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La faible productivité de l’agriculture en Afrique subsaharienne est due en grande partie à la dégradation de la fertilité des sols. Les agricultures familiales, pilier de la sécurité alimentaire de cette grande région, doivent relever le défi de la restauration et du maintien de la capacité productive des terres. Les pratiques endogènes des producteurs telles que les associations céréales-légumineuses, les jachères pâturées, les parcs arborés... ne permettent plus d’entretenir la fertilité sur des surfaces cultivées qui s’agrandissent, surtout lorsque les sols sont carencés. Durant quatre décennies, les décideurs et acteurs du secteur agricole ont privilégié la vulgarisation des engrais de synthèse. Mais l’utilisation des engrais minéraux demeure faible et bien en deçà de la moyenne de la consommation mondiale (15 kg/ha contre 135 kg/ha). Après avoir longuement promu l’utilisation de fumure organique, la recherche invite désormais à diversifier les sources de biomasse fertilisante via l’agroforesterie, les associations avec les légumineuses, l’agriculture de conservation. D’autres techniques de conservation de l’eau et du sol ont également été mises en avant. C’est bien la combinaison de différentes pratiques qui est à construire avec les agriculteurs pour chaque situation de production, en fonction des ressources disponibles localement, d’un apport raisonné d’engrais de synthèse et d’amendement, des savoirs paysans et scientifiques. Pour cela, il est nécessaire (i) de modifier les postures des chercheurs et des décideurs vis-à-vis des ruraux et (ii) de réviser les politiques publiques toujours focalisées sur l’usage des engrais minéraux, afin de fournir des services d’appui-conseil plus diversifiés, performants et intégrant les besoins de transitions agroécologiques indispensables aujourd’hui dans un contexte de changement climatique.

OBJECTIVE: To determine the impact of comprehensiveness of cytology registration on the proportion of cervical cancer patients without a recent screening history. METHODS: For Danish women diagnosed with cervical cancer in 2003-2007, we used cytology data from the nationwide Danish Pathology Data Bank and the National Health Service Register. In five steps, we included data from an increasing number of cervical screening laboratories into the analysis, and calculated the proportions of screened women who had cytology registered in two screening rounds prior to the cancer diagnosis. RESULTS: In total, 1867 cervical cancer patients were included in the analysis. When looking only at the screening history in the laboratory that diagnosed the cancer, it appeared that only 40% of women were screened in the last two rounds. This proportion increased to 55% when nationwide screening data were used. This corresponded to a 25% decrease in the proportion of patients without a recent screening history. CONCLUSION: The level of comprehensiveness of screening data makes a measurable difference when evaluating the screening histories of women with cervical cancer. It is important that actions for the improvement of a screening program are based on comprehensive cytology registrations. [ABSTRACT FROM AUTHOR]

Au début de la crise sanitaire due à la Covid-19, certains observateurs ont alerté les décideurs d’une possible crise alimentaire dans les mois à venir en Afrique de l’Ouest. En vue d’alimenter ce débat, nous avons mené une étude en nous entretenant avec 75 acteurs du secteur agricole dans deux régions du Burkina Faso − le Yatenga et les Hauts-Bassins. Dans les deux situations, les agriculteurs et les éleveurs ont pu continuer leurs activités mais certains ont eu des difficultés de commercialisation. Les maraîchers et les arboriculteurs ont été les plus touchés par cette crise du fait des difficultés à écouler leurs produits périssables sur les marchés ouest-africains. Les éleveurs ont été moins concernés par la baisse des prix mais les commerçants de bétail sur pied ont aussi rencontré des difficultés à exporter vers les pays côtiers. Enfin, les sociétés cotonnières ont dû faire face à une baisse du prix international du coton-fibre et les producteurs de coton ont dû faire face à une baisse du prix d’achat du coton-graine à la fin de 2020. Malgré cette crise, l’agriculture burkinabè a continué à jouer pleinement son rôle nourricier grâce à la mobilisation des agriculteurs, des commerçants et des transporteurs, même si elle montre des fragilités dues à sa forte dépendance aux marchés extérieurs pour entre autres les légumes, le bétail, le coton, les mangues, l’anacarde et les intrants agricoles et d’élevage. Cette crise permet de réfléchir à des axes d’intervention afin de rendre l’agriculture burkinabè moins dépendante des marchés extérieurs et des facteurs de production importés. Cela implique la substitution des produits alimentaires importés par des produits locaux et une transition agroécologique permettant de réduire l’importation d’intrants de synthèse.

Le conseil agricole occupe une place prépondérante dans l’appui aux processus d’innovation, particulièrement dans les pays du Sud. Or, l’accompagnement de l’innovation nécessite une diversité de formes d’appuis, appelés services support à l’innovation (SSI). À partir d’une analyse exploratoire à Madagascar, cet article questionne la place du conseil agricole vis-à-vis de la diversité des organisations et des activités d’accompagnement de l’innovation. Les principales organisations fournissant des SSI ont été étudiées dans quatre régions des Hautes Terres de Madagascar et leur offre de SSI caractérisée. Les résultats montrent que le conseil technique reste prépondérant dans l’éventail de l’offre de SSI, avec un fort pluralisme des fournisseurs de conseil et une diversité de combinaisons avec les autres SSI. Or, les porteurs d’innovation doivent bénéficier d’autres SSI, tels que le renforcement de capacité, la mise en réseau, des appuis institutionnels, un accès au financement, intrants et équipements nécessaires à l’innovation. Ces résultats appellent à renouveler les postures du conseiller agricole vers davantage d’appui au renforcement de capacité et interrogent la stratégie des organisations vis-à-vis de leur appui à l’innovation : la spécialisation dans le conseil, la combinaison à d’autres SSI ou la collaboration avec d’autres organisations. Ces éléments renouvellent le constat du pluralisme de l’offre de conseil qui, analysé par le prisme des SSI, ne s’applique pas seulement à l’échelon de l’agent-conseiller ou de l’organisation, mais également dans des réseaux d’organisations aux configurations variables. Les perspectives de cette analyse sont d’assurer la coordination des dispositifs de conseil avec les autres fournisseurs de SSI pour une plus grande efficacité dans l’accompagnement des porteurs d’innovation.

Evolution of relations between agriculture and breeding was studied in peanut basin in Senegal and cotton area in northern Cameroon. Joint development of animal traction, peanut and cotton furthered the emergence of mixed systems (agriculture and breeding). The producer’s strategy of capitalization in cattle is still existing but conflicts in access to natural resources and evolution of urban markets let them to intensify breeding systems, especially in high populated areas located near cities. To make these evolutions sustainable, it’s necessary to enhance vegetal biomass production and to reduce losses of water and soil nutrients. Weaknesses of approaches based only on technology transfer have been shown. Research must get involved more actively in developing different options with farmers to manage production areas (from farm to region). At the end, a renewed framework for analysis and intervention is proposed. It combines 3 complementary approaches related to (i) technical farming systems, (ii) management of production units and organization of commodity chains, and (iii) collective resource management.

Aims: Clustering algorithms have been widely applied to tumor DNA methylation datasets to define methylation-based cancer subtypes. This study aimed to evaluate the agreement between subtypes obtained from common clustering strategies., Materials & Methods: We used tumor DNA methylation data from 409 women with breast cancer from the Melbourne Collaborative Cohort Study (MCCS) and 781 breast tumors from The Cancer Genome Atlas (TCGA). Agreement was assessed using the adjusted Rand index for various combinations of number of CpGs, number of clusters and clustering algorithms (hierarchical, K-means, partitioning around medoids, and recursively partitioned mixture models)., Results: Inconsistent agreement patterns were observed for between-algorithm and within-algorithm comparisons, with generally poor to moderate agreement (ARI <0.7). Results were qualitatively similar in the MCCS and TCGA, showing better agreement for moderate number of CpGs and fewer clusters (K = 2). Restricting the analysis to CpGs that were differentially-methylated between tumor and normal tissue did not result in higher agreement., Conclusion: Our study highlights that common clustering strategies involving an arbitrary choice of algorithm, number of clusters and number of methylation sites are likely to identify different DNA methylation-based breast tumor subtypes.

Background: Tumour DNA methylation has been investigated as a potential marker for breast cancer survival, but findings often lack replication across studies., Methods: This study sought to replicate previously reported associations for individual CpG sites and multi-CpG signatures using an Australian sample of 425 women with breast cancer from the Melbourne Collaborative Cohort Study (MCCS). Candidate methylation sites (N = 22) and signatures (N = 3) potentially associated with breast cancer survival were identified from five prior studies that used The Cancer Genome Atlas (TCGA) methylation dataset, which shares key characteristics with the MCCS: comparable sample size, tissue type (formalin-fixed paraffin-embedded; FFPE), technology (Illumina HumanMethylation450 array), and participant characteristics (age, ancestry, and disease subtype and severity). Cox proportional hazard regression analyses were conducted to assess associations between these markers and both breast cancer-specific survival and overall survival, adjusting for relevant participant characteristics., Results: Our findings revealed partial replication for both individual CpG sites (9 out of 22) and multi-CpG signatures (2 out of 3). These associations were maintained after adjustment for participant characteristics and were stronger for breast cancer-specific mortality than for overall mortality. In fully-adjusted models, strong associations were observed for a CpG in PRAC2 (per standard deviation [SD], HR = 1.67, 95%CI: 1.24-2.25) and a signature based on 28 CpGs developed using elastic net (per SD, HR = 1.48, 95%CI: 1.09-2.00)., Conclusions: While further studies are needed to confirm and expand on these findings, our study suggests that DNA methylation markers hold promise for improving breast cancer prognostication., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Human Research Ethics Committee of Cancer Council Victoria. Informed consent was obtained from all subjects involved in the study. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s).)

Evidence suggests that inflammation may be associated with a higher risk of endometrial cancer, but previous reviews have typically examined a limited number of biomarkers. This study aimed to critically appraise the evidence on the effect of 13 circulating inflammatory biomarkers on endometrial cancer risk. MEDLINE and EMBASE databases were searched for prospective cohort, (nested) case-control and case-cohort studies, and Mendelian randomization (MR) studies published up to 31 March 2023. We performed a random-effects meta-analysis to estimate the pooled risk ratio and 95 % confidence interval (CI) for the association between each biomarker and endometrial cancer risk. Heterogeneity between studies was assessed using the I 2 statistic. Eight studies were included in the meta-analysis. Comparing groups with the highest versus lowest concentration of biomarker, adiponectin levels were inversely associated with risk of endometrial cancer (risk ratio (RR) =0.75, 95 % CI: 0.57-0.99, I2: 9 %). Higher levels of CRP (RR=1.18, 95 % CI: 1.05-1.33, I 2 : 2 %) and TNF-α (RR=1.58, 95 % CI: 1.13-2.21, I 2 : 0 %) were positively associated with risk of endometrial cancer. There was suggestive evidence for a positive association was also found for IL-6 (RR=1.29, 95 % CI: 0.88-1.88, I 2 : 0 %) and leptin (RR=1.50, 95 % CI: 0.83-2.71, I 2 : 0 %). Our findings suggest that circulating inflammatory biomarkers are likely involved in the carcinogenesis of endometrial cancer. Future studies should consider prospective or MR design and measure a wider range of inflammatory markers., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Brigid M Lynch reports administrative support was provided by Cancer Council Victoria. Brigid M Lynch reports a relationship with Australasian Epidemiological Association that includes: board membership. Brigid M Lynch serves as an Associate Editor for Cancer Epidemiology If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Young breast and bowel cancers (e.g., those diagnosed before age 40 or 50 years) have far greater morbidity and mortality in terms of years of life lost, and are increasing in incidence, but have been less studied. For breast and bowel cancers, the familial relative risks, and therefore the familial variances in age-specific log(incidence), are much greater at younger ages, but little of these familial variances has been explained. Studies of families and twins can address questions not easily answered by studies of unrelated individuals alone. We describe existing and emerging family and twin data that can provide special opportunities for discovery. We present designs and statistical analyses, including novel ideas such as the VALID (Variance in Age-specific Log Incidence Decomposition) model for causes of variation in risk, the DEPTH (DEPendency of association on the number of Top Hits) and other approaches to analyse genome-wide association study data, and the within-pair, ICE FALCON (Inference about Causation from Examining FAmiliaL CONfounding) and ICE CRISTAL (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLysis) approaches to causation and familial confounding. Example applications to breast and colorectal cancer are presented. Motivated by the availability of the resources of the Breast and Colon Cancer Family Registries, we also present some ideas for future studies that could be applied to, and compared with, cancers diagnosed at older ages and address the challenges posed by young breast and bowel cancers., (© 2024 The Authors. Genetic Epidemiology published by Wiley Periodicals LLC.)

Self-rated health (SRH) is a subjective indicator of overall health based on a single questionnaire item. Previous evidence found that it is a strong predictor of mortality, although the underlying mechanism is poorly understood. Epigenetic age is an objective, emerging biomarker of health, estimated using DNA methylation data at hundreds of sites across the genome. This study aimed to assess the overlap and interaction between SRH and epigenetic ageing in predicting mortality risk. We used DNA methylation data from 1059 participants in the Melbourne Collaborative Cohort Study (mean age: 69 years) to calculate three age-adjusted measures of epigenetic ageing: GrimAge, PhenoAge, and DunedinPACE. SRH was assessed using a five-category questionnaire item ("excellent, very good, good, fair, poor"). Cox models were used to assess the associations of SRH, epigenetic ageing, and their interaction, with all-cause mortality over up to 17 years of follow-up (N deaths  = 345). The association of SRH with mortality per category increase was HR = 1.29; 95%CI: 1.14-1.46. The association was slightly attenuated after adjusting for all three epigenetic ageing measures (HR = 1.25, 95%CI: 1.10-1.41). A strong gradient was observed in the association of GrimAge (P interaction  = 0.006) and DunedinPACE (P interaction  = 0.002) with mortality across worsening SRH strata. For example, the association between DunedinPACE and mortality in participants with "excellent" SRH was HR = 1.02, 95%CI: 0.73-1.43 and for "fair/poor" HR = 1.72, 95%CI: 1.35-2.20. SRH and epigenetic ageing were synergistic risk factors of mortality in our study. These findings suggest that consideration of subjective and objective factors may improve general health assessment, which has implications for the ongoing development of molecular markers of ageing., (© 2024. The Author(s).)

DNA methylation is an epigenetic mark that plays a critical role in regulating gene expression. DNA methyltransferase (DNMT) inhibitors, inhibit global DNA methylation and have been a key tool in studies of DNA methylation. A major bottleneck is the lack of tools to induce global DNA methylation. Here, we engineered a CRISPR based approach, that we initially designed, to enable site-specific DNA methylation. Using the synergistic activation mediator (SAM) system, we unexpectedly find that regardless of the targeted sequence any sgRNA induces global genome-wide DNA methylation. We term this method SAM-DNMT3A and show that induction of global DNA methylation is a unique vulnerability in ER-positive breast cancer suggesting a therapeutic approach. Our findings highlight the need of caution when using CRISPR based approaches for inducing DNA methylation and demonstrate a method for global induction of DNA methylation., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Epigenetic age quantifies biological age using DNA methylation information and is a potential pathway by which physical activity benefits general health. We aimed to assess the cross-sectional and longitudinal associations between physical activity and epigenetic age in middle-aged and older Australians. Blood DNA methylation data for 6208 participants (40% female) in the Melbourne Collaborative Cohort Study (MCCS) were available at baseline (1990-1994, mean age, 59 years) and, of those, for 1009 at follow-up (2003-2007, mean age, 69 years). Physical activity measurements (weighted scores at baseline and follow-up and total MET hours per week at follow-up) were calculated from self-reported questionnaire data. Five blood methylation-based markers of ageing (PCGrimAge, PCPhenoAge, bAge, DNAmFitAge, and DunedinPACE) and four fitness-related markers (DNAmGaitspeed, DNAmGripmax, DNAmVO2max, and DNAmFEV1) were calculated and adjusted for age. Linear regression was used to examine the cross-sectional and longitudinal associations between physical activity and epigenetic age. Effect modification by age, sex, and BMI was assessed. At baseline, a standard deviation (SD) increment in physical activity was associated with 0.03-SD (DNAmFitAge, 95%CI = 0.01, 0.06, P = 0.02) to 0.07-SD (bAge, 95%CI = 0.04, 0.09, P = 2 × 10 -8 ) lower epigenetic age. These associations were attenuated after adjustment for other lifestyle variables. Only weak evidence was found for the longitudinal association (N = 1009) of changes in physical activity and epigenetic age (e.g. DNAmFitAge: adjusted β =  - 0.04, 95%CI =  - 0.08, 0.01). The associations were not modified by age, sex, or BMI. In middle-aged and older Australians, higher levels of self-reported physical activity were associated with slightly lower epigenetic age., (© 2024. The Author(s).)

Significance: Further investigation of the potential susceptibility regions identified in our study may lead to a better understanding of glioma genetic risk and the underlying biological etiology of glioma. Our study suggests sex may play a role in genetic susceptibility and highlights the importance of sex-specific analysis in future glioma research., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Age is one of the strongest risk factors for breast cancer. Measures of biological age based on DNA methylation have gained popularity for their strong association with risk of many diseases, including cancer, which may help to identify high-risk subgroups for targeted prevention., Methods: We carried out a systematic review of prospective studies that examined the association of methylation-based markers of ageing with risk of invasive breast cancer in healthy (breast cancer-free) women, published up to May 2023. The search of three databases (MEDLINE, EMBASE and Web of Science) identified 2913 individual abstracts eligible for screening. Risk of bias assessment was conducted using ROBINS-E., Results: Ten prospective studies met the eligibility criteria, and these were heterogeneous in design and findings. The most frequently assessed epigenetic ageing measures were Horvath's first-generation clock, PhenoAge and GrimAge. Four studies reported mainly positive associations, five null associations and one reported a negative association. These associations were generally weak and the results were not consistent across epigenetic ageing measures., Conclusion: The summarised evidence is insufficient to support a role for current epigenetic ageing measures to stratify breast cancer risk. PROSPERO Registration: This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42023417559)., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

The role of nutrition in healthy ageing is acknowledged but details of optimal dietary composition are still uncertain. We aimed to investigate the cross-sectional associations between dietary exposures, including macronutrient composition, food groups, specific foods, and overall diet quality, with methylation-based markers of ageing. Blood DNA methylation data from 5310 participants (mean age 59 years) in the Melbourne Collaborative Cohort Study were used to calculate five methylation-based measures of ageing: PCGrimAge, PCPhenoAge, DunedinPACE, ZhangAge, TelomereAge. For a range of dietary exposures, we estimated (i) the 'equal-mass substitution effect', which quantifies the effect of adding the component of interest to the diet while keeping overall food mass constant, and (ii) the 'total effect', which quantifies the effect of adding the component of interest to the current diet. For 'equal-mass substitution effects', the strongest association for macronutrients was for fibre intake (e.g. DunedinPACE, per 12 g/day - 0.10 [standard deviations]; 95%CI - 0.15, - 0.05, p < 0.001). Associations were positive for protein (e.g. PCGrimAge, per 33 g/day 0.04; 95%CI 0.01-0.08, p = 0.005). For food groups, the evidence tended to be weak, though sugar-sweetened drinks showed positive associations, as did artificially-sweetened drinks (e.g. DunedinPACE, per 91 g/day 0.06, 95%CI 0.03-0.08, p < 0.001). 'Total effect' estimates were generally very similar. Scores reflecting overall diet quality suggested that healthier diets were associated with lower levels of ageing markers. High intakes of fibre and low intakes of protein and sweetened drinks, as well as overall healthy diets, showed the most consistent associations with lower methylation-based ageing in our study., (© 2024. The Author(s).)

Objective: Screening high-risk individuals with low-dose CT reduces mortality from lung cancer, but many lung cancers occur in individuals who are not eligible for screening. Risk biomarkers may be useful to refine risk models and improve screening eligibility criteria. We evaluated if blood-based DNA methylation markers can improve a traditional lung cancer prediction model., Methods and Analysis: This study used four prospective cohorts with blood samples collected prior to lung cancer diagnosis. The study was restricted to participants with a history of smoking, and one control was individually matched to each lung cancer case using incidence density sampling by cohort, sex, date of blood collection, age and smoking status. To train a DNA methylation-based risk score, we used participants from Melbourne Collaborative Cohort Study-Australia (n=648) and Northern Sweden Health and Disease Study-Sweden (n=380) based on five selected CpG sites. The risk discriminative performance of the methylation score was subsequently validated in participants from European Investigation into Cancer and Nutrition-Italy (n=267) and Norwegian Women and Cancer-Norway (n=185) and compared with that of the questionnaire-based PLCOm2012 lung cancer risk model., Results: The area under the receiver operating characteristic curve (AUC) for the PLCOm2012 model in the validation studies was 0.70 (95% CI: 0.65 to 0.75) compared with 0.73 (95% CI: 0.68 to 0.77) for the methylation score model ( P difference =0.07). Incorporating the methylation score with the PLCOm2012 model did not improve the risk discrimination (AUC: 0.73, 95% CI: 0.68 to 0.77, P difference =0.73)., Conclusions: This study suggests that the methylation-based risk prediction score alone provides similar lung cancer risk-discriminatory performance as the questionnaire-based PLCOm2012 risk model., Competing Interests: Competing interests: MC-H holds shares in the O-SMOSE company. Consulting activities conducted by the company are independent of the present work and MC-H has no conflict of interest to declare. All other authors declare no conflict of interest., (© World Health Organization 2024. Licensee BMJ.)

Epigenetic age is an emerging marker of health that is highly predictive of disease and mortality risk. There is a lack of evidence on whether lifestyle changes are associated with changes in epigenetic aging. We used data from 1 041 participants in the Melbourne Collaborative Cohort Study with blood DNA methylation measures at baseline (1990-1994, mean age: 57.4 years) and follow-up (2003-2007, mean age: 68.8 years). The Alternative Healthy Eating Index-2010 (AHEI-2010), the Mediterranean Dietary Score, and the Dietary Inflammatory Index were used as measures of diet quality, and weight, waist circumference, and waist-to-hip ratio as measures of body size. Five age-adjusted epigenetic aging measures were considered: GrimAge, PhenoAge, PCGrimAge, PCPhenoAge, and DunedinPACE. Multivariable linear regression models including restricted cubic splines were used to assess the cross-sectional and longitudinal associations of body size and diet quality with epigenetic aging. Associations between weight and epigenetic aging cross-sectionally at both time points were positive and appeared greater for DunedinPACE (per SD: β ~0.24) than for GrimAge and PhenoAge (β ~0.10). The longitudinal associations with weight change were markedly nonlinear (U-shaped) with stable weight being associated with the lowest epigenetic aging at follow-up, except for DunedinPACE, for which only weight gain showed a positive association. We found negative, linear associations for AHEI-2010 both cross-sectionally and longitudinally. Other adiposity measures and dietary scores showed similar results. In middle-aged to older adults, declining diet quality and weight gain may increase epigenetic age, while the association for weight loss may require further investigation. Our study sheds light on the potential of weight management and dietary improvement in slowing aging processes., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

No randomized controlled trial has evaluated the effect of long-term alcohol interventions on mortality. Results reported in existing observational studies may be subject to selection bias and time-varying confounding. Using data from the Australian Longitudinal Study on Women's Health 1946-1951 birth cohort, collected regularly from 1996-2016, we estimated all-cause and cancer mortality had women been assigned various alcohol interventions (in categories ranging from 0 to >30 g/day ethanol, or reduced to ≤20 g/day if higher) at baseline, and had they maintained these levels of consumption. The cumulative risks for all-cause and cancer mortality were 5.6% (10,118 women followed for 20 years) and 2.9% (18 years), respectively. For all-cause and cancer mortality, baseline ethanol up to 30 g/day showed lower risk and >30 g/day showed higher risk relative to abstention. Had women sustainedly followed the interventions, a similar relationship was observed for all-cause mortality. However, the negative association observed for intakes ≤30 g/day and positive association for intakes >30 g/day was not evident for cancer mortality. Our findings suggest that all-cause mortality could have been lower than observed if this cohort of women had consumed some alcohol (no more than 30 g/day) rather than no consumption, but cancer mortality might not., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Glucose-6-phosphate dehydrogenase (G6PD) deficiency in erythrocytes causes acute haemolytic anaemia upon exposure to fava beans, drugs, or infection; and it predisposes to neonatal jaundice. The polymorphism of the X-linked G6PD gene has been studied extensively: allele frequencies of up to 25% of different G6PD deficient variants are known in many populations; variants that cause chronic non-spherocytic haemolytic anaemia (CNSHA) are instead all rare. WHO recommends G6PD testing to guide 8-aminoquinolines administration to prevent relapse of Plasmodium vivax infection. From a literature review focused on polymorphic G6PD variants we have retrieved G6PD activity values of 2291 males, and for the mean residual red cell G6PD activity of 16 common variants we have obtained reliable estimates, that range from 1.9% to 33%. There is variation in different datasets: for most variants most G6PD deficient males have a G6PD activity below 30% of normal. There is a direct relationship between residual G6PD activity and substrate affinity (K m G6P ), suggesting a mechanism whereby polymorphic G6PD deficient variants do not entail CNSHA. Extensive overlap in G6PD activity values of individuals with different variants, and no clustering of mean values above or below 10% support the merger of class II and class III variants., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Genome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer., Methods: Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs., Results: Assuming a 1 × 10 -5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (OR int  = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (OR int  = 0.91, 95% CI 0.88-0.94)., Conclusions: Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Methylation marks of exposure to health risk factors may be useful markers of cancer risk as they might better capture current and past exposures than questionnaires, and reflect different individual responses to exposure. We used data from seven case-control studies nested within the Melbourne Collaborative Cohort Study of blood DNA methylation and risk of colorectal, gastric, kidney, lung, prostate and urothelial cancer, and B-cell lymphoma (N cases = 3123). Methylation scores (MS) for smoking, body mass index (BMI), and alcohol consumption were calculated based on published data as weighted averages of methylation values. Rate ratios (RR) and 95% confidence intervals for association with cancer risk were estimated using conditional logistic regression and expressed per SD increase of the MS, with and without adjustment for health-related confounders. The contribution of MS to discriminate cases from controls was evaluated using the area under the curve (AUC). After confounder adjustment, we observed: large associations (RR = 1.5-1.7) with lung cancer risk for smoking MS; moderate associations (RR = 1.2-1.3) with urothelial cancer risk for smoking MS and with mature B-cell neoplasm risk for BMI and alcohol MS; moderate to small associations (RR = 1.1-1.2) for BMI and alcohol MS with several cancer types and cancer overall. Generally small AUC increases were observed after inclusion of several MS in the same model (colorectal, gastric, kidney, urothelial cancers: +3%; lung cancer: +7%; B-cell neoplasms: +8%). Methylation scores for smoking, BMI and alcohol consumption show independent associations with cancer risk, and may provide some improvements in risk prediction., (© 2023 UICC.)

Background: Glioma accounts for approximately 80% of malignant adult brain cancer and its most common subtype, glioblastoma, has one of the lowest 5-year cancer survivals. Fifty risk-associated variants within 34 glioma genetic risk regions have been found by genome-wide association studies (GWAS) with a sex difference reported for 8q24.21 region. We conducted an Australian GWAS by glioma subtype and sex., Methods: We analyzed genome-wide data from the Australian Genomics and Clinical Outcomes of Glioma (AGOG) consortium for 7 573 692 single nucleotide polymorphisms (SNPs) for 560 glioma cases and 2237 controls of European ancestry. Cases were classified as glioblastoma, non-glioblastoma, astrocytoma or oligodendroglioma. Logistic regression analysis was used to assess the associations of SNPs with glioma risk by subtype and by sex., Results: We replicated the previously reported glioma risk associations in the regions of 2q33.3 C2orf80, 2q37.3 D2HGDH, 5p15.33 TERT, 7p11.2 EGFR, 8q24.21 CCDC26, 9p21.3 CDKN2BAS, 11q21 MAML2, 11q23.3 PHLDB1, 15q24.2 ETFA, 16p13.3 RHBDF1, 16p13.3 LMF1, 17p13.1 TP53, 20q13.33 RTEL, and 20q13.33 GMEB2 (P < .05). We also replicated the previously reported sex difference at 8q24.21 CCDC26 (P = .0024) with the association being nominally significant for both sexes (P < .05)., Conclusions: Our study supports a stronger female risk association for the region 8q24.21 CCDC26 and highlights the importance of analyzing glioma GWAS by sex. A better understanding of sex differences could provide biological insight into the cause of glioma with implications for prevention, risk prediction and treatment., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

DNA methylation marks that are inherited from parents to offspring are known to play a role in cancer risk and could explain part of the familial risk for cancer. We therefore conducted a genome-wide search for heritable methylation marks associated with prostate cancer risk. Peripheral blood DNA methylation was measured for 133 of the 469 members of 25 multiple-case prostate cancer families, using the EPIC array. We used these families to systematically search the genome for methylation marks with Mendelian patterns of inheritance, then we tested the 1,000 most heritable marks for association with prostate cancer risk. After correcting for multiple testing, 41 heritable methylation marks were associated with prostate cancer risk. Separate analyses, based on 869 incident cases and 869 controls from a prospective cohort study, showed that 9 of these marks near the metastable epiallele VTRNA2-1 were also nominally associated with aggressive prostate cancer risk in the population., (© 2023. The Author(s).)

Aim: The kynurenine pathway is increasingly recognised to play a role in inflammation and disease. We assessed the cross-sectional and longitudinal associations of adiposity measures (body mass index, waist-hip ratio, waist circumference and fat mass ratio) with plasma concentrations of kynurenine pathway metabolites and traditional markers of inflammation., Methods: We used data from 970 Melbourne Collaborative Cohort Study participants who had plasma markers measured at baseline (median age 59 years) and follow-up (median age 70 years). Linear regression was used to assess cross-sectional and longitudinal associations between four adiposity measures and concentrations of i) nine kynurenine pathway metabolites; ii) two derived markers; iii) eight traditional inflammatory markers., Results: Cross-sectionally, most kynurenine metabolites were strongly associated with adiposity measures at both time points; associations were generally stronger than for most inflammation markers except CRP (e.g. body mass index at baseline, quinolinic acid (per S.D. β = 0.30, 95%CI: 0.24-0.36, P = 10 -21 ), kynurenine (β = 0.25, 95%CI: 0.19-0.31, P = 10 -16 ) and CRP (β = 0.31, 95%CI: 0.25-0.37, P = 10 -24 ), and remained largely unchanged after adjustment for confounders. Longitudinally, changes in adiposity measures over approximately a decade were positively associated with changes in kynurenine metabolite concentrations (in particular for 3-hydroxyanthranilic acid, kynurenine and quinolinic acid), and more strongly so than for other markers of inflammation, including CRP., Conclusions: In middle-aged and older adults, plasma concentrations of kynurenine metabolites are strongly associated with adiposity, both cross-sectionally and longitudinally. Our study demonstrates that kynurenine metabolites may be valuable markers to monitor the adverse consequences of obesity., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Several studies have reported short sleep duration in people with non-alcoholic fatty liver disease (NAFLD) but other sleep characteristics have been less studied. We aimed to assess the cross-sectional association of NAFLD with sleep duration and quality in an Iranian population sample., Methods: We used data from 9,151 participants in the Shahrekord Prospective Epidemiological Research Studies in Iran (PERSIAN) Cohort Study, including 1,320 that were diagnosed with NAFLD. Log-binomial regression models sequentially adjusted for sociodemographic, lifestyle, clinical and biological variables were used to estimate relative risks (RR) and 95% confidence intervals (95% CI) for the association between NAFLD and sleep characteristics., Results: Participants with NAFLD had shorter sleep duration, later wake-up time and bedtime, worse sleep efficiency, and more frequent daytime napping and use of sleeping pills, in age- and sex-adjusted models. After controlling for sociodemographic, lifestyle, clinical, and biological variables the associations remained strong for sleep efficiency (per 10%, RR = 0.92, 95%CI: 0.88-0.96) and use of sleeping pills (RR = 1.48, 95%CI: 1.17-1.88). The association between NAFLD and sleep efficiency was stronger in participants aged > 60 years (RR = 0.81, 0.70-0.93) and 40-60 years (RR = 0.87, 0.82-0.94), compared with those aged < 40 years (P-heterogeneity < 0.001). More frequent daytime napping in participants with NAFLD, compared with non-NAFLD, was observed in males but not females (P-heterogeneity = 0.007), and in those with body mass index (BMI) < 30 but not in obese participants (P-heterogeneity < 0.001)., Conclusions: Diagnosis of NAFLD is associated with several poor sleep characteristics in middle-aged Iranians. Although longitudinal studies would help to clarify the direction of causality, our study shows that poor sleep is an important aspect of NAFLD., (© 2023. The Author(s).)

This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential of BMI-associated cytosine-phosphate-guanine (CpG) sites to provide information about metabolic health. We pooled summary statistics from six trans-ethnic epigenome-wide association studies (EWASs) of BMI representing nine cohorts (n = 17,034), replicated these findings in the Women's Health Initiative (WHI, n = 4,822), and developed an epigenetic prediction score of BMI. In the pooled EWASs, 1,265 CpG sites were associated with BMI (p < 1E-7) and 1,238 replicated in the WHI (FDR < 0.05). We performed several stratified analyses to examine whether these associations differed between individuals of European and African descent, as defined by self-reported race/ethnicity. We found that five CpG sites had a significant interaction with BMI by race/ethnicity. To examine the utility of the significant CpG sites in predicting BMI, we used elastic net regression to predict log-normalized BMI in the WHI (80% training/20% testing). This model found that 397 sites could explain 32% of the variance in BMI in the WHI test set. Individuals whose methylome-predicted BMI overestimated their BMI (high epigenetic BMI) had significantly higher glucose and triglycerides and lower HDL cholesterol and LDL cholesterol compared to accurately predicted BMI. Individuals whose methylome-predicted BMI underestimated their BMI (low epigenetic BMI) had significantly higher HDL cholesterol and lower glucose and triglycerides. This study confirmed 553 and identified 685 CpG sites associated with BMI. Participants with high epigenetic BMI had poorer metabolic health, suggesting that the overestimation may be driven in part by cardiometabolic derangements characteristic of metabolic syndrome., Competing Interests: Declaration of interests K.M.J. is an employee of Bristol Myers Squibb., (Copyright © 2022 American Society of Human Genetics. All rights reserved.)

Limited evidence exists on the link between inflammation and epigenetic aging. We aimed to (a) assess the cross-sectional and prospective associations of 22 inflammation-related plasma markers and a signature of inflammaging with epigenetic aging and (b) determine whether epigenetic aging and inflammaging are independently associated with mortality. Blood samples from 940 participants in the Melbourne Collaborative Cohort Study collected at baseline (1990-1994) and follow-up (2003-2007) were assayed for DNA methylation and 22 inflammation-related markers, including well-established markers (eg, interleukins and C-reactive protein) and metabolites of the tryptophan-kynurenine pathway. Four measures of epigenetic aging (PhenoAge, GrimAge, DunedinPoAm, and Zhang) and a signature of inflammaging were considered, adjusted for age, and transformed to Z scores. Associations were assessed using linear regression, and mortality hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated using Cox regression. Cross-sectionally, most inflammation-related markers were associated with epigenetic aging measures, although with generally modest effect sizes (regression coefficients per SD ≤ 0.26) and explaining altogether between 1% and 11% of their variation. Prospectively, baseline inflammation-related markers were not, or only weakly, associated with epigenetic aging after 11 years of follow-up. Epigenetic aging and inflammaging were strongly and independently associated with mortality, for example, inflammaging: HR = 1.41, 95% CI = 1.27-1.56, p = 2 × 10-10, which was only slightly attenuated after adjustment for 4 epigenetic aging measures: HR = 1.35, 95% CI = 1.22-1.51, p = 7 × 10-9). Although cross-sectionally associated with epigenetic aging, inflammation-related markers accounted for a modest proportion of its variation. Inflammaging and epigenetic aging are essentially nonoverlapping markers of biological aging and may be used jointly to predict mortality., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Lifestyle-related phenotypes have been shown to be heritable and associated with DNA methylation. We aimed to investigate whether genetic predisposition to tobacco smoking, alcohol consumption, and higher body mass index (BMI) moderates the effect of these phenotypes on blood DNA methylation. We calculated polygenic scores (PGS) to quantify genetic predisposition to these phenotypes using training ( N = 7,431) and validation ( N = 4,307) samples. Using paired genetic-methylation data ( N = 4,307), gene-environment interactions (i.e., PGS × lifestyle) were assessed using linear mixed-effects models with outcomes: 1) methylation at sites found to be strongly associated with smoking (1,061 CpGs), alcohol consumption (459 CpGs), and BMI (85 CpGs) and 2) two epigenetic ageing measures, PhenoAge and GrimAge . In the validation sample, PGS explained ~1.4% ( P = 1 × 10 -14 ), ~0.6% ( P = 2 × 10 -7 ), and ~8.7% ( P = 7 × 10 -87 ) of variance in smoking initiation, alcohol consumption, and BMI, respectively. Nominally significant interaction effects ( P < 0.05) were found at 61, 14, and 7 CpGs for smoking, alcohol consumption, and BMI, respectively. There was strong evidence that all lifestyle-related phenotypes were positively associated with PhenoAge and GrimAge , except for alcohol consumption with PhenoAge . There was weak evidence that the association of smoking with GrimAge was attenuated in participants genetically predisposed to smoking (interaction term: -0.022, standard error [SE] = 0.012, P = 0.058) and that the association of alcohol consumption with PhenoAge was attenuated in those genetically predisposed to drink alcohol (interaction term: -0.030, SE = 0.015, P = 0.041). In conclusion, genetic susceptibility to unhealthy lifestyles did not strongly modify the association between observed lifestyle behaviour and blood DNA methylation. Potential associations were observed for epigenetic ageing measures, which should be replicated in additional studies.

The kynurenine pathway is implicated in aging, longevity, and immune regulation, but longitudinal studies and assessment of the cerebrospinal fluid (CSF) are lacking. We investigated tryptophan (Trp) and downstream kynurenine metabolites and their associations with age and change over time in four cohorts using comprehensive, targeted metabolomics. The study included 1574 participants in two cohorts with repeated metabolite measurements (mean age at baseline 58 years ± 8 SD and 62 ± 10 SD), 3161 community-dwelling older adults (age range 71-74 years), and 109 CSF donors (mean age 73 years ± 7 SD). In the first two cohorts, age was associated with kynurenine (Kyn), quinolinic acid (QA), and the kynurenine to tryptophan ratio (KTR), and inversely with Trp. Consistent with these findings, Kyn, QA, and KTR increased over time, whereas Trp decreased. Similarly, QA and KTR were higher in community-dwelling older adults of age 74 compared to 71, whereas Trp was lower. Kyn and QA were more strongly correlated with age in the CSF compared to serum and increased in a subset of participants with repeated CSF sampling ( n = 33) over four years. We assessed associations with frailty and mortality in two cohorts. QA and KTR were most strongly associated with mortality and frailty. Our study provides robust evidence of changes in tryptophan and kynurenine metabolism with human aging and supports links with adverse health outcomes. Our results suggest that aging activates the inflammation and stress-driven kynurenine pathway systemically and in the brain, but we cannot determine whether this activation is harmful or adaptive. We identified a relatively stronger age-related increase of the potentially neurotoxic end-product QA in brain., Competing Interests: Per Magne Ueland is a member of the steering board of the nonprofit Foundation to Promote Research into Functional Vitamin B12 Deficiency, which owns Bevital, the company that did biochemical analyses. All the other authors, Stein-Erik H. Solvang, Allison Hodge, Leiv Otto Watne, Otavio Cabral-Marques, Jan Erik Nordrehaug, Graham G. Giles, Pierre-Antoine Dugué, Ottar Nygård, Adrian McCann, Ane-Victoria Idland, Øivind Midttun, Arve Ulvik, Nathalie B. Halaas, Grethe S. Tell, and Lasse M. Giil, report no conflicts of interest., (Copyright © 2022 Stein-Erik H. Solvang et al.)

Background: DNA methylation in blood may reflect adverse exposures accumulated over the lifetime and could therefore provide potential improvements in the prediction of cancer risk. A substantial body of research has shown associations between epigenetic aging and risk of disease, including cancer. Here we aimed to study epigenetic measures of aging and lifestyle-related factors in association with risk of breast cancer., Methods: Using data from four prospective case-control studies nested in three cohorts of European ancestry participants, including a total of 1,655 breast cancer cases, we calculated three methylation-based measures of lifestyle factors (body mass index [BMI], tobacco smoking and alcohol consumption) and seven measures of epigenetic aging (Horvath-based, Hannum-based, PhenoAge and GrimAge). All measures were regression-adjusted for their respective risk factors and expressed per standard deviation (SD). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional or unconditional logistic regression and pooled using fixed-effects meta-analysis. Subgroup analyses were conducted by age at blood draw, time from blood sample to diagnosis, oestrogen receptor-positivity status and tumour stage., Results: None of the measures of epigenetic aging were associated with risk of breast cancer in the pooled analysis: Horvath 'age acceleration' (AA): OR per SD = 1.02, 95%CI: 0.95-1.10; AA-Hannum: OR = 1.03, 95%CI:0.95-1.12; PhenoAge: OR = 1.01, 95%CI: 0.94-1.09 and GrimAge: OR = 1.03, 95%CI: 0.94-1.12, in models adjusting for white blood cell proportions, body mass index, smoking and alcohol consumption. The BMI-adjusted predictor of BMI was associated with breast cancer risk, OR per SD = 1.09, 95%CI: 1.01-1.17. The results for the alcohol and smoking methylation-based predictors were consistent with a null association. Risk did not appear to substantially vary by age at blood draw, time to diagnosis or tumour characteristics., Conclusion: We found no evidence that methylation-based measures of aging, smoking or alcohol consumption were associated with risk of breast cancer. A methylation-based marker of BMI was associated with risk and may provide insights into the underlying associations between BMI and breast cancer., (© 2022. The Author(s).)

Educational inequalities in all-cause mortality have been observed for decades. However, the underlying biological mechanisms are not well known. We aimed to assess the role of DNA methylation changes in blood captured by epigenetic clocks in explaining these inequalities. Data were from 8 prospective population-based cohort studies, representing 13 021 participants. First, educational inequalities and their portion explained by Horvath DNAmAge, Hannum DNAmAge, DNAmPhenoAge, and DNAmGrimAge epigenetic clocks were assessed in each cohort via counterfactual-based mediation models, on both absolute (hazard difference) and relative (hazard ratio) scales, and by sex. Second, estimates from each cohort were pooled through a random effect meta-analysis model. Men with low education had excess mortality from all causes of 57 deaths per 10 000 person-years (95% confidence interval [CI]: 38, 76) compared with their more advantaged counterparts. For women, the excess mortality was 4 deaths per 10 000 person-years (95% CI: -11, 19). On the relative scale, educational inequalities corresponded to hazard ratios of 1.33 (95% CI: 1.12, 1.57) for men and 1.15 (95% CI: 0.96, 1.37) for women. DNAmGrimAge accounted for the largest proportion, approximately 50%, of the educational inequalities for men, while the proportion was negligible for women. Most of this mediation was explained by differential effects of unhealthy lifestyles and morbidities of the World Health Organization (WHO) risk factors for premature mortality. These results support DNA methylation-based epigenetic aging as a signature of educational inequalities in life expectancy emphasizing the need for policies to address the unequal social distribution of these WHO risk factors., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Smoking-related epigenetic changes have been linked to lung cancer, but the contribution of epigenetic alterations unrelated to smoking remains unclear. We sought for a sparse set of CpG sites predicting lung cancer and explored the role of smoking in these associations. We analysed CpGs in relation to lung cancer in participants from two nested case-control studies, using (LASSO)-penalised regression. We accounted for the effects of smoking using known smoking-related CpGs, and through conditional-independence network. We identified 29 CpGs (8 smoking-related, 21 smoking-unrelated) associated with lung cancer. Models additionally adjusted for Comprehensive Smoking Index-(CSI) selected 1 smoking-related and 49 smoking-unrelated CpGs. Selected CpGs yielded excellent discriminatory performances, outperforming information provided by CSI only. Of the 8 selected smoking-related CpGs, two captured lung cancer-relevant effects of smoking that were missed by CSI. Further, the 50 CpGs identified in the CSI-adjusted model complementarily explained lung cancer risk. These markers may provide further insight into lung cancer carcinogenesis and help improving early identification of high-risk patients., (© 2022. The Author(s).)

Background: Questions remain about the effect on mortality of physical activity and sedentary behaviour over time. We summarized the evidence from studies that assessed exposure from multiple time points and critiqued the analytic approaches used., Methods: A search was performed on MEDLINE, Embase, Emcare, Scopus and Web of Science up to January 2021 for studies of repeatedly assessed physical activity or sedentary behaviour in relation to all-cause or cause-specific mortality. Relative risks from individual studies were extracted. Each study was assessed for risk of bias from multiple domains., Results: We identified 64 eligible studies (57 on physical activity, 6 on sedentary behaviour, 1 on both). Cox regression with a time-fixed exposure history (n = 45) or time-varying covariates (n = 13) were the most frequently used methods. Only four studies used g-methods, which are designed to adjust for time-varying confounding. Risk of bias arose primarily from inadequate adjustment for time-varying confounders, participant selection, exposure classification and changes from measured exposure. Despite heterogeneity in methods, most studies found that being consistently or increasingly active over adulthood was associated with lower all-cause and cardiovascular-disease mortality compared with being always inactive. Few studies examined physical-activity changes and cancer mortality or effects of sedentary-behaviour changes on mortality outcomes., Conclusions: Accumulating more evidence using longitudinal data while addressing the methodological challenges would provide greater insight into the health effects of initiating or maintaining a more active and less sedentary lifestyle., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Inflammation is a key feature of aging. We aimed to (i) investigate the association of 34 blood markers potentially involved in inflammatory processes with age and mortality and (ii) develop a signature of "inflammaging.", Methods: Thirty-four blood markers relating to inflammation, B vitamin status, and the kynurenine pathway were measured in 976 participants in the Melbourne Collaborative Cohort Study at baseline (median age = 59 years) and follow-up (median age = 70 years). Associations with age and mortality were assessed using linear and Cox regression, respectively. A parsimonious signature of inflammaging was developed and its association with mortality was compared with 2 marker scores calculated across all markers associated with age and mortality, respectively., Results: The majority of markers (30/34) were associated with age, with stronger associations observed for neopterin, cystatin C, interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), several markers of the kynurenine pathway and derived indices KTR (kynurenine/tryptophan ratio), PAr index (ratio of 4-pyridoxic acid and the sum of pyridoxal 5'-phosphate and pyridoxal), and HK:XA (3-hydroxykynurenine/xanthurenic acid ratio). Many markers (17/34) showed an association with mortality, in particular IL-6, neopterin, C-reactive protein, quinolinic acid, PAr index, and KTR. The inflammaging signature included 10 markers and was strongly associated with mortality (hazard ratio [HR] per SD = 1.40, 95% CI: 1.24-1.57, p = 2 × 10-8), similar to scores based on all age-associated (HR = 1.38, 95% CI: 1.23-1.55, p = 4 × 10-8) and mortality-associated markers (HR = 1.43, 95% CI: 1.28-1.60, p = 1 × 10-10), respectively. Strong evidence of replication of the inflammaging signature association with mortality was found in the Hordaland Health Study., Conclusion: Our study highlights the key role of the kynurenine pathway and vitamin B6 catabolism in aging, along with other well-established inflammation-related markers. A signature of inflammaging based on 10 markers was strongly associated with mortality., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We considered whether weight is more informative than body mass index (BMI) = weight/height2 when predicting breast cancer risk for postmenopausal women, and if the weight association differs by underlying familial risk. We studied 6,761 women postmenopausal at baseline with a wide range of familial risk from 2,364 families in the Prospective Family Study Cohort. Participants were followed for on average 11.45 years and there were 416 incident breast cancers. We used Cox regression to estimate risk associations with log-transformed weight and BMI after adjusting for underlying familial risk. We compared model fits using the Akaike information criterion (AIC) and nested models using the likelihood ratio test. The AIC for the weight-only model was 6.22 units lower than for the BMI-only model, and the log risk gradient was 23% greater. Adding BMI or height to weight did not improve fit (ΔAIC = 0.90 and 0.83, respectively; both P = 0.3). Conversely, adding weight to BMI or height gave better fits (ΔAIC = 5.32 and 11.64; P = 0.007 and 0.0002, respectively). Adding height improved only the BMI model (ΔAIC = 5.47; P = 0.006). There was no evidence that the BMI or weight associations differed by underlying familial risk (P > 0.2). Weight is more informative than BMI for predicting breast cancer risk, consistent with nonadipose as well as adipose tissue being etiologically relevant. The independent but multiplicative associations of weight and familial risk suggest that, in terms of absolute breast cancer risk, the association with weight is more important the greater a woman's underlying familial risk., Prevention Relevance: Our results suggest that the relationship between BMI and breast cancer could be due to a relationship between weight and breast cancer, downgraded by inappropriately adjusting for height; potential importance of anthropometric measures other than total body fat; breast cancer risk associations with BMI and weight are across a continuum., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: Critical inter-provincial differences within Iran in the pattern of non-communicable diseases (NCDs) and difficulties inherent to identifying prevention methods to reduce mortality from NCDs have challenged the implementation of the provincial health system plan. The Shahrekord Cohort Study (SCS) was designed to address these gaps in Chaharmahal and Bakhtiari, a province of high altitude in the southwest of Iran, characterized by its large Bakhtiari population, along with Fars and Turk ethnicity groups., Methods: This ongoing cohort, a prospective, large-scale longitudinal study, includes a unique, rich biobank and was conducted for the first time in Chaharmahal and Bakhtiari Province in Iran. SCS is a part of the PERSIAN (Prospective Epidemiological Research Studies in IrAN) cohort. The study began in 2015, recruited 10075 participants (52.8% female, 47.2% male) from both urban (n=7034) and rural (n=3041) areas, and participants will be annually followed up for at least 15 years. A cross-sectional analysis was conducted using baseline data from the SCS, using descriptive statistics and logistic regression. Data analysis was performed using Stata software., Results: The prevalence of NCDs was 9.8% for type 2 diabetes, 17.1% for hypertension, 11.6% for thyroid disease, 0.2% for multiple sclerosis and 5.7, 0.9 and 1.3% for ischemic heart disease, stroke and myocardial infarction, respectively. The prevalence of multimorbidity (≥2 NCDs) was higher in women (39.1%) than men (24.9%). The means (standard deviations) of age, BMI, systolic blood pressure and fasting blood glucose were 49.5 (9) years, 27.6 (4.6) kg/m 2 , 115.4 (17.3) mmHg and 96.7 (27.3) mg/dL, respectively. Logistic regression models showed that older age, female gender, living in an urban area, non-native ethnicity, high wealth index, unemployment, obesity, low physical activity, hypertriglyceridemia, high fasting blood sugar, alkaline urine pH and high systolic and diastolic blood pressure were associated with increased prevalence of NCDs., Conclusions: The SCS provides a platform for epidemiological studies that will be useful to better control NCDs in the southwest of Iran and to foster research collaboration. The SCS will be an essential resource for identifying NCD risk factors in this region and designing relevant public health interventions., (© 2021. The Author(s).)

Background: Self-reported information may not accurately capture smoking exposure. We aimed to evaluate whether smoking-associated DNA methylation markers improve urothelial cell carcinoma (UCC) risk prediction., Methods: Conditional logistic regression was used to assess associations between blood-based methylation and UCC risk using two matched case-control samples: 404 pairs from the Melbourne Collaborative Cohort Study (MCCS) and 440 pairs from the Women's Health Initiative (WHI) cohort. Results were pooled using fixed-effects meta-analysis. We developed methylation-based predictors of UCC and evaluated their prediction accuracy on two replication data sets using the area under the curve (AUC)., Results: The meta-analysis identified associations ( P < 4.7 × 10 -5 ) for 29 of 1,061 smoking-associated methylation sites, but these were substantially attenuated after adjustment for self-reported smoking. Nominally significant associations ( P < 0.05) were found for 387 (36%) and 86 (8%) of smoking-associated markers without/with adjustment for self-reported smoking, respectively, with same direction of association as with smoking for 387 (100%) and 79 (92%) markers. A Lasso-based predictor was associated with UCC risk in one replication data set in MCCS [ N = 134; odds ratio per SD (OR) = 1.37; 95% CI, 1.00-1.90] after confounder adjustment; AUC = 0.66, compared with AUC = 0.64 without methylation information. Limited evidence of replication was found in the second testing data set in WHI ( N = 440; OR = 1.09; 95% CI, 0.91-1.30)., Conclusions: Combination of smoking-associated methylation marks may provide some improvement to UCC risk prediction. Our findings need further evaluation using larger data sets., Impact: DNA methylation may be associated with UCC risk beyond traditional smoking assessment and could contribute to some improvements in stratification of UCC risk in the general population., (©2021 American Association for Cancer Research.)

Genetic variants in FOXO3 are associated with longevity. Here, we assessed whether blood DNA methylation at FOXO3 was associated with cancer risk, survival, and mortality. We used data from eight prospective case-control studies of breast ( n = 409 cases), colorectal ( n = 835), gastric ( n = 170), kidney ( n = 143), lung ( n = 332), prostate ( n = 869), and urothelial ( n = 428) cancer and B-cell lymphoma ( n = 438). Case-control pairs were matched on age, sex, country of birth, and smoking (lung cancer study). Conditional logistic regression was used to assess associations between cancer risk and methylation at 45 CpGs of FOXO3 included on the HumanMethylation450 assay. Mixed-effects Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations with cancer survival (total n = 2286 deaths). Additionally, using data from 1088 older participants, we assessed associations of FOXO3 methylation with overall and cause-specific mortality ( n = 354 deaths). Methylation at a CpG in the first exon region of FOXO3 (6:108882981) was associated with gastric cancer survival (HR = 2.39, 95% CI: 1.60-3.56, p = 1.9 × 10 -5 ). Methylation at three CpGs in TSS1500 and gene body was associated with lung cancer survival ( p < 6.1 × 10 -5 ). We found no evidence of associations of FOXO3 methylation with cancer risk and mortality. Our findings may contribute to understanding the implication of FOXO3 in longevity.

Objective: In previous studies using Illumina Infinium methylation arrays, we have identified DNA methylation marks associated with cancer predisposition and progression. In the present study, we have sought to find appropriate technology to both technically validate our data and expand our understanding of DNA methylation in these genomic regions. Here, we aimed to assess the repeatability of methylation measures made using QIAseq targeted methyl panel and to compare them with those obtained from the Illumina HumanMethylation450 (HM450K) assay. We included in the analysis high molecular weight DNA extracted from whole blood (WB) and DNA extracted from formalin-fixed paraffin-embedded tissues (FFPE)., Results: The repeatability of QIAseq-methylation measures was assessed at 40 CpGs, using the Intraclass Correlation Coefficient (ICC). The mean ICCs and 95% confidence intervals (CI) were 0.72 (0.62-0.81), 0.59 (0.47-0.71) and 0.80 (0.73-0.88) for WB, FFPE and both sample types combined, respectively. For technical replicates measured using QIAseq and HM450K, the mean ICCs (95% CI) were 0.53 (0.39-0.68), 0.43 (0.31-0.56) and 0.70 (0.59-0.80), respectively. Bland-Altman plots indicated good agreement between QIAseq and HM450K measurements. These results demonstrate that the QIAseq targeted methyl panel produces reliable and reproducible methylation measurements across the 40 CpGs that were examined., (© 2021. The Author(s).)

Background: Nutritional epidemiology research using self-reported dietary intake is prone to measurement error. Objective methods are being explored to overcome this limitation., Objectives: We aimed to examine 1) the association between plasma markers related to inflammation and derive marker scores for dietary patterns [Mediterranean dietary score (MDS), energy-adjusted Dietary Inflammatory Index (E-DIITM), Alternative Healthy Eating Index 2010 (AHEI)] and 2) the associations of these marker scores with mortality., Methods: Weighted marker scores were derived from the cross-sectional association between 30 plasma markers and each dietary score (assessed using food-frequency questionnaires) using linear regression for 770 participants in the Melbourne Collaborative Cohort Study (aged 50-82 y). Prospective associations between marker scores and mortality (n = 249 deaths) were assessed using Cox regression (median follow-up: 14.4 y)., Results: The MDS, E-DII, and AHEI were associated (P < 0.05) with 9, 14, and 11 plasma markers, respectively. Healthier diets (higher MDS and AHEI, and lower anti-inflammatory, E-DII) were associated with lower concentrations of kynurenines, neopterin, IFN-γ, cytokines, and C-reactive protein. Five of 6 markers common to the 3 dietary scores were components of the kynurenine pathway. The 3 dietary-based marker scores were highly correlated (Spearman ρ: -0.74, -0.82, and 0.93). Inverse associations (for 1-SD increment) were observed with all-cause mortality for the MDS marker score (HR: 0.84; 95% CI: 0.72-0.98) and the AHEI marker score (HR: 0.76; 95% CI: 0.66-0.89), whereas a positive association was observed with the E-DII marker score (HR: 1.18; 95% CI: 1.01-1.39). The same magnitude of effect was not observed for the respective dietary patterns., Conclusions: Markers involved in inflammation-related processes are associated with dietary quality, including a substantial overlap between markers associated with the MDS, the E-DII, and the AHEI, especially kynurenines. Unfavorable marker scores, reflecting poorer-quality diets, were associated with increased mortality., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field., Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels., Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

We investigated aberrant DNA methylation (DNAm) changes and the contribution of ageing-associated methylomic drift and age acceleration to early-onset colorectal cancer (EOCRC) carcinogenesis. Genome-wide DNAm profiling using the Infinium HM450K on 97 EOCRC tumour and 54 normal colonic mucosa samples was compared with: (1) intermediate-onset CRC (IOCRC; diagnosed between 50-70 years; 343 tumour and 35 normal); and (2) late-onset CRC (LOCRC; >70 years; 318 tumour and 40 normal). CpGs associated with age-related methylation drift were identified using a public dataset of 231 normal mucosa samples from people without CRC. DNAm-age was estimated using epiTOC2. Common to all three age-of-onset groups, 88,385 (20% of all CpGs) CpGs were differentially methylated between tumour and normal mucosa. We identified 234 differentially methylated genes that were unique to the EOCRC group; 13 of these DMRs/genes were replicated in EOCRC compared with LOCRCs from TCGA. In normal mucosa from people without CRC, we identified 28,154 CpGs that undergo ageing-related DNAm drift, and of those, 65% were aberrantly methylated in EOCRC tumours. Based on the mitotic-based DNAm clock epiTOC2, we identified age acceleration in normal mucosa of people with EOCRC compared with normal mucosa from the IOCRC, LOCRC groups ( p = 3.7 × 10 -16 ) and young people without CRC ( p = 5.8 × 10 -6 ). EOCRC acquires unique DNAm alterations at 234 loci. CpGs associated with ageing-associated drift were widely affected in EOCRC without needing the decades-long accrual of DNAm drift as commonly seen in intermediate- and late-onset CRCs. Accelerated ageing in normal mucosa from people with EOCRC potentially underlies the earlier age of diagnosis in CRC carcinogenesis.

Mammograms contain information that predicts breast cancer risk. We developed two novel mammogram-based breast cancer risk measures based on image brightness (Cirrocumulus) and texture (Cirrus). Their risk prediction when fitted together, and with an established measure of conventional mammographic density (Cumulus), is not known. We used three studies consisting of: 168 interval cases and 498 matched controls; 422 screen-detected cases and 1197 matched controls; and 354 younger-diagnosis cases and 944 controls frequency-matched for age at mammogram. We conducted conditional and unconditional logistic regression analyses of individually- and frequency-matched studies, respectively. We estimated measure-specific risk gradients as the change in odds per standard deviation of controls after adjusting for age and body mass index (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). For interval, screen-detected and younger-diagnosis cancer risks, the best fitting models (OPERAs [95% confidence intervals]) involved: Cumulus (1.81 [1.41-2.31]) and Cirrus (1.72 [1.38-2.14]); Cirrus (1.49 [1.32-1.67]) and Cirrocumulus (1.16 [1.03 to 1.31]); and Cirrus (1.70 [1.48 to 1.94]) and Cirrocumulus (1.46 [1.27-1.68]), respectively. The AUCs were: 0.73 [0.68-0.77], 0.63 [0.60-0.66], and 0.72 [0.69-0.75], respectively. Combined, our new mammogram-based measures have twice the risk gradient for screen-detected and younger-diagnosis breast cancer (P ≤ 10 -12 ), have at least the same discriminatory power as the current polygenic risk score, and are more correlated with causal factors than conventional mammographic density. Discovering more information about breast cancer risk from mammograms could help enable risk-based personalised breast screening., (© 2020 UICC.)