Florence Guida

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

Summary 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.

Dynamics of Smoking-Induced Genome-Wide Methylation Changes with Time Since Smoking Cessation

Several studies have recently identified strong epigenetic signals related to tobacco smoking. However, an aspect that did not receive much attention is the evolution of epigenetic changes with time since smoking cessation. We conducted a series of epigenome-wide association studies to capture the dynamics of smoking-induced epigenetic changes after smoking cessation, using genome-wide methylation profiles obtained from blood samples in 745 women from 2 European populations. Two distinct classes of CpG sites were identified: sites whose methylation reverts to levels typical of never smokers within decades after smoking cessation, and sites remaining differentially methylated, even more than 35 years after smoking cessation. Our results suggest that the dynamics of methylation changes following smoking cessation are driven by a differential and site-specific magnitude of the smoking-induced alterations (with persistent sites being most affected) irrespective of the intensity and duration of smoking. Analyses of the link between methylation and expression levels revealed that methylation predominantly and remotely down-regulates gene expression. Among genes whose expression was associated with our candidate CpG sites, LRRN3 appeared to be particularly interesting as it was one of the few genes whose methylation and expression were directly associated, and the only gene in which both methylation and gene expression were found associated with smoking. Our study highlights persistent epigenetic markers of smoking, which can potentially be detected decades after cessation. Such historical signatures are promising biomarkers to refine individual risk profiling of smoking-induced chronic disease such as lung cancer.

Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts

DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk. In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case–control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in AHRR (OR for 1 s.d.=0.37, 95% CI: 0.31–0.54, P-value=3.3 × 10−11) and cg03636183 in F2RL3 (OR for 1 s.d.=0.40, 95% CI: 0.31–0.56, P-value=3.9 × 10−10), previously shown to be strongly hypomethylated in smokers. These associations remain significant after adjustment for smoking and are confirmed in additional 664 case–control pairs tightly matched for smoking from the MCCS, NSHDS and EPIC HD cohorts. The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk.

Tobacco smoking, alcohol drinking and risk of oral cavity cancer by subsite: results of a French population-based case-control study, the ICARE study.

The objective was to examine the role of tobacco smoking and alcohol drinking in the incidence of oral cavity cancer by subsite in France, a high-incidence area. We analysed detailed data on lifelong tobacco smoking and alcohol drinking from 772 oral cavity cancer cases and 3555 controls included in a population-based case–control study, the ICARE study. Tobacco smoking increased the risk of oral cavity cancer even for the smaller quantities and durations, whereas alcohol drinking increased this risk only in heavy drinkers who were also ever smokers. The combined effect of smoking and drinking was greater than multiplicative. The floor of the mouth was the subsite that was the most affected by the harmful effects of tobacco and alcohol, whereas the gums were less susceptible. The risk associated with tobacco and alcohol consumption did not differ between intraoral cavity and subsites usually included in the oropharynx (soft palate and base of the tongue). Population-attributable risks for oral cavity cancer were 78.6% for tobacco smoking, 7.3% for alcohol drinking and 80.7% for tobacco and/or alcohol consumption. These results indicate that regular oral check-ups should be targeted at smokers and heavy drinkers, and that prevention efforts should be focused on smoking cessation.

Risk of lung cancer and occupational history: results of a French population-based case-control study, the ICARE study.

Objectives: To assess the risk of lung cancer associated with occupations and industries. Methods: A French population-based case-control study included 2923 cases and 3555 controls. Lifelong occupational history was collected. Two lists of occupations known (A) or suspected (B) to be associated with lung cancer were used. Occupations and industries not included in these lists were also explored. Results: Among men, the smoking-adjusted odds ratio was 1.97 for list A (attributable fraction: 12.3%), 1.4 for list B (due especially to carpenters/joiners and transport workers). Among unlisted occupations, excess risks were found for welders, plumbers, and several construction crafts. Odds ratios among women were elevated for list A, list B (due especially to launderers/dry cleaners), cleaners and hairdressers. Conclusions: These results confirm the role of known occupations and give insight into new occupational risk factors among men and women.

Cigarette smoking and lung cancer in women: results of the French ICARE case-control study.

BACKGROUND The incidence of female lung cancer in developed countries has been increasing since 1950. In order to have recent and reliable data on the association between cigarette smoking and the risk of lung cancer in women, we analysed cases from a French population-based case-control study. METHODS The ICARE study is a multicenter case-control study on respiratory cancers (lung and UADT cancers), set up in 10 départements that include a general cancer registry. We included 648 women lung cancer cases up to 76 years of age, with a histologically confirmed primary lung cancer. The 775 controls were randomly selected from the general population and frequency-matched with cases by age and département. RESULTS Overall, smoking cigarettes at some time was associated with a 8-fold increase in lung cancer risk (OR=8.2, 95% CI 6.0-11.4). A dose-response relationship was observed as a function of duration, intensity and pack-years. Using restricted splines cubic models, we have shown that intensity dose-response departed significantly from linearity while the risk increased linearly with duration and decreased linearly with time since cessation. The following characteristics were associated with a higher relative risk: smoke inhalation, smoking non-filter cigarettes, smoking dark tobacco cigarettes and starting at a young age. In addition, duration, intensity and time since cessation was significantly related with histological type. This was not the case for characteristics such as the use of a filter or not, the inhalation pattern, or the type of tobacco smoked. The proportion of lung cancer cases attributable to cigarette smoking was 55% (95% CI: [47-63%]). CONCLUSIONS Our results confirm that cigarette smoking is by far the most important cause of the current epidemic of lung cancer among French women and that the most important smoking-related variables for varying the risk of lung cancer are the duration, the intensity and the time since cessation.

DNA methylation changes measured in pre-diagnostic peripheral blood samples are associated with smoking and lung cancer risk.

DNA methylation changes are associated with cigarette smoking. We used the Illumina Infinium HumanMethylation450 array to determine whether methylation in DNA from pre‐diagnostic, peripheral blood samples is associated with lung cancer risk. We used a case‐control study nested within the EPIC‐Italy cohort and a study within the MCCS cohort as discovery sets (a total of 552 case‐control pairs). We validated the top signals in 429 case‐control pairs from another 3 studies. We identified six CpGs for which hypomethylation was associated with lung cancer risk: cg05575921 in the AHRR gene (p‐valuepooled = 4 × 10−17), cg03636183 in the F2RL3 gene (p‐valuepooled = 2 × 10 − 13), cg21566642 and cg05951221 in 2q37.1 (p‐valuepooled = 7 × 10−16 and 1 × 10−11 respectively), cg06126421 in 6p21.33 (p‐valuepooled = 2 × 10−15) and cg23387569 in 12q14.1 (p‐valuepooled = 5 × 10−7). For cg05951221 and cg23387569 the strength of association was virtually identical in never and current smokers. For all these CpGs except for cg23387569, the methylation levels were different across smoking categories in controls (p‐valuesheterogeneity ≤ 1.8 x10 − 7), were lowest for current smokers and increased with time since quitting for former smokers. We observed a gain in discrimination between cases and controls measured by the area under the ROC curve of at least 8% (p‐values ≥ 0.003) in former smokers by adding methylation at the 6 CpGs into risk prediction models including smoking status and number of pack‐years. Our findings provide convincing evidence that smoking and possibly other factors lead to DNA methylation changes measurable in peripheral blood that may improve prediction of lung cancer risk.

Effect Modification of the Association of Cumulative Exposure and Cancer Risk by Intensity of Exposure and Time Since Exposure Cessation: A Flexible Method Applied to Cigarette Smoking and Lung Cancer in the SYNERGY Study

The indiscriminate use of the cumulative exposure metric (the product of intensity and duration of exposure) might bias reported associations between exposure to hazardous agents and cancer risk. To assess the independent effects of duration and intensity of exposure on cancer risk, we explored effect modification of the association of cumulative exposure and cancer risk by intensity of exposure. We applied a flexible excess odds ratio model that is linear in cumulative exposure but potentially nonlinear in intensity of exposure to 15 case-control studies of cigarette smoking and lung cancer (1985-2009). Our model accommodated modification of the excess odds ratio per pack-year of cigarette smoking by time since smoking cessation among former smokers. We observed negative effect modification of the association of pack-years of cigarette smoking and lung cancer by intensity of cigarette smoke for persons who smoked more than 20-30 cigarettes per day. Patterns of effect modification were similar across individual studies and across major lung cancer subtypes. We observed strong negative effect modification by time since smoking cessation. Application of our method in this example of cigarette smoking and lung cancer demonstrated that reducing a complex exposure history to a metric such as cumulative exposure is too restrictive.

Welding and lung cancer in a pooled analysis of case-control studies.

Several epidemiologic studies have indicated an increased risk of lung cancer among welders. We used the SYNERGY project database to assess welding as a risk factor for developing lung cancer. The database includes data on 15,483 male lung cancer cases and 18,388 male controls from 16 studies in Europe, Canada, China, and New Zealand conducted between 1985 and 2010. Odds ratios and 95% confidence intervals between regular or occasional welding and lung cancer were estimated, with adjustment for smoking, age, study center, and employment in other occupations associated with lung cancer risk. Overall, 568 cases and 427 controls had ever worked as welders and had an odds ratio of developing lung cancer of 1.44 (95% confidence interval: 1.25, 1.67) with the odds ratio increasing for longer duration of welding. In never and light smokers, the odds ratio was 1.96 (95% confidence interval: 1.37, 2.79). The odds ratios were somewhat higher for squamous and small cell lung cancers than for adenocarcinoma. Another 1,994 cases and 1,930 controls had ever worked in occupations with occasional welding. Work in any of these occupations was associated with some elevation of risk, though not as much as observed in regular welders. Our findings lend further support to the hypothesis that welding is associated with an increased risk of lung cancer.

Tea and coffee consumption and risk of oral cavity cancer: results of a large population-based case-control study, the ICARE study.

BACKGROUND Results on the relationship between coffee and tea drinking and the risk of oral cavity cancer are contrasted. The aim of this study was to evaluate the relation between coffee and tea drinking and the risk of oral cavity cancer in France, a high incidence area. MATERIAL AND METHODS We conducted a population based case-control study with face-to-face interviews and standardized questionnaires (the ICARE study, Investigation of occupational and environmental causes of respiratory cancers). We used data from 689 cases of oral cavity squamous cell carcinoma and 3481 controls. Odds-ratios (ORs) and 95% confidence intervals (95% CI) associated with tea and coffee consumption (quantity, duration, cumulative consumption) were estimated by unconditional logistic regression with adjustment for age, gender, area of residence, education, body mass index, tobacco smoking and alcohol drinking. RESULTS We observed inverse associations between oral cavity cancer and tea or coffee consumption (odds ratio, 0.39; 95% CI 0.21-0.70, for the highest quartile of tea consumption, and 0.60, 95% CI 0.34-1.05, for the highest quartile of coffee consumption). Exclusive tea or coffee consumption was associated with a reduced risk of oral cavity cancer and their joint effect was multiplicative. No differences in risk between men and women or between consumers of tobacco and alcohol and non-consumers were observed. The odds ratios related to the subsites usually included in the oropharynx (soft palate and base of the tongue) did not differ significantly from that observed for the other subsites of the oral cavity. CONCLUSIONS Tea and coffee drinking may decrease the risk of oral cavity cancer through antioxidant components which play a role in the repair of cellular damages. These findings need further investigation in prospective studies and the underlying mechanisms in humans remain to be clarified.