A multi-omics approach to investigate the inflammatory response to life course socioeconomic position.

Aim: Inflammation represents a potential pathway through which socioeconomic position (SEP) is biologically embedded. Materials & methods: We analyzed inflammatory biomarkers in response to life course SEP by integrating multi-omics DNA-methylation, gene expression and protein level in 178 European Prospective Investigation into Cancer and Nutrition-Italy participants. Results & conclusion: We identified 61 potential cis acting CpG loci whose methylation levels were associated with gene expression at a Bonferroni correction. We examined the relationships between life course SEP and these 61 cis-acting regulatory methylation sites individually and jointly using several scores. Less-advantaged SEP participants exhibit, later in life, a lower inflammatory methylome score, suggesting an overall increased expression of the corresponding inflammatory genes or proteins, supporting the hypothesis that SEP impacts adult physiology through inflammation.

Reducing socio-economic inequalities in all-cause mortality: a counterfactual mediation approach.

BACKGROUND: Socio-economic inequalities in mortality are well established, yet the contribution of intermediate risk factors that may underlie these relationships remains unclear. We evaluated the role of multiple modifiable intermediate risk factors underlying socio-economic-associated mortality and quantified the potential impact of reducing early all-cause mortality by hypothetically altering socio-economic risk factors. METHODS: Data were from seven cohort studies participating in the LIFEPATH Consortium (total n = 179 090). Using both socio-economic position (SEP) (based on occupation) and education, we estimated the natural direct effect on all-cause mortality and the natural indirect effect via the joint mediating role of smoking, alcohol intake, dietary patterns, physical activity, body mass index, hypertension, diabetes and coronary artery disease. Hazard ratios (HRs) were estimated, using counterfactual natural effect models under different hypothetical actions of either lower or higher SEP or education. RESULTS: Lower SEP and education were associated with an increase in all-cause mortality within an average follow-up time of 17.5 years. Mortality was reduced via modelled hypothetical actions of increasing SEP or education. Through higher education, the HR was 0.85 [95% confidence interval (CI) 0.84, 0.86] for women and 0.71 (95% CI 0.70, 0.74) for men, compared with lower education. In addition, 34% and 38% of the effect was jointly mediated for women and men, respectively. The benefits from altering SEP were slightly more modest. CONCLUSIONS: These observational findings support policies to reduce mortality both through improving socio-economic circumstances and increasing education, and by altering intermediaries, such as lifestyle behaviours and morbidities.

Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis.

Differences in health status by socioeconomic position (SEP) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. DNA methylation (DNAm) has been proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life.We examined the association of education level, as an indicator of SEP, and lifestyle-related variables with four biomarkers of age-dependent DNAm dysregulation: the total number of stochastic epigenetic mutations (SEMs) and three epigenetic clocks (Horvath, Hannum and Levine), in 18 cohorts spanning 12 countries.The four biological aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect.Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity.

Social adversity and epigenetic aging: a multi-cohort study on socioeconomic differences in peripheral blood DNA methylation.

Low socioeconomic status (SES) is associated with earlier onset of age-related chronic conditions and reduced life-expectancy, but the underlying biomolecular mechanisms remain unclear. Evidence of DNA-methylation differences by SES suggests a possible association of SES with epigenetic age acceleration (AA). We investigated the association of SES with AA in more than 5,000 individuals belonging to three independent prospective cohorts from Italy, Australia, and Ireland. Low SES was associated with greater AA (ß = 0.99 years; 95% CI 0.39,1.59; p = 0.002; comparing extreme categories). The results were consistent across different SES indicators. The associations were only partially modulated by the unhealthy lifestyle habits of individuals with lower SES. Individuals who experienced life-course SES improvement had intermediate AA compared to extreme SES categories, suggesting reversibility of the effect and supporting the relative importance of the early childhood social environment. Socioeconomic adversity is associated with accelerated epigenetic aging, implicating biomolecular mechanisms that may link SES to age-related diseases and longevity.

Socioeconomic status and the 25 × 25 risk factors as determinants of premature mortality: a multicohort study and meta-analysis of 1·7 million men and women.

BACKGROUND: In 2011, WHO member states signed up to the 25 × 25 initiative, a plan to cut mortality due to non-communicable diseases by 25% by 2025. However, socioeconomic factors influencing non-communicable diseases have not been included in the plan. In this study, we aimed to compare the contribution of socioeconomic status to mortality and years-of-life-lost with that of the 25 × 25 conventional risk factors. METHODS: We did a multicohort study and meta-analysis with individual-level data from 48 independent prospective cohort studies with information about socioeconomic status, indexed by occupational position, 25 × 25 risk factors (high alcohol intake, physical inactivity, current smoking, hypertension, diabetes, and obesity), and mortality, for a total population of 1 751 479 (54% women) from seven high-income WHO member countries. We estimated the association of socioeconomic status and the 25 × 25 risk factors with all-cause mortality and cause-specific mortality by calculating minimally adjusted and mutually adjusted hazard ratios [HR] and 95% CIs. We also estimated the population attributable fraction and the years of life lost due to suboptimal risk factors. FINDINGS: During 26·6 million person-years at risk (mean follow-up 13·3 years [SD 6·4 years]), 310 277 participants died. HR for the 25 × 25 risk factors and mortality varied between 1·04 (95% CI 0·98-1·11) for obesity in men and 2 ·17 (2·06-2·29) for current smoking in men. Participants with low socioeconomic status had greater mortality compared with those with high socioeconomic status (HR 1·42, 95% CI 1·38-1·45 for men; 1·34, 1·28-1·39 for women); this association remained significant in mutually adjusted models that included the 25 × 25 factors (HR 1·26, 1·21-1·32, men and women combined). The population attributable fraction was highest for smoking, followed by physical inactivity then socioeconomic status. Low socioeconomic status was associated with a 2·1-year reduction in life expectancy between ages 40 and 85 years, the corresponding years-of-life-lost were 0·5 years for high alcohol intake, 0·7 years for obesity, 3·9 years for diabetes, 1·6 years for hypertension, 2·4 years for physical inactivity, and 4·8 years for current smoking. INTERPRETATION: Socioeconomic circumstances, in addition to the 25 × 25 factors, should be targeted by local and global health strategies and health risk surveillance to reduce mortality. FUNDING: European Commission, Swiss State Secretariat for Education, Swiss National Science Foundation, the Medical Research Council, NordForsk, Portuguese Foundation for Science and Technology.

Dietary Patterns of European Children and Their Parents in Association with Family Food Environment: Results from the I.Family Study.

The aim of this study was to determine whether an association exists between children's  and  parental  dietary  patterns  (DP),  and  whether  the  number  of  shared  meals  or  soft  drink  availability  during  meals  strengthens  this  association.  In  2013/2014  the  I.Family  study  cross-sectionally assessed the dietary intakes of families from eight European countries using 24-h  dietary recalls. Usual energy and food intakes from six- to 16-year-old children and their parents  were estimated based on the NCI Method. A total of 1662 child-mother and 789 child-father dyads  were included; DP were derived using cluster analysis. We investigated the association between  children's and parental DP and whether the number of shared meals or soft drink availability  moderated this association using mixed effects logistic regression models. Three DP comparable in  children and parents were obtained: Sweet & Fat, Refined Cereals, and Animal Products. Children  were more likely to be allocated to the Sweet & Fat DP when their fathers were allocated to the  Sweet & Fat DP and when they shared at least one meal per day (OR 3.18; 95% CI 1.84; 5.47). Being  allocated to the Sweet & Fat DP increased when the mother or the father was allocated to the Sweet  & Fat DP and when soft drinks were available (OR 2.78; 95% CI 1.80; 4.28 or OR 4.26; 95% CI 2.16;  8.41, respectively). Availability of soft drinks and negative parental role modeling are important  predictors of children's dietary patterns.

Biological marks of early-life socioeconomic experience is detected in the adult inflammatory transcriptome.

Consistent evidence is accumulating to link lower socioeconomic position (SEP) and poorer health, and the inflammatory system stands out as a potential pathway through which socioeconomic environment is biologically embedded. Using bloodderived genome-wide transcriptional profiles from 268 Italian participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we evaluated the association between early life, young and later adulthood SEP and the expression of 845 genes involved in human inflammatory responses. These were examined individually and jointly using several inflammatory scores. Our results consistently show that participants whose father had a manual (as compared to nonmanual) occupation exhibit, later in life, a higher inflammatory score, hence indicating an overall increased level of expression for the selected inflammatory-related genes. Adopting a life course approach, these associations remained statistically significant upon adjustment for later-in-life socioeconomic experiences. Sensitivity analyses indicated that our findings were not affected by the way the inflammatory score was calculated, and were replicated in an independent study. Our study provides additional evidence that childhood SEP is associated with a sustainable upregulation of the inflammatory transcriptome, independently of subsequent socioeconomic experiences. Our results support the hypothesis that early social inequalities impacts adult physiology.

Prospective associations between socio-economic status and dietary patterns in European children: the Identification and Prevention of Dietary- and Lifestyle-induced Health Effects in Children and Infants (IDEFICS) Study.

Exploring changes in children's diet over time and the relationship between these changes and socio-economic status (SES) may help to understand the impact of social inequalities on dietary patterns. The aim of the present study was to describe dietary patterns by applying a cluster analysis to 9301 children participating in the baseline (2-9 years old) and follow-up (4-11 years old) surveys of the Identification and Prevention of Dietary- and Lifestyle-induced Health Effects in Children and Infants Study, and to describe the cluster memberships of these children over time and their association with SES. We applied the K-means clustering algorithm based on the similarities between the relative frequencies of consumption of forty-two food items. The following three consistent clusters were obtained at baseline and follow-up: processed (higher frequency of consumption of snacks and fast food); sweet (higher frequency of consumption of sweet foods and sweetened drinks); healthy (higher frequency of consumption of fruits, vegetables and wholemeal products). Children with higher-educated mothers and fathers and the highest household income were more likely to be allocated to the healthy cluster at baseline and follow-up and less likely to be allocated to the sweet cluster. Migrants were more likely to be allocated to the processed cluster at baseline and follow-up. Applying the cluster analysis to derive dietary patterns at the two time points allowed us to identify groups of children from a lower socio-economic background presenting persistently unhealthier dietary profiles. This finding reflects the need for healthy eating interventions specifically targeting children from lower socio-economic backgrounds.

Educational level and risk of colorectal cancer in EPIC with specific reference to tumor location.

Existing evidence is inconclusive on whether socioeconomic status (SES) and educational inequalities influence colorectal cancer (CRC) risk, and whether low or high SES/educational level is associated with developing CRC. The aim of our study was to investigate the relationship between educational level and CRC. We studied data from 400,510 participants in the EPIC (European Prospective Investigation into Cancer and Nutrition) study, of whom 2,447 developed CRC (colon: 1,551, rectum: 896, mean follow-up 8.3 years). Cox proportional hazard regression analysis stratified by age, gender and center, and adjusted for potential confounders were used to estimate hazard ratios (HR) and 95% confidence intervals (95%CI). Relative indices of inequality (RII) for education were estimated using Cox regression models. We conducted separate analyses for tumor location, gender and geographical region. Compared with participants with college/university education, participants with vocational secondary education or less had a nonsignificantly lower risk of developing CRC. When further stratified for tumor location, adjusted risk estimates for the proximal colon were statistically significant for primary education or less (HR 0.73, 95%CI 0.57-0.94) and for vocational secondary education (HR 0.76, 95%CI 0.58-0.98). The inverse association between low education and CRC risk was particularly found in women and Southern Europe. These associations were statistically significant for CRC, for colon cancer and for proximal colon cancer. In conclusion, CRC risk, especially in the proximal colon, is lower in subjects with a lower educational level compared to those with a higher educational level. This association is most pronounced in women and Southern Europe.

Occupational exposures contribute to educational inequalities in lung cancer incidence among men: Evidence from the EPIC prospective cohort study.

The aim of this study is to investigate to what extent occupational exposures may explain socioeconomic inequalities in lung cancer incidence after adjusting for smoking and dietary factors. Analyses were based on a subsample of the European Prospective Investigation into Cancer and Nutrition (EPIC study), a prospective cohort. The analyses included 703 incident lung cancer cases among men in Denmark, the United Kingdom, Germany, Italy, Spain and Greece. The socioeconomic position was measured using the highest level of education. The estimates of relative indices of inequality (RII) were computed with Cox regression models. We first adjusted for smoking (with detailed information on duration and quantity) and dietary factors (fruits and vegetables consumption) and then for occupational exposures. The exposure to three carcinogens [asbestos, heavy metals and polycyclic aromatic hydrocarbons (PAH)] was analyzed. The occupational exposures explained 14% of the socioeconomic inequalities remaining after adjustment for smoking and fruits and vegetables consumption. The inequalities remained nevertheless statistically significant. The RII decreased from 1.87 (95% CI: 1.36-2.56) to 1.75 (1.27-2.41). The decrease was more pronounced when adjusting for asbestos than for heavy metals or PAH. Analyses by birth cohort suggested an effect of occupational exposures among older men, while due to small number of endpoints, no conclusion could be drawn about the role of occupational exposures in educational inequalities among younger men. Our study revealed that the impact of occupational exposures on socioeconomic inequalities in cancer incidence, rarely studied until now, exists while of modest magnitude.

The role of smoking and diet in explaining educational inequalities in lung cancer incidence.

BACKGROUND: Studies in many countries have reported higher lung cancer incidence and mortality in individuals with lower socioeconomic status. METHODS: To investigate the role of smoking in these inequalities, we used data from 391,251 participants in the European Prospective Investigation into Cancer and Nutrition study, a cohort of individuals in 10 European countries. We collected information on smoking (history and quantity), fruit and vegetable consumption, and education through questionnaires at study entry and gathered data on lung cancer incidence for a mean of 8.4 years. Socioeconomic status was defined as the highest attained level of education, and participants were grouped by sex and region of residence (Northern Europe, Germany, or Southern Europe). Relative indices of inequality (RIIs) of lung cancer risk unadjusted and adjusted for smoking were estimated using Cox regression models. Additional analyses were performed by histological type. RESULTS: During the study period, 939 men and 692 women developed lung cancer. Inequalities in lung cancer risk (RII(men) = 3.62, 95% confidence interval [CI] = 2.77 to 4.73, 117 vs 52 per 100,000 person-years for lowest vs highest education level; RII(women) = 2.39, 95% CI = 1.77 to 3.21, 46 vs 25 per 100,000 person-years) decreased after adjustment for smoking but remained statistically significant (RII(men) = 2.29, 95% CI = 1.75 to 3.01; RII(women) = 1.59, 95% CI = 1.18 to 2.13). Large RIIs were observed among men and women in Northern European countries and among men in Germany, but inequalities in lung cancer risk were reverse (RIIs < 1) among women in Southern European countries. Inequalities differed by histological type. Adjustment for smoking reduced inequalities similarly for all histological types and among men and women in all regions. In all analysis, further adjustment for fruit and vegetable consumption did not change the estimates. CONCLUSION: Self-reported smoking consistently explains approximately 50% of the inequalities in lung cancer risk due to differences in education.

Lung cancers attributable to environmental tobacco smoke and air pollution in non-smokers in different European countries: a prospective study.

BACKGROUND: Several countries are discussing new legislation on the ban of smoking in public places, and on the acceptable levels of traffic-related air pollutants. It is therefore useful to estimate the burden of disease associated with indoor and outdoor air pollution. METHODS: We have estimated exposure to Environmental Tobacco Smoke (ETS) and to air pollution in never smokers and ex-smokers in a large prospective study in 10 European countries (European Prospective Investigation into Cancer and Nutrition)(N = 520,000). We report estimates of the proportion of lung cancers attributable to ETS and air pollution in this population. RESULTS: The proportion of lung cancers in never- and ex-smokers attributable to ETS was estimated as between 16 and 24%, mainly due to the contribution of work-related exposure. We have also estimated that 5-7% of lung cancers in European never smokers and ex-smokers are attributable to high levels of air pollution, as expressed by NO2 or proximity to heavy traffic roads. NO2 is the expression of a mixture of combustion (traffic-related) particles and gases, and is also related to power plants and waste incinerator emissions. DISCUSSION: We have estimated risks of lung cancer attributable to ETS and traffic-related air pollution in a large prospective study in Europe. Information bias can be ruled out due to the prospective design, and we have thoroughly controlled for potential confounders, including restriction to never smokers and long-term ex-smokers. Concerning traffic-related air pollution, the thresholds for indicators of exposure we have used are rather strict, i.e. they correspond to the high levels of exposure that characterize mainly Southern European countries (levels of NO2 in Denmark and Sweden are closer to 10-20 ug/m3, whereas levels in Italy are around 30 or 40, or higher).Therefore, further reduction in exposure levels below 30 ug/m3 would correspond to additional lung cancer cases prevented, and our estimate of 5-7% is likely to be an underestimate. Overall, our prospective study draws attention to the need for strict legislation concerning the quality of air in Europe.

Development and validation of a food frequency questionnaire for the assessment of dietary total antioxidant capacity.

The total antioxidant capacity (TAC) of the diet may be an important tool to monitor the protective effect of plant foods in epidemiological studies. We developed a semi-quantitative FFQ for the assessment of dietary TAC by 3 different assays, i.e., Trolox equivalent antioxidant capacity (TEAC), total radical-trapping antioxidant parameter (TRAP) and ferric reducing-antioxidant power (FRAP). The FFQ consists of 53 questions about the major sources of dietary TAC in Northern Italy and was validated against a 3-d weighed food record (3D-WR) in 285 individuals (159 males and 126 females) aged 35-88 y and living in the province of Parma (Italy). Plasma TAC was also evaluated in a subgroup of subjects using the TEAC and FRAP assays. The FFQ was associated with 3D-WR (quadratic-weighted kappa = 0.49 for TEAC, 0.53 for TRAP, and 0.49 for FRAP; P < 0.0001) and proved reasonably accurate to classify individuals into quartiles of TAC intake. The FFQ had a good repeatability when readministered after 1 y in 55 subjects (quadratic-weighted kappa for intertertile agreement = 0.66 for TEAC, 0.70 for TRAP and 0.68 for FRAP; P < 0.0001). With both dietary instruments, the main contributors to TAC intake were coffee and tea in women and alcoholic beverages in men, followed by fruits and vegetables in both sexes. Plasma TAC and dietary TAC were not associated. In conclusion, our FFQ has the potential for being used to rank subjects on the basis of their antioxidant intake as determined by dietary TAC in large epidemiological studies. The FFQ should be validated in external populations before being used for research purposes.

EPIC-Italy cohorts and multipurpose national surveys. A comparison of some socio-demographic and life-style characteristics.

BACKGROUND: EPIC-Italy cohort study recruited subjects who voluntarily accepted to participate in the project. From the self-selected bases of the population sample, some bias could derive in the data interpretation when risk estimation for cancer disease related to life-style factors is the principal concern. Knowledge of the bias related to self-selected sampling is important for better directing the interpretation of the EPIC-Italy study results. METHODS: We investigated the characteristics of volunteer subjects recruited in the EPIC-Italy cohorts and compared them with those of the randomly selected subjects recruited in the Multipurpose ISTAT Surveys realized in the same period (1993-1998) in which the EPIC-cohorts were recruited. RESULTS: We found some differences, and in particular a different attitude towards cigarettes smoking and wine consumption, between the EPIC cohort and the Multipurpose ISTAT Surveys, as well as among geographical areas within the EPIC cohort. CONCLUSIONS: The uneven distribution of some characteristics suggests that the self-selected subjects were characterized by an overall lower consumption of wine and cigarette smoking even when the educational level was considered. This could suggest a generally more healthy life-style among subjects recruited on a volountary bases.