et al., 2020, Anthropometry, body fat composition and reproductive factors and risk of oesophageal and gastric cancer by subtype and subsite in the UK Biobank cohort, PLoS One, Vol: 15, Pages: 1-22, ISSN: 1932-6203
BackgroundObesity has been positively associated with upper gastrointestinal cancers, but prospective data by subtype/subsite are limited. Obesity influences hormonal factors, which may play a role in these cancers. We examined anthropometry, body fat and reproductive factors in relation to oesophageal and gastric cancer by subtype/subsite in the UK Biobank cohort.MethodsAmong 458,713 UK Biobank participants, 339 oesophageal adenocarcinomas, 124 oesophageal squamous cell carcinomas, 137 gastric cardia and 92 gastric non-cardia cancers were diagnosed during a mean of 6.5 years follow-up. Cox models estimated multivariable hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsBody mass index (BMI), hip circumference, waist circumference, waist-to-hip ratio, waist-to-height ratio, total body fat and trunk fat were positively associated with oesophageal adenocarcinoma (highest vs lowest category: HR = 2.33, 95%-CI:1.65–3.28; HR = 1.56, 95%-CI:1.15–2.13; HR = 2.30, 95%-CI:1.47–3.57; HR = 1.71, 95%-CI:1.01–2.90; HR = 2.87, 95%-CI:1.88–4.38; HR = 1.96, 95%-CI:1.30–2.96; HR = 2.34, 95%-CI:1.70–3.22, respectively). Although there were no statistically significant associations in combined sex analyses, BMI (HR = 1.83, 95%-CI:1.00–3.37), waist circumference (HR = 2.21, 95%-CI:1.27–3.84) and waist-to-hip ratio (HR = 1.92, 95%-CI:1.11–3.29) were associated with gastric cardia cancer in men; however, mutual adjustment attenuated the associations for BMI and waist-to-hip ratio. For oesophageal squamous cell carcinoma, statistically significant inverse associations were observed among women for BMI, hip circumference, waist circumference, waist-to-height ratio, total body fat and trunk fat, although they were based on small numbers. In addition, older age at first (HR = 0.44, 95%-CI:0.22–0.88) and last live birth (HR = 0.44, 95%-CI:0.22–0.87) were inversely associated with oesophageal squamous cell carc
Thomas M, Sakoda LC, Hoffmeister M, et al., 2020, Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 107, Pages: 432-444, ISSN: 0002-9297
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Christakoudi S, Tsilidis KK, Muller DC, et al., 2020, ABSI (A Body Shape Index) achieves better mortality risk stratification than alternative indices of abdominal obesity: results from a large European cohort, Scientific Reports, Vol: 10, ISSN: 2045-2322
Abdominal and general adiposity are independently associated with mortality, but there is no consensus on how best to assess abdominal adiposity. We compared the ability of alternative waist indices to complement body mass index (BMI) when assessing all-cause mortality. We used data from 352,985 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) and Cox proportional hazards models adjusted for other risk factors. During a mean follow-up of 16.1 years, 38,178 participants died. Combining in one model BMI and a strongly correlated waist index altered the association patterns with mortality, to a predominantly negative association for BMI and a stronger positive association for the waist index, while combining BMI with the uncorrelated A Body Shape Index (ABSI) preserved the association patterns. Sex-specific cohort-wide quartiles of waist indices correlated with BMI could not separate high-risk from low-risk individuals within underweight (BMI<18.5 kg/m2) or obese (BMI≥30 kg/m2) categories, while the highest quartile of ABSI separated 18%-39% of the individuals within each BMI category, which had 22%-55% higher risk of death. In conclusion, only a waist index independent of BMI by design, such as ABSI, complements BMI and enables efficient risk stratification, which could facilitate personalisation of screening, treatment and monitoring.
Loveday C, Sud A, Jones ME, et al., 2020, Prioritisation by FIT to mitigate the impact of delays in the 2-week wait colorectal cancer referral pathway during the COVID-19 pandemic: a UK modelling study, Gut, Vol: 70, Pages: 1053-1060, ISSN: 0017-5749
OBJECTIVE: To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent from the COVID-19 pandemic. DESIGN: We modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2-6 months in the 2WW pathway. We stratified by age group, individual-level benefit in CRC survival versus age-specific nosocomial COVID-19-related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008-2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval. RESULTS: Delay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk-benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged >60. Prioritisation out of delay for the 18% of symptomatic referrals with FIT >10 µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by >80%. CONCLUSIONS: Delays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the a
Sud A, Torr B, Jones M, et al., 2020, Effect of delays in the UK two-week wait cancer referral pathway during the COVID-19 pandemic on cancer survival: a modelling study, The Lancet Oncology, Vol: 21, Pages: 1035-1044, ISSN: 1213-9432
Background: During the COVID-19 lockdown, referrals via the 2 Week Wait (2WW) urgent pathway for suspected cancer in England are reported to have dropped by up to 84%. We aimed to examine the impact on cancer survival of different scenarios of lockdown accumulated-backlog. We also aimed to examine by tumour-referral-group and age, survival benefit per referred patient considering survival decrement from delayed referral versus risk of death from nosocomial SARS-CoV-2 infection.Methods: To construct the underlying models, we used age- and stage-stratified 10 year cancer survival estimates for England 2007-2017 for 20 common tumour-types. We applied per-day hazard ratios for cancer progression generated from observational studies of delay to-treatment. We quantified the annual numbers of cancers diagnosed via the 2WW-pathway using the 2WW age- and stage-specific breakdowns. From these, for per-patient delays of 1- 6 months, we estimated aggregate number of lives lost and life-years lost in England. Using referral-to-diagnosis conversion rates and COVID-19 case fatality rates, we also estimated the survival increment per patient referred. Findings: Per month across England in 2013-2016, on average 6,281 patients with Stage 1- 3 cancer were diagnosed via the 2WW pathway of whom 1,691 would be predicted to die within 10 years from their disease. We estimated 2WW-pathway presentational-delay from three months of lockdown will result in total in 181/361/542 attributable additional deaths (if % reduction in referrals was 25/50/75% respectively). Limited diagnostic capacity to address the backlog may result in additional delays: 401/811/1,231 attributable additional deaths are estimated if additional diagnostic capacity is delayed until months 3-8 post-lockdown. 2-month delay in 2WW investigatory referral results in average loss of life-years per-referred-patient of between 0 and 0.7, depending on age and tumour-type. Interpretation: Prompt provision of additional capacity f
Elliott P, Muller DC, Schneider-Luftman D, et al., 2020, Estimated 24-hour urinary sodium excretion and incident cardiovascular disease and mortality among 398 628 individuals in UK biobank., Hypertension, Vol: 76, Pages: 1-9, ISSN: 0194-911X
We report on an analysis to explore the association between estimated 24-hour urinary sodium excretion (surrogate for sodium intake) and incident cardiovascular disease (CVD) and mortality. Data were obtained from 398 628 UK Biobank prospective cohort study participants (40-69 years) recruited between 2006 and 2010, with no history of CVD, renal disease, diabetes mellitus or cancer, and cardiovascular events and mortality recorded during follow-up. Hazard ratios between 24-hour sodium excretion were estimated from spot urinary sodium concentrations across incident CVD and its components and all-cause and cause-specific mortality. In restricted cubic splines analyses, there was little evidence for an association between estimated 24-hour sodium excretion and CVD, coronary heart disease, or stroke; hazard ratios for CVD (95% CIs) for the 15th and 85th percentiles (2.5 and 4.2 g/day, respectively) compared with the 50th percentile of estimated sodium excretion (3.2 g/day) were 1.05 (1.01-1.10) and 0.96 (0.92-1.00), respectively. An inverse association was observed with heart failure, but that was no longer apparent in sensitivity analysis. A J-shaped association was observed between estimated sodium excretion and mortality. Our findings do not support a J-shaped association of estimated sodium excretion with CVD, although such an association was apparent for all-cause and cause-specific mortality across a wide range of diseases. Reasons for these differences are unclear; methodological limitations, including the use of estimating equations based on spot urinary data, need to be considered in interpreting our findings.
Maric T, Kanu C, Muller DC, et al., 2020, Fetal growth and fetoplacental circulation in pregnancies following bariatric surgery: a prospective study, Publisher: WILEY, Pages: 839-846, ISSN: 1470-0328
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Ji X, Mukherjee S, Landi MT, et al., 2020, Protein-altering germline mutations implicate novel genes related to lung cancer development., Nature Communications, Vol: 11, Pages: 1-14, ISSN: 2041-1723
Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10-15) and replication (adjusted OR = 2.93, P = 2.22 × 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.
Elliott J, Bodinier B, Bond TA, et al., 2020, Predictive accuracy of a polygenic risk score-enhanced prediction model vs a clinical risk score for coronary artery disease, JAMA: Journal of the American Medical Association, Vol: 323, Pages: 636-645, ISSN: 0098-7484
Importance The incremental value of polygenic risk scores in addition to well-established risk prediction models for coronary artery disease (CAD) is uncertain.Objective To examine whether a polygenic risk score for CAD improves risk prediction beyond pooled cohort equations.Design, Setting, and Participants Observational study of UK Biobank participants enrolled from 2006 to 2010. A case-control sample of 15 947 prevalent CAD cases and equal number of age and sex frequency–matched controls was used to optimize the predictive performance of a polygenic risk score for CAD based on summary statistics from published genome-wide association studies. A separate cohort of 352 660 individuals (with follow-up to 2017) was used to evaluate the predictive accuracy of the polygenic risk score, pooled cohort equations, and both combined for incident CAD.Exposures Polygenic risk score for CAD, pooled cohort equations, and both combined.Main Outcomes and Measures CAD (myocardial infarction and its related sequelae). Discrimination, calibration, and reclassification using a risk threshold of 7.5% were assessed.Results In the cohort of 352 660 participants (mean age, 55.9 years; 205 297 women [58.2%]) used to evaluate the predictive accuracy of the examined models, there were 6272 incident CAD events over a median of 8 years of follow-up. CAD discrimination for polygenic risk score, pooled cohort equations, and both combined resulted in C statistics of 0.61 (95% CI, 0.60 to 0.62), 0.76 (95% CI, 0.75 to 0.77), and 0.78 (95% CI, 0.77 to 0.79), respectively. The change in C statistic between the latter 2 models was 0.02 (95% CI, 0.01 to 0.03). Calibration of the models showed overestimation of risk by pooled cohort equations, which was corrected after recalibration. Using a risk threshold of 7.5%, addition of the polygenic risk score to pooled cohort equations resulted in a net reclassification improvement of 4.4% (95% CI, 3.5% to 5.3%) for cases and −0.4% (95% CI, &
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