Lung cancer and socioeconomic status in a pooled analysis of case-control studies.

BACKGROUND: An association between low socioeconomic status (SES) and lung cancer has been observed in several studies, but often without adequate control for smoking behavior. We studied the association between lung cancer and occupationally derived SES, using data from the international pooled SYNERGY study. METHODS: Twelve case-control studies from Europe and Canada were included in the analysis. Based on occupational histories of study participants we measured SES using the International Socio-Economic Index of Occupational Status (ISEI) and the European Socio-economic Classification (ESeC). We divided the ISEI range into categories, using various criteria. Stratifying by gender, we calculated odds ratios (OR) and 95% confidence intervals (CI) by unconditional logistic regression, adjusting for age, study, and smoking behavior. We conducted analyses by histological subtypes of lung cancer and subgroup analyses by study region, birth cohort, education and occupational exposure to known lung carcinogens. RESULTS: The analysis dataset included 17,021 cases and 20,885 controls. There was a strong elevated OR between lung cancer and low SES, which was attenuated substantially after adjustment for smoking, however a social gradient persisted. SES differences in lung cancer risk were higher among men (lowest vs. highest SES category: ISEI OR 1.84 (95% CI 1.61-2.09); ESeC OR 1.53 (95% CI 1.44-1.63)), than among women (lowest vs. highest SES category: ISEI OR 1.54 (95% CI 1.20-1.98); ESeC OR 1.34 (95% CI 1.19-1.52)). CONCLUSION: SES remained a risk factor for lung cancer after adjustment for smoking behavior.

Novel genetic variants in the P38MAPK pathway gene ZAK and susceptibility to lung cancer.

The P38MAPK pathway participates in regulating cell cycle, inflammation, development, cell death, cell differentiation, and tumorigenesis. Genetic variants of some genes in the P38MAPK pathway are reportedly associated with lung cancer risk. To substantiate this finding, we used six genome-wide association studies (GWASs) to comprehensively investigate the associations of 14 904 single nucleotide polymorphisms (SNPs) in 108 genes of this pathway with lung cancer risk. We identified six significant lung cancer risk-associated SNPs in two genes (CSNK2B and ZAK) after correction for multiple comparisons by a false discovery rate (FDR) <0.20. After removal of three CSNK2B SNPs that are located in the same locus previously reported by GWAS, we performed the LD analysis and found that rs3769201 and rs7604288 were in high LD. We then chose two independent representative SNPs of rs3769201 and rs722864 in ZAK for further analysis. We also expanded the analysis by including these two SNPs from additional GWAS datasets of Harvard University (984 cases and 970 controls) and deCODE (1319 cases and 26 380 controls). The overall effects of these two SNPs were assessed using all eight GWAS datasets (OR = 0.92, 95%CI = 0.89-0.95, and P = 1.03 × 10-5 for rs3769201; OR = 0.91, 95%CI = 0.88-0.95, and P = 2.03 × 10-6 for rs722864). Finally, we performed an expression quantitative trait loci (eQTL) analysis and found that these two SNPs were significantly associated with ZAK mRNA expression levels in lymphoblastoid cell lines. In conclusion, the ZAK rs3769201 and rs722864 may be functional susceptibility loci for lung cancer risk.

Prices of over-the-counter drugs used by 15-year-old adolescents in Germany and their association with socioeconomic background.

BACKGROUND: In Germany, over-the-counter (OTC) drugs are normally reimbursed up to the age of 12 years only. The aim of this study was to analyse prices of over-the-counter drugs used by adolescents in Germany and their association with socioeconomic factors. METHODS: Based on the German GINIplus and LISAplus birth cohorts, data on drug utilization among 15-year-old adolescents (n = 4677) were collected using a self-administered questionnaire. The reported drugs were subdivided into prescription drugs and OTC drugs. The drugs' prices were tracked by the pharmaceutical identification numbers. RESULTS: Overall, 1499 OTC drugs with clearly identifiable prices were eligible for analysis. Their mean price was €9.75 (95% confidence interval: €9.27-10.22). About 75% of the OTC drugs cost less than €10. Higher mean prices were associated with residing in Munich (€10.74; 95% confidence interval: €9.97-11.52) and with higher paternal education (e.g. highest education level: €10.17; 95% confidence interval: €9.47-10.86). Adolescents residing in Munich (in comparison with the less wealthy region of Wesel) and adolescents with higher educated fathers were also significantly more likely to use OTC drugs costing ≥ €10 or ≥ €25, respectively. CONCLUSIONS: The price of €10 for non-reimbursable OTC drugs may represent a (psychological) threshold. Higher prices could discourage especially adolescents from a lower socioeconomic background from taking medically advisable but non-reimbursable OTC drugs.

Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study.

BACKGROUND: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. METHODS AND FINDINGS: We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79-1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. CONCLUSIONS: Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

Functional variants in DCAF4 associated with lung cancer risk in European populations.

Cullin-RING ubiquitin ligases (CRLs) responsible for substrate specificity of ubiquitination play a key role in cell-cycle control and DNA damage response. In this study, we assessed associations between 16 599 SNPs in 115 CRL genes and lung cancer risk by using summary data of six published genome-wide association studies (GWASs) of 12 160 cases and 16 838 cases of European ancestry. As a result, we identified three independent SNPs in DCAF4 (rs117781739, rs12587742 and rs2240980) associated with lung cancer risk (odds ratio = 0.91, 1.09 and 1.09, respectively; 95% confidence interval = 0.88-0.95, 1.05-1.14 and 1.05-1.13, respectively; and P = 3.99 × 10-6, 4.97 × 10-5 and 1.44 × 10-5, respectively) after multiple comparison correction by a false discovery rate <0.05. Since SNP rs12587742 is located within the promoter region and one CpG island of DCAF4, we further performed in silico functional analyses and found that the rs12587742 variant A allele was associated with an increased mRNA expression (P = 2.20 × 10-16, 1.79 × 10-13 and 0.001 in blood cells, normal lung tissues and tumor tissues of lung squamous carcinoma, respectively) and a decreased methylation status (P = 2.48 × 10-9 and 0.032 in adipose and lung tumor tissues, respectively). Moreover, evidence from differential expression analyses further supported an oncogenic effect of DCAF4 on lung cancer, with higher mRNA levels in both lung squamous carcinoma and adenocarcinoma (P = 4.48 × 10-11 and 1.22 × 10-9, respectively) than in adjacent normal tissues. Taken together, our results suggest that rs12587742 is associated with an increased lung cancer risk, possibly by up-regulating mRNA expression and decreasing methylation status of DCAF4.

Gene-set meta-analysis of lung cancer identifies pathway related to systemic lupus erythematosus.

INTRODUCTION: Gene-set analysis (GSA) is an approach using the results of single-marker genome-wide association studies when investigating pathways as a whole with respect to the genetic basis of a disease. METHODS: We performed a meta-analysis of seven GSAs for lung cancer, applying the method META-GSA. Overall, the information taken from 11,365 cases and 22,505 controls from within the TRICL/ILCCO consortia was used to investigate a total of 234 pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: META-GSA reveals the systemic lupus erythematosus KEGG pathway hsa05322, driven by the gene region 6p21-22, as also implicated in lung cancer (p = 0.0306). This gene region is known to be associated with squamous cell lung carcinoma. The most important genes driving the significance of this pathway belong to the genomic areas HIST1-H4L, -1BN, -2BN, -H2AK, -H4K and C2/C4A/C4B. Within these areas, the markers most significantly associated with LC are rs13194781 (located within HIST12BN) and rs1270942 (located between C2 and C4A). CONCLUSIONS: We have discovered a pathway currently marked as specific to systemic lupus erythematosus as being significantly implicated in lung cancer. The gene region 6p21-22 in this pathway appears to be more extensively associated with lung cancer than previously assumed. Given wide-stretched linkage disequilibrium to the area APOM/BAG6/MSH5, there is currently simply not enough information or evidence to conclude whether the potential pleiotropy of lung cancer and systemic lupus erythematosus is spurious, biological, or mediated. Further research into this pathway and gene region will be necessary.

Exposure-Response Analyses of Asbestos and Lung Cancer Subtypes in a Pooled Analysis of Case-Control Studies.

BACKGROUND: Evidence is limited regarding risk and the shape of the exposure-response curve at low asbestos exposure levels. We estimated the exposure-response for occupational asbestos exposure and assessed the joint effect of asbestos exposure and smoking by sex and lung cancer subtype in general population studies. METHODS: We pooled 14 case-control studies conducted in 1985-2010 in Europe and Canada, including 17,705 lung cancer cases and 21,813 controls with detailed information on tobacco habits and lifetime occupations. We developed a quantitative job-exposure-matrix to estimate job-, time period-, and region-specific exposure levels. Fiber-years (ff/ml-years) were calculated for each subject by linking the matrix with individual occupational histories. We fit unconditional logistic regression models to estimate odds ratios (ORs), 95% confidence intervals (CIs), and trends. RESULTS: The fully adjusted OR for ever-exposure to asbestos was 1.24 (95% CI, 1.18, 1.31) in men and 1.12 (95% CI, 0.95, 1.31) in women. In men, increasing lung cancer risk was observed with increasing exposure in all smoking categories and for all three major lung cancer subtypes. In women, lung cancer risk for all subtypes was increased in current smokers (ORs ~two-fold). The joint effect of asbestos exposure and smoking did not deviate from multiplicativity among men, and was more than additive among women. CONCLUSIONS: Our results in men showed an excess risk of lung cancer and its subtypes at low cumulative exposure levels, with a steeper exposure-response slope in this exposure range than at higher, previously studied levels. (See video abstract at, http://links.lww.com/EDE/B161.).

Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk-A re-analysis of eight GWASs.

PURPOSE: mRNA degradation is an important regulatory step for controlling gene expression and cell functions. Genetic abnormalities involved in mRNA degradation genes were found to be associated with cancer risks. Therefore, we systematically investigated the roles of genetic variants in the general mRNA degradation pathway in lung cancer risk. EXPERIMENTAL DESIGN: Meta-analyses were conducted using summary data from six lung cancer genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung and additional two GWASs from Harvard University and deCODE in the International Lung Cancer Consortium. Expression quantitative trait loci analysis (eQTL) was used for in silico functional validation of the identified significant susceptibility loci. RESULTS: This pathway-based analysis included 6816 single nucleotide polymorphisms (SNP) in 68 genes in 14 463 lung cancer cases and 44 188 controls. In the single-locus analysis, we found that 20 SNPs were associated with lung cancer risk with a false discovery rate threshold of <0.05. Among the 11 newly identified SNPs in CNOT6, which were in high linkage disequilibrium, the rs2453176 with a RegulomDB score "1f" was chosen as the tagSNP for further analysis. We found that the rs2453176 T allele was significantly associated with lung cancer risk (odds ratio = 1.11, 95% confidence interval = 1.04-1.18) in the eight GWASs. In the eQTL analysis, we found that levels of CNOT6 mRNA expression were significantly correlated with the rs2453176 T allele, which provided additional biological basis for the observed positive association. CONCLUSION: The CNOT6 rs2453176 SNP may be a new functional susceptible locus for lung cancer risk. © 2016 Wiley Periodicals, Inc.

Lung Cancer Among Firefighters: Smoking-Adjusted Risk Estimates in a Pooled Analysis of Case-Control Studies.

OBJECTIVES: The aim of this study was to explore lung cancer risk among firefighters, with adjustment for smoking. METHODS: We used pooled information from the SYNERGY project including 14 case-control studies conducted in Europe, Canada, New Zealand, and China, with lifetime work histories and smoking habits for 14,748 cases of lung cancer and 17,543 controls. We estimated odds ratios by unconditional logistic regression with adjustment for smoking and having ever been employed in a job known to present an excess risk of lung cancer. RESULTS: There was no increased lung cancer risk overall or by specific cell type among firefighters (n = 190), neither before nor after smoking adjustment. We observed no significant exposure-response relationship in terms of work duration. CONCLUSIONS: We found no evidence of an excess lung cancer risk related to occupational exposure as a firefighter.

Complementary and Alternative Medicine Use Among Chronically Ill Adolescents from 2 German Birth Cohorts.

BACKGROUND: Pediatric use of complementary and alternative medicine (CAM) is popular in Europe, and utilization may be even more prevalent in chronically ill children/adolescents. This study's aim is to assess CAM use among adolescents with chronic conditions. METHODS: Data on drug utilization (past 4 weeks) and consultation with CAM providers (past year) were collected using a self-administered questionnaire from 4,677 adolescents from the German GINIplus/LISAplus birth cohorts. All reported drugs were classified into therapeutic categories (conventional drugs, homeopathy, herbal drugs, etc.). Additionally, participants were asked to list any chronic diseases (that were parent-reported, physician-verified diagnoses such as allergies, atopic dermatitis, asthma, or other chronic diseases) that they had had over the previous 5 years. RESULTS: Compared with the total sample, drug utilization in general (60.1% vs. 41.1%), homeopathy use (11.1% vs. 8.1%), and consultation with CAM providers (16.9% vs. 10.9%) was significantly more prevalent among chronically ill adolescents. However, chronically ill adolescents used relatively (proportion of the defined therapeutic category among all drugs used) more conventional drugs than healthy adolescents. CONCLUSION: Compared with healthy adolescents, CAM use is more prevalent among adolescents with chronic conditions. Nevertheless, CAM may predominantly be used as a complementary treatment option rather than substituting conventional drugs.

What is the impact of different spirometric criteria on the prevalence of spirometrically defined COPD and its comorbidities? Results from the population-based KORA study.

BACKGROUND: There is an ongoing debate about the appropriate spirometric criterion for airway obstruction to detect COPD. Furthermore, the association of different criteria with comorbidity prevalence and inflammatory biomarkers in advanced age is unclear. MATERIALS AND METHODS: Spirometry was performed in a population-based study (n=2,256) covering an age range of 41-90 years. COPD was spirometrically determined either by a fixed ratio (FR) of <0.7 for forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) or by FEV1/FVC below the lower limit of normal (LLN). Comorbidity prevalences and circulating biomarker levels (C-reactive protein [CRP], interleukin [IL]-6) were compared between subjects with or without COPD by the two criteria using logistic and multiple regression models, adjusting for sex and age. RESULTS: The prevalence of spirometrically defined COPD by FR increased with age from 10% in subjects aged <65 years to 26% in subjects aged ≥75 years. For LLN-defined COPD, it remained below 10% for all age groups. Overall, COPD diagnosis was not associated with specific comorbidities, except for a lower prevalence of obesity in both FR- and LLN-defined cases. Both CRP and IL-6 tended to be higher in cases by both criteria. CONCLUSION: In a population-based cohort of adults up to the age of 90 years, the prevalence of spirometrically defined COPD was higher for the FR criterion than for the LLN criterion. This difference increased with age. Neither prevalences of common comorbidities nor levels of the biomarkers, CRP or IL-6, were conclusively associated with the selection of the COPD criterion. Results have to be considered in light of the predominantly mild cases of airway obstruction in the examined study population.

Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk.

Metabolism of nicotine by cytochrome P450 2A6 (CYP2A6) is a suspected determinant of smoking dose and, consequently, lung cancer risk. We conducted a genome-wide association study (GWAS) of CYP2A6 activity, as measured by the urinary ratio of trans-3'-hydroxycotinine and its glucuronide conjugate over cotinine (total 3HCOT/COT), among 2,239 smokers in the Multiethnic Cohort (MEC) study. We identified 248 CYP2A6 variants associated with CYP2A6 activity (P < 5 × 10-8). CYP2A6 activity was correlated (r = 0.32; P < 0.0001) with total nicotine equivalents (a measure of nicotine uptake). When we examined the effect of these variants on lung cancer risk in the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium GWAS dataset (13,479 cases and 43,218 controls), we found that the vast majority of these individual effects were directionally consistent and associated with an increased lung cancer risk. Two hundred and twenty-six of the 248 variants associated with CYP2A6 activity in the MEC were available in TRICL. Of them, 81% had directionally consistent risk estimates, and six were globally significantly associated with lung cancer. When conditioning on nine known functional variants and two deletions, the top two SNPs (rs56113850 in MEC and rs35755165 in TRICL) remained significantly associated with CYP2A6 activity in MEC and lung cancer in TRICL. The present data support the hypothesis that a greater CYP2A6 activity causes smokers to smoke more extensively and be exposed to higher levels of carcinogens, resulting in an increased risk for lung cancer. Although the variants identified in these studies may be used as risk prediction markers, the exact causal variants remain to be identified. Cancer Res; 76(19); 5768-76. ©2016 AACR.

Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes - A Meta-Analysis.

BACKGROUND: Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. METHODS: Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N=12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium. RESULTS: Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR=0.48, 95%CI=0.30-0.75, p=0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR=0.68, 95%CI=0.61-0.77, p=4.9∗10-10). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype. CONCLUSION: We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke.

Occupational prestige, social mobility and the association with lung cancer in men.

BACKGROUND: The nature of the association between occupational social prestige, social mobility, and risk of lung cancer remains uncertain. Using data from the international pooled SYNERGY case-control study, we studied the association between lung cancer and the level of time-weighted average occupational social prestige as well as its lifetime trajectory. METHODS: We included 11,433 male cases and 14,147 male control subjects. Each job was translated into an occupational social prestige score by applying Treiman's Standard International Occupational Prestige Scale (SIOPS). SIOPS scores were categorized as low, medium, and high prestige (reference). We calculated odds ratios (OR) with 95 % confidence intervals (CI), adjusting for study center, age, smoking, ever employment in a job with known lung carcinogen exposure, and education. Trajectories in SIOPS categories from first to last and first to longest job were defined as consistent, downward, or upward. We conducted several subgroup and sensitivity analyses to assess the robustness of our results. RESULTS: We observed increased lung cancer risk estimates for men with medium (OR = 1.23; 95 % CI 1.13-1.33) and low occupational prestige (OR = 1.44; 95 % CI 1.32-1.57). Although adjustment for smoking and education reduced the associations between occupational prestige and lung cancer, they did not explain the association entirely. Traditional occupational exposures reduced the associations only slightly. We observed small associations with downward prestige trajectories, with ORs of 1.13, 95 % CI 0.88-1.46 for high to low, and 1.24; 95 % CI 1.08-1.41 for medium to low trajectories. CONCLUSIONS: Our results indicate that occupational prestige is independently associated with lung cancer among men.

Modeling Lung Carcinogenesis in Radon-Exposed Miner Cohorts: Accounting for Missing Information on Smoking.

Epidemiological miner cohort data used to estimate lung cancer risks related to occupational radon exposure often lack cohort-wide information on exposure to tobacco smoke, a potential confounder and important effect modifier. We have developed a method to project data on smoking habits from a case-control study onto an entire cohort by means of a Monte Carlo resampling technique. As a proof of principle, this method is tested on a subcohort of 35,084 former uranium miners employed at the WISMUT company (Germany), with 461 lung cancer deaths in the follow-up period 1955-1998. After applying the proposed imputation technique, a biologically-based carcinogenesis model is employed to analyze the cohort's lung cancer mortality data. A sensitivity analysis based on a set of 200 independent projections with subsequent model analyses yields narrow distributions of the free model parameters, indicating that parameter values are relatively stable and independent of individual projections. This technique thus offers a possibility to account for unknown smoking habits, enabling us to unravel risks related to radon, to smoking, and to the combination of both.

Associations of Residential Long-Term Air Pollution Exposures and Satellite-Derived Greenness with Insulin Resistance in German Adolescents.

BACKGROUND: Epidemiological studies have identified associations between air pollution and green space access with type 2 diabetes in adults. However, it remains unclear to what extent associations with greenness are attributable to air pollution exposure. OBJECTIVES: We aimed to investigate associations between long-term exposure to air pollution and satellite-derived greenness with insulin resistance in adolescents. METHODS: A total of 837 participants of two German birth cohorts (LISAplus and GINIplus) were included in the analysis. Generalized additive models were used to determine the association of individual satellite-derived greenness defined by the Normalized Difference Vegetation Index (NDVI), long-term air pollution exposure estimated by land-use regression (LUR) models with insulin resistance (HOMA-IR) in 15-year-old adolescents. Models were adjusted for study area, cohort, socioeconomic, and individual characteristics such as body mass index, physical activity, and smoking. RESULTS: Increases of 2 SDs in nitrogen dioxide (NO2; 8.9 µg/m3) and particulate matter ≤ 10 µm in diameter (PM10; 6.7 µg/m3) were significantly associated with 11.4% (95% CI: 4.4, 18.9) and 11.4% (95% CI: 0.4, 23.7) higher HOMA-IR. A 2-SD increase in NDVI in a 1,000-m buffer (0.2 units) was significantly associated with a lower HOMA-IR (-7.4%; 95% CI: -13.3, -1.1). Associations tended to be stronger in adolescents who spent more time outside and in those with lower socioeconomic status. In combined models including both air pollution and greenness, only NO2 remained significantly associated with HOMA-IR, whereas effect estimates for all other exposures attenuated after adjustment for NO2. CONCLUSIONS: NO2, often considered as a marker of traffic, was independently associated with insulin resistance. The observed association between higher greenness exposure and lower HOMA-IR in adolescents might thus be attributable mainly to the lower co-exposure to traffic-related air pollution. CITATION: Thiering E, Markevych I, Brüske I, Fuertes E, Kratzsch J, Sugiri D, Hoffmann B, von Berg A, Bauer CP, Koletzko S, Berdel D, Heinrich J. 2016. Associations of residential long-term air pollution exposures and satellite-derived greenness with insulin resistance in German adolescents. Environ Health Perspect 124:1291-1298; http://dx.doi.org/10.1289/ehp.1509967.

Neighbourhood and physical activity in German adolescents: GINIplus and LISAplus.

INTRODUCTION: Impact of neighbourhood on physical activity (PA) is under-investigated in European adolescents, and few studies have used objective data on both exposures and outcomes. Therefore we investigated the association between objectively measured neighbourhood characteristics and PA in 15-year-old German adolescents. METHODS: Study populations comprised of 688 adolescents residing in the urban Munich area and 504 from the rural Wesel area from the GINIplus and LISAplus birth cohorts. Neighbourhood was defined as a circular 500-m buffer around the residence. Greenness was calculated 1) as the mean Normalized Difference Vegetation Index (NDVI), and 2) as percent tree cover. Neighbourhood green spaces and sport and leisure facilities were defined as present or absent in a neighbourhood (data only available for Munich). Data on PA were collected from one-week triaxial accelerometry (hip-worn ActiGraph GT3X). Minutes of PA were classified into moderate-to-vigorous (MVPA), light and sedentary using Romanzini's et al. triaxial cutoffs, and averaged over the recording period. Activity diaries were used for differentiation between school and leisure (total minus school) PA. Area-specific associations were assessed by adjusted negative binomial regressions. RESULTS: In the Wesel area, residing in a neighbourhood with higher NDVI was associated with 9% more leisure MVPA among females and with 8% more leisure MVPA in rural dwellers. In the Munich area, residing in a neighbourhood with sport facilities was associated with 9% more leisure MVPA. The latter association was only significant in urban dwellers while neighbourhood leisure facilities increased MVPA in rural dwellers. Estimates were very similar when total MVPA was considered rather than solely leisure. CONCLUSION: There is indication that neighbourhood features could be associated with MVPA in German adolescents. However, different features seem to be important across sexes and in rural/urban settings, which need to be specifically addressed in future studies.

A longitudinal comparison of drug use among 10-year-old children and 15-year-old adolescents from the German GINIplus and LISAplus birth cohorts.

PURPOSE: The purpose of this study was to compare longitudinal data on drug utilization between 10-year-old children and 15-year-old adolescents and to analyse the association of drug use at the age of 15 years with drug use at the age of 10 years. METHODS: Based on the German GINIplus (German infant study on the Influence of Nutrition Intervention plus environmental and genetic influences on allergy development) and LISAplus (Influence of lifestyle factors on the immune system and allergies in East and West Germany plus the influence of traffic emissions and genetics) birth cohorts, data on drug utilization (past 4 weeks) were collected using a self-administered questionnaire for 3642 children (10-year follow-up) and 4677 adolescents (15-year follow-up). The drugs were classified by therapeutic categories (conventional drugs, homeopathic drugs, etc.) and by codes according to the anatomical therapeutic chemical (ATC) classification system. Associations of adolescents' drug use with gender, study area, maternal education, parental income, presence of chronic conditions, and prior drug use at the age of 10 years were analysed using a logistic regression model. RESULTS: The 4-week prevalence rates of overall drug use were similar for adolescents (41.1%) and children (42.3%). However, adolescents used noticeably more anti-inflammatory drugs, analgesics, and systemic antihistamines. Exactly 3194 children/adolescents participated in both follow-ups. Adolescents' use of anti-inflammatory drugs was predicted (OR = 3.37) by use of anti-inflammatory drugs as a child. In summary, the strongest predictor of adolescents' use of specific therapeutic categories or ATC groups was the previous use of the same therapeutic drug category or ATC group as a 10-year-old child. CONCLUSIONS: Despite similar prevalence rates of overall drug utilization among both age groups, there is a noticeable difference concerning the use of drugs from specific ATC groups. Drug use as a child may partly determine what they use as an adolescent.

Changes in dietary intake during puberty and their determinants: results from the GINIplus birth cohort study.

BACKGROUND: Understanding changes in dietary intake during puberty could aid the mapping of dietary interventions for primary prevention. The present study describes dietary changes from childhood to adolescence, and their associations with parental education, family income, child education, body mass index (BMI), pubertal onset and screen-time sedentary behaviour. METHODS: Dietary data (n = 1232) were obtained from food frequency questionnaires at the 10- and 15-year follow-ups of the GINIplus birth cohort study. Intakes of 17 food groups, macronutrients and antioxidant vitamins, were described by a) paired Wilcoxon rank sum tests, comparing average intakes at each time-point, and b) Cohen's kappa "tracking" coefficients, measuring stability of intakes (maintenance of relative tertile positions across time). Further, associations of changes (tertile position increase or decrease vs. tracking) with parental education, family income, child education, pubertal onset, BMI, and screen-time, were assessed by logistic regression and multinomial logistic regression models stratified by baseline intake tertile. RESULTS: Both sexes increased average intakes of water and decreased starchy vegetables, margarine and dairy. Females decreased meat and retinol intakes and increased vegetables, grains, oils and tea. Males decreased fruit and carbohydrates and increased average intakes of meat, caloric drinks, water, protein, fat, polyunsaturated fatty acids (PUFAs), vitamin C and alpha-tocopherol. Both sexes presented mainly "fair" tracking levels [κw = 0.21-0.40]. Females with high (vs. low) parental education were more likely to increase their nut intake [OR = 3.8; 95 % CI = (1.7;8.8)], and less likely to decrease vitamin C intakes [0.2 (0.1;0.5)], while males were less likely to increase egg consumption [0.2 (0.1;0.5)] and n3 PUFAs [0.2 (0.1;0.5)]. Females with a higher (vs. low) family income were more likely to maintain medium wholegrain intakes [0.2 (0.1;0.7) for decrease vs. tracking, and 0.1 (0.0;0.5) for increase vs. tracking], and were less likely to decrease vitamin C intakes [0.2 (0.1;0.6)]. Males with high education were less likely to increase sugar-sweetened foods [0.1 (0.1;0.4)]. Finally, BMI in females was negatively associated with decreasing protein intakes [0.7 (0.6;0.9)]. In males BMI was positively associated with increasing margarine [1.4 (1.1;1.6)] and vitamin C intakes [1.4 (1.1;1.6)], and negatively associated with increasing n3 PUFA. CONCLUSIONS: Average dietary intakes changed significantly, despite fair tracking levels, suggesting the presence of trends in dietary behaviour during puberty. Family income and parental education predominantly influenced intake changes. Our results support the rationale for dietary interventions targeting children, and suggest that sex-specific subpopulations, e.g. low socio-economic status, should be considered for added impact.

Lung cancer among coal miners, ore miners and quarrymen: smoking-adjusted risk estimates from the synergy pooled analysis of case-control studies.

OBJECTIVES: Working in mines and quarries has been associated with an elevated lung cancer risk but with inconsistent results for coal miners. This study aimed to estimate the smoking-adjusted lung cancer risk among coal miners and compare the risk pattern with lung cancer risks among ore miners and quarrymen. METHODS: We estimated lung cancer risks of coal and ore miners and quarrymen among 14 251 lung cancer cases and 17 267 controls from the SYNERGY pooled case-control study, controlling for smoking and employment in other at-risk occupations. RESULTS: Ever working as miner or quarryman (690 cases, 436 controls) was associated with an elevated odds ratio (OR) of 1.55 [95% confidence interval (95% CI) 1.34-1.79] for lung cancer. Ore miners (53 cases, 24 controls) had a higher OR (2.34, 95% CI 1.36-4.03) than quarrymen (67 cases, 39 controls; OR 1.92, 95% CI 1.21-3.05) and coal miners (442 cases, 297 controls; OR 1.40, 95% CI 1.18-1.67), but CI overlapped. We did not observe trends by duration of exposure or time since last exposure. CONCLUSIONS: This pooled analysis of population-based studies demonstrated an excess lung cancer risk among miners and quarrymen that remained increased after adjustment for detailed smoking history and working in other at-risk occupations. The increase in risk among coal miners were less pronounced than for ore miners or quarrymen.