Wolfgang Ahrens

A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25.

Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 × 10-10). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 × 10-20 overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N′-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.

Occupational exposure to carcinogens in the European Union

OBJECTIVES To construct a computer assisted information system for the estimation of the numbers of workers exposed to established and suspected human carcinogens in the member states of the European Union (EU). METHODS A database called CAREX (carcinogen exposure) was designed to provide selected exposure data and documented estimates of the number of workers exposed to carcinogens by country, carcinogen, and industry. CAREX includes data on agents evaluated by the International Agency for Research on Cancer (IARC) (all agents in groups 1 and 2A as of February 1995, and selected agents in group 2B) and on ionising radiation, displayed across the 55 industrial classes. The 1990–3 occupational exposure was estimated in two phases. Firstly, estimates were generated by the CAREX system on the basis of national labour force data and exposure prevalence estimates from two reference countries (Finland and the United States) which had the most comprehensive data available on exposures to these agents. For selected countries, these estimates were then refined by national experts in view of the perceived exposure patterns in their own countries compared with those of the reference countries. RESULTS About 32 million workers (23% of those employed) in the EU were exposed to agents covered by CAREX. At least 22 million workers were exposed to IARC group 1 carcinogens. The exposed workers had altogether 42 million exposures (1.3 mean exposures for each exposed worker). The most common exposures were solar radiation (9.1 million workers exposed at least 75% of working time), environmental tobacco smoke (7.5 million workers exposed at least 75% of working time), crystalline silica (3.2 million exposed), diesel exhaust (3.0 million), radon (2.7 million), and wood dust (2.6 million). CONCLUSION These preliminary estimates indicate that in the early 1990s, a substantial proportion of workers in the EU were exposed to carcinogens.

The IDEFICS cohort: design, characteristics and participation in the baseline survey.

Background:The European IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) study was set up to determine the aetiology of overweight, obesity and related disorders in children, and to develop and evaluate a tailored primary prevention programme.Objective:This paper focuses on the aetiological element of the multicentre study, the measures and examinations, sociodemographic characteristics of the study sample and proportions of participation.Design:Prospective cohort study with an embedded intervention study that started with a baseline survey in eight countries in 2007–2008.Subjects and measurements:Baseline participants of the prospective cohort study were 16 224 children aged 2–9 years. Parents reported sociodemographic, behavioural, medical, nutritional and other lifestyle data for their children and families. Examinations of children included anthropometry, blood pressure, fitness, accelerometry, DNA from saliva and physiological markers in blood and urine. The built environment, sensory taste perception and other mechanisms of childrens food choices and consumer behaviour were studied in subgroups.Results:Between 1507 and 2567, children with a mean age of 6.0 years and an even sex distribution were recruited from each country. Of them, 82% lived in two-parent families. The distribution of standardised income levels differed by study sample, with low-income groups being strongly represented in Cyprus, Italy and Germany. At least one 24-h dietary recall was obtained for two-thirds of the children. Blood pressure and anthropometry were assessed in more than 90%. A 3-day accelerometry was performed in 46%, motor fitness was assessed in 41%, cardiorespiratory fitness in 35% and ∼11% participated in taste perception tests. The proportion of children donating venous blood, urine and saliva was 57, 86 and 88%, respectively.Conclusion:The IDEFICS cohort provides valuable data to investigate the interplay of social, environmental, genetic, physiological and behavioural factors in the development of major diet- and lifestyle-related disorders affecting children at present.

A century of trends in adult human height

Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3–19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8–144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries. DOI: http://dx.doi.org/10.7554/eLife.13410.001

Cigarette smoking and lung cancer – relative risk estimates for the major histological types from a pooled analysis of case-control studies

Lung cancer is mainly caused by smoking, but the quantitative relations between smoking and histologic subtypes of lung cancer remain inconclusive. By using one of the largest lung cancer datasets ever assembled, we explored the impact of smoking on risks of the major cell types of lung cancer. This pooled analysis included 13,169 cases and 16,010 controls from Europe and Canada. Studies with population controls comprised 66.5% of the subjects. Adenocarcinoma (AdCa) was the most prevalent subtype in never smokers and in women. Squamous cell carcinoma (SqCC) predominated in male smokers. Age‐adjusted odds ratios (ORs) were estimated with logistic regression. ORs were elevated for all metrics of exposure to cigarette smoke and were higher for SqCC and small cell lung cancer (SCLC) than for AdCa. Current male smokers with an average daily dose of >30 cigarettes had ORs of 103.5 (95% confidence interval (CI): 74.8–143.2) for SqCC, 111.3 (95% CI: 69.8–177.5) for SCLC and 21.9 (95% CI: 16.6–29.0) for AdCa. In women, the corresponding ORs were 62.7 (95% CI: 31.5–124.6), 108.6 (95% CI: 50.7–232.8) and 16.8 (95% CI: 9.2–30.6), respectively. Although ORs started to decline soon after quitting, they did not fully return to the baseline risk of never smokers even 35 years after cessation. The major result that smoking exerted a steeper risk gradient on SqCC and SCLC than on AdCa is in line with previous population data and biological understanding of lung cancer development.

Lung cancer and cigarette smoking in Europe: An update of risk estimates and an assessment of inter-country heterogeneity

Ten case‐control studies have been carried out in 6 European countries to investigate the major risk factors for lung cancer. Carcinogenic effect from cigarette smoke was the most relevant interest in our study, which has included 7,609 cases of lung cancer and 10,431 controls, mainly population based. The results indicate elevated odds ratios (ORs; 23.9 among men and 8.7 among women) with attributable risks exceeding 90% for men and close to 60% for women. A large, and statistically significant, variability of the results across countries was detected after adjusting for the most common confounding variables, and after controlling, at least in part, for the instability of the ORs due to the small number of non‐smokers in some of the study subsets. This pattern of lung cancer risk associated with cigarettes smoke, across different European regions, reflects inherent characteristics of the studies as well as differences in smoking habits, particularly calender periods of starting, and it is likely to have been influenced by effect modifiers like indoor radon exposure, occupation, air pollution and dietary habits.

The possible role of radiofrequency radiation in the development of uveal melanoma.

There are few epidemiologic studies dealing with electromagnetic radiation and uveal melanoma. The majority of these studies are exploratory and are based on job and industry titles only. We conducted a hospital-based and population-based case-control study of uveal melanoma and occupational exposures to different sources of electromagnetic radiation, including radiofrequency radiation. We then pooled these results. We interviewed a total of 118 female and male cases with uveal melanoma and 475 controls matching on sex, age, and study regions. Exposure to radiofrequency-transmitting devices was rated as (a) no radiofrequency radiation exposure, (b) possible exposure to mobile phones, or (c) probable/certain exposure to mobile phones. Exposures were rated independently by two of the authors who did not know case or control status. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). We found an elevated risk for exposure to radiofrequency-transmitting devices (exposure to radio sets, OR = 3.0, 95% CI = 1.4–6.3; probable/certain exposure to mobile phones, OR = 4.2, 95% CI = 1.2–14.5). Other sources of electromagnetic radiation such as high-voltage lines, electrical machines, complex electrical environments, visual display terminals, or radar units were not associated with uveal melanoma. This is the first study describing an association between radiofrequency radiation exposure and uveal melanoma. Several methodologic limitations prevent our results from providing clear evidence on the hypothesized association.

Prevalence of overweight and obesity in European children below the age of 10

Background:There is a lack of common surveillance systems providing comparable figures and temporal trends of the prevalence of overweight (OW), obesity and related risk factors among European preschool and school children. Comparability of available data is limited in terms of sampling design, methodological approaches and quality assurance. The IDEFICS (Identification and prevention of Dietary- and lifestyle-induced health Effects in Children and infantS) study provides one of the largest European data sets of young children based on state-of-the-art methodology.Objective:To assess the European distribution of weight status according to different classification systems based on body mass index (BMI) in children (2.0–9.9 years). To describe the prevalence of weight categories by region, sex, age and socioeconomic position.Design:Between 2007 and 2010, 18 745 children from eight European countries participated in an extensive, highly standardised protocol including, among other measures, anthropometric examinations and parental reports on socio-demographic characteristics.Results:The combined prevalence of OW/obesity ranges from more than 40% in southern Europe to less than 10% in northern Europe. Overall, the prevalence of OW was higher in girls (21.1%) as compared with boys (18.6%). The prevalence of OW shows a negative gradient with social position, with some variation of the strength and consistency of this association across Europe. Overall, population groups with low income and/or lower education levels show the highest prevalence of obesity. The use of different reference systems to classify OW results in substantial differences in prevalence estimates and can even reverse the reported difference between boys and girls.Conclusions:There is a higher prevalence of obesity in populations from southern Europe and in population groups with lower education and income levels. Our data confirm the need to develop and reinforce European public health policies to prevent early obesity and to reduce these health inequalities and regional disparities.

Exposure to Diesel Motor Exhaust and Lung Cancer Risk in a Pooled Analysis from Case-Control Studies in Europe and Canada

RATIONALE Diesel motor exhaust is classified by the International Agency for Research on Cancer as probably carcinogenic to humans. The epidemiologic evidence is evaluated as limited because most studies lack adequate control for potential confounders and only a few studies have reported on exposure-response relationships. OBJECTIVES Investigate lung cancer risk associated with occupational exposure to diesel motor exhaust, while controlling for potential confounders. METHODS The SYNERGY project pooled information on lifetime work histories and tobacco smoking from 13,304 cases and 16,282 controls from 11 case-control studies conducted in Europe and Canada. A general population job exposure matrix based on ISCO-68 occupational codes, assigning no, low, or high exposure to diesel motor exhaust, was applied to determine level of exposure. MEASUREMENTS AND MAIN RESULTS Odds ratios of lung cancer and 95% confidence intervals were estimated by unconditional logistic regression, adjusted for age, sex, study, ever-employment in an occupation with established lung cancer risk, cigarette pack-years, and time-since-quitting smoking. Cumulative diesel exposure was associated with an increased lung cancer risk highest quartile versus unexposed (odds ratio 1.31; 95% confidence interval, 1.19-1.43), and a significant exposure-response relationship (P value < 0.01). Corresponding effect estimates were similar in workers never employed in occupations with established lung cancer risk, and in women and never-smokers, although not statistically significant. CONCLUSIONS Our results show a consistent association between occupational exposure to diesel motor exhaust and increased risk of lung cancer. This association is unlikely explained by bias or confounding, which we addressed by adjusted models and subgroup analyses.

Gender differences in lung cancer risk by smoking: a multicentre case-control study in Germany and Italy.

Several studies in the past have shown appreciably higher lung cancer risk estimates associated with smoking exposure among men than among women, while more recent studies in the USA report just the opposite. To evaluate this topic in a European population we conducted a case–control study of lung cancer in three German and three Italian centres. Personal interviews and standardized questionnaires were used to obtain detailed life-long smoking and occupational histories from 3723 male and 900 female cases and 4075 male and 1094 female controls. Lung cancer risk comparing ever-smokers with never-smokers was higher among men (odds ratios (OR) adjusted for age and centre = 16.1, 95% confidence interval (CI) 12.8–20.3) than among women (OR = 4.2, CI 3.5–5.1). Because the smoking habits of women were different from men, we conducted more detailed analyses using comparable levels of smoking exposure. After restriction to smokers and adjustment for other smoking variables, risk estimates did not differ appreciably between genders. The analysis of duration of smoking (0–19, 20–39, 40+ years) adjusted for cigarette consumption and time since quitting smoking revealed similar risk estimates in men (OR = 1.0, 3.3 [CI 2.6–4.2], 4.1 [CI 3.1–5.6]) and women (OR = 1.0, 2.7 [CI 1.7–4.1], 3.3 [CI 1.9–5.8]). The same was true of the analysis of average or cumulative smoking consumption, and also of analyses stratified by different histological types. We conclude that for comparable exposure to tobacco smoke, the risk of lung cancer is comparable in women and men.