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1.  Fractional exhaled nitric oxide in childhood is associated with 17q11.2-q12 and 17q12-q21 variants 
The fractional concentration of nitric oxide in exhaled air (FeNO) is a biomarker of eosinophilic airway inflammation and associated with childhood asthma. Identification of common genetic variants associated with childhood FeNO may help to define biological mechanisms related to specific asthma phenotypes.
To identify genetic variants associated with childhood FeNO, and their relation with asthma.
FeNO was measured in children aged 5 to 15 years. In 14 genome-wide association (GWA) studies (N = 8,858), we examined the associations of ~2.5 million single nucleotide polymorphisms (SNPs) with FeNO. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci (eQTLs) in genome-wide expression datasets of lymphoblastoid cell lines (N = 1,830), and were related with asthma in a previously published GWA dataset (cases: n=10,365; controls: n=16,110).
We identified 3 SNPs associated with FeNO: rs3751972 in LYR motif containing 9 (LYRM9) (P = 1.97×10−10) and rs944722 in inducible nitric oxide synthase 2 (NOS2) (P = 1.28×10−9) both located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB) (P = 1.88×10−8) at 17q12-q21. We found a cis eQTL for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. Rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. Rs8069176 at 17q12-q21, and not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma.
This study identified 3 variants associated with FeNO, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight in the regulation of FeNO. This study highlights that both shared and distinct genetic factors affect FeNO and childhood asthma.
PMCID: PMC4334587  PMID: 24315451
airway inflammation; asthma phenotypes; biomarker; genetics; genome-wide association study
2.  Is There a Threshold Concentration of Cat Allergen Exposure on Respiratory Symptoms in Adults? 
PLoS ONE  2015;10(6):e0127457.
Background and Objective
Cat allergen concentrations higher than 8 μg/g in settled house dust, have been suggested to provoke exacerbation of allergic respiratory symptoms. However, whether the 8μg/g of indoor cat allergen concentration is indeed the minimal exposure required for triggering the asthma related respiratory symptoms or the development of sensitization has not yet been confirmed. We studied the associations between domestic cat allergen concentrations and allergic symptoms in the European Community Respiratory Health Survey II, with the aim of confirming this suggested threshold.
Cat allergen concentrations were measured in the mattress dust of 3003 participants from 22 study centres. Levels of specific immunoglobulin E to cat allergens were measured in serum samples using an immunoassay. Information on allergic symptoms, medication use, home environment and smoking was obtained from a face-to-face interview.
Domestic cat allergen concentrations were not associated with allergic/ asthmatic symptoms in the entire study population, nor in the subset sensitized to cat allergen. We also found no association among individuals exposed to concentrations higher than 8 μg/g. However, exposure to medium cat allergen concentrations (0.24-0.63 μg/g) was positively associated with reported asthmatic respiratory symptoms in subjects who have experienced allergic symptoms when near animals.
The proposed 8 μg/g threshold of cat allergen concentrations for the exacerbation of allergic/ respiratory symptoms was not confirmed in a general European adult population. Potential biases attributable to avoidance behaviours and an imprecise exposure assessment cannot be excluded.
PMCID: PMC4452769  PMID: 26035304
3.  Natural-Cause Mortality and Long-Term Exposure to Particle Components: An Analysis of 19 European Cohorts within the Multi-Center ESCAPE Project 
Beelen, Rob | Hoek, Gerard | Raaschou-Nielsen, Ole | Stafoggia, Massimo | Andersen, Zorana Jovanovic | Weinmayr, Gudrun | Hoffmann, Barbara | Wolf, Kathrin | Samoli, Evangelia | Fischer, Paul H. | Nieuwenhuijsen, Mark J. | Xun, Wei W. | Katsouyanni, Klea | Dimakopoulou, Konstantina | Marcon, Alessandro | Vartiainen, Erkki | Lanki, Timo | Yli-Tuomi, Tarja | Oftedal, Bente | Schwarze, Per E. | Nafstad, Per | De Faire, Ulf | Pedersen, Nancy L. | Östenson, Claes-Göran | Fratiglioni, Laura | Penell, Johanna | Korek, Michal | Pershagen, Göran | Eriksen, Kirsten Thorup | Overvad, Kim | Sørensen, Mette | Eeftens, Marloes | Peeters, Petra H. | Meliefste, Kees | Wang, Meng | Bueno-de-Mesquita, H. Bas | Sugiri, Dorothea | Krämer, Ursula | Heinrich, Joachim | de Hoogh, Kees | Key, Timothy | Peters, Annette | Hampel, Regina | Concin, Hans | Nagel, Gabriele | Jaensch, Andrea | Ineichen, Alex | Tsai, Ming-Yi | Schaffner, Emmanuel | Probst-Hensch, Nicole M. | Schindler, Christian | Ragettli, Martina S. | Vilier, Alice | Clavel-Chapelon, Françoise | Declercq, Christophe | Ricceri, Fulvio | Sacerdote, Carlotta | Galassi, Claudia | Migliore, Enrica | Ranzi, Andrea | Cesaroni, Giulia | Badaloni, Chiara | Forastiere, Francesco | Katsoulis, Michail | Trichopoulou, Antonia | Keuken, Menno | Jedynska, Aleksandra | Kooter, Ingeborg M. | Kukkonen, Jaakko | Sokhi, Ranjeet S. | Vineis, Paolo | Brunekreef, Bert
Environmental Health Perspectives  2015;123(6):525-533.
Studies have shown associations between mortality and long-term exposure to particulate matter air pollution. Few cohort studies have estimated the effects of the elemental composition of particulate matter on mortality.
Our aim was to study the association between natural-cause mortality and long-term exposure to elemental components of particulate matter.
Mortality and confounder data from 19 European cohort studies were used. Residential exposure to eight a priori–selected components of particulate matter (PM) was characterized following a strictly standardized protocol. Annual average concentrations of copper, iron, potassium, nickel, sulfur, silicon, vanadium, and zinc within PM size fractions ≤ 2.5 μm (PM2.5) and ≤ 10 μm (PM10) were estimated using land-use regression models. Cohort-specific statistical analyses of the associations between mortality and air pollution were conducted using Cox proportional hazards models using a common protocol followed by meta-analysis.
The total study population consisted of 291,816 participants, of whom 25,466 died from a natural cause during follow-up (average time of follow-up, 14.3 years). Hazard ratios were positive for almost all elements and statistically significant for PM2.5 sulfur (1.14; 95% CI: 1.06, 1.23 per 200 ng/m3). In a two-pollutant model, the association with PM2.5 sulfur was robust to adjustment for PM2.5 mass, whereas the association with PM2.5 mass was reduced.
Long-term exposure to PM2.5 sulfur was associated with natural-cause mortality. This association was robust to adjustment for other pollutants and PM2.5.
Beelen R, Hoek G, Raaschou-Nielsen O, Stafoggia M, Andersen ZJ, Weinmayr G, Hoffmann B, Wolf K, Samoli E, Fischer PH, Nieuwenhuijsen MJ, Xun WW, Katsouyanni K, Dimakopoulou K, Marcon A, Vartiainen E, Lanki T, Yli-Tuomi T, Oftedal B, Schwarze PE, Nafstad P, De Faire U, Pedersen NL, Östenson C-G, Fratiglioni L, Penell J, Korek M, Pershagen G, Eriksen KT, Overvad K, Sørensen M, Eeftens M, Peeters PH, Meliefste K, Wang M, Bueno-de-Mesquita HB, Sugiri D, Krämer U, Heinrich J, de Hoogh K, Key T, Peters A, Hampel R, Concin H, Nagel G, Jaensch A, Ineichen A, Tsai MY, Schaffner E, Probst-Hensch NM, Schindler C, Ragettli MS, Vilier A, Clavel-Chapelon F, Declercq C, Ricceri F, Sacerdote C, Galassi C, Migliore E, Ranzi A, Cesaroni G, Badaloni C, Forastiere F, Katsoulis M, Trichopoulou A, Keuken M, Jedynska A, Kooter IM, Kukkonen J, Sokhi RS, Vineis P, Brunekreef B. 2015. Natural-cause mortality and long-term exposure to particle components: an analysis of 19 European cohorts within the Multi-Center ESCAPE Project. Environ Health Perspect 123:525–533;
PMCID: PMC4455583  PMID: 25712504
4.  Ambient Air Pollution and Adult Asthma Incidence in Six European Cohorts (ESCAPE) 
Environmental Health Perspectives  2015;123(6):613-621.
Short-term exposure to air pollution has adverse effects among patients with asthma, but whether long-term exposure to air pollution is a cause of adult-onset asthma is unclear.
We aimed to investigate the association between air pollution and adult onset asthma.
Asthma incidence was prospectively assessed in six European cohorts. Exposures studied were annual average concentrations at home addresses for nitrogen oxides assessed for 23,704 participants (including 1,257 incident cases) and particulate matter (PM) assessed for 17,909 participants through ESCAPE land-use regression models and traffic exposure indicators. Meta-analyses of cohort-specific logistic regression on asthma incidence were performed. Models were adjusted for age, sex, overweight, education, and smoking and included city/area within each cohort as a random effect.
In this longitudinal analysis, asthma incidence was positively, but not significantly, associated with all exposure metrics, except for PMcoarse. Positive associations of borderline significance were observed for nitrogen dioxide [adjusted odds ratio (OR) = 1.10; 95% CI: 0.99, 1.21 per 10 μg/m3; p = 0.10] and nitrogen oxides (adjusted OR = 1.04; 95% CI: 0.99, 1.08 per 20 μg/m3; p = 0.08). Nonsignificant positive associations were estimated for PM10 (adjusted OR = 1.04; 95% CI: 0.88, 1.23 per 10 μg/m3), PM2.5 (adjusted OR = 1.04; 95% CI: 0.88, 1.23 per 5 μg/m3), PM2.5absorbance (adjusted OR = 1.06; 95% CI: 0.95, 1.19 per 10–5/m), traffic load (adjusted OR = 1.10; 95% CI: 0.93, 1.30 per 4 million vehicles × meters/day on major roads in a 100-m buffer), and traffic intensity (adjusted OR = 1.10; 95% CI: 0.93, 1.30 per 5,000 vehicles/day on the nearest road). A nonsignificant negative association was estimated for PMcoarse (adjusted OR = 0.98; 95% CI: 0.87, 1.14 per 5 μg/m3).
Results suggest a deleterious effect of ambient air pollution on asthma incidence in adults. Further research with improved personal-level exposure assessment (vs. residential exposure assessment only) and phenotypic characterization is needed.
Jacquemin B, Siroux V, Sanchez M, Carsin AE, Schikowski T, Adam M, Bellisario V, Buschka A, Bono R, Brunekreef B, Cai Y, Cirach M, Clavel-Chapelon F, Declercq C, de Marco R, de Nazelle A, Ducret-Stich RE, Ferretti VV, Gerbase MW, Hardy R, Heinrich J, Janson C, Jarvis D, Al Kanaani Z, Keidel D, Kuh D, Le Moual N, Nieuwenhuijsen MJ, Marcon A, Modig L, Pin I, Rochat T, Schindler C, Sugiri D, Stempfelet M, Temam S, Tsai MY, Varraso R, Vienneau D, Vierkötter A, Hansell AL, Krämer U, Probst-Hensch NM, Sunyer J, Künzli N, Kauffmann F. 2015. Ambient air pollution and adult asthma incidence in six European cohorts (ESCAPE). Environ Health Perspect 123:613–621;
PMCID: PMC4455584  PMID: 25712593
5.  Predictors of microbial agents in dust and respiratory health in the Ecrhs 
Dampness and mould exposure have been repeatedly associated with respiratory health. However, less is known about the specific agents provoking or arresting health effects in adult populations. We aimed to assess predictors of microbial agents in mattress dust throughout Europe and to investigate associations between microbial exposures, home characteristics and respiratory health.
Seven different fungal and bacterial parameters were assessed in mattress dust from 956 adult ECRHS II participants in addition to interview based home characteristics. Associations between microbial parameters and the asthma score and lung function were examined using mixed negative binomial regression and linear mixed models, respectively.
Indoor dampness and pet keeping were significant predictors for higher microbial agent concentrations in mattress dust. Current mould and condensation in the bedroom were significantly associated with lung function decline and current mould at home was positively associated with the asthma score. Higher concentrations of muramic acid were associated with higher mean ratios of the asthma score (aMR 1.37, 95%CI 1.17-1.61). There was no evidence for any association between fungal and bacterial components and lung function.
Indoor dampness was associated with microbial levels in mattress dust which in turn was positively associated with asthma symptoms.
Electronic supplementary material
The online version of this article (doi:10.1186/s12890-015-0042-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4425915  PMID: 25929252
Molds; Fungi; Microbials; Indoor Air; Asthma; Airways
6.  The association between physical activity and healthcare costs in children – results from the GINIplus and LISAplus cohort studies 
BMC Public Health  2015;15:437.
Physical inactivity in children is an important risk factor for the development of various morbidities and mortality in adulthood, physical activity already has preventive effects during childhood. The objective of this study is to estimate the association between physical activity, healthcare utilization and costs in children.
Cross-sectional data of 3356 children aged 9 to 12 years were taken from the 10-year follow-up of the birth cohort studies GINIplus and LISAplus, including information on healthcare utilization and physical activity given by parents via self-administered questionnaires. Using a bottom-up approach, direct costs due to healthcare utilization and indirect costs resulting from parental work absence were estimated for the base year 2007. A two-step regression model compared effects on healthcare utilization and costs for a higher (≥7 h/week) versus a lower (<7 h/week) level of moderate-to-vigorous physical activity (MVPA) adjusted for age, gender, BMI, education and income of parents, single parenthood and study region. Recycled predictions estimated adjusted mean costs per child and activity group.
The analyses for the association between physical activity, healthcare utilization and costs showed no statistically significant results. Different directions of estimates were noticeable throughout cost components in the first step as well as the second step of the regression model. For higher MVPA (≥7 h/week) compared with lower MVPA (<7 h/week) total direct costs accounted for 392 EUR (95% CI: 342–449 EUR) versus 398 EUR (95% CI: 309–480 EUR) and indirect costs accounted for 138 EUR (95% CI: 124–153 EUR) versus 127 EUR (95% CI: 111–146 EUR).
The results indicate that childhood might be too early in life, to detect significant preventive effects of physical activity on healthcare utilization and costs, as diseases attributable to lacking physical activity might first occur later in life. This underpins the importance of clarifying the long-term effects of physical activity as it may strengthen the promotion of physical activity in children from a health economic perspective.
PMCID: PMC4423115  PMID: 25925399
Physical activity; Healthcare utilization; Healthcare costs; Direct costs; Indirect costs; Children; Cross-sectional study
7.  Utilization of complementary and alternative medicine (CAM) among children from a German birth cohort (GINIplus): patterns, costs, and trends of use 
The use of complementary and alternative medicine (CAM) is widespread among children in Germany and other European countries. Only a few studies are available on trends in pediatric CAM use over time. The study’s objective was to present updated results for prevalence, predictors, and costs of CAM use among German children and a comparison with findings from a previous follow-up of the same birth cohort.
Data were collected for 3013 children on their utilization of medicinal products (during the last 4 weeks) and consultation with CAM providers (in the preceding year) from a German birth cohort study (GINIplus, 15-year follow-up) using a self-administered questionnaire. The reported medicinal CAMs were classified into six categories (homeopathy, herbal drugs, nutritionals, minerals and trace elements, microorganisms, further CAM). Drug prices were traced using pharmaceutical identification numbers (PZNs), or otherwise conservatively estimated. Finally, the results were compared with data obtained from the 10-year follow-up of the same birth cohort study by adopting the identical methodology.
In all, 26% of the reported 2489 drugs were medicinal CAM. The 4-week prevalence for homeopathy and herbal drug use was 7.5% and 5.6%, respectively. Some 13.9% of the children used at least one type of medicinal CAM in the preceding 4 weeks. The 1-year prevalence for consultation with CAM providers was 10.8%. From the drugs identified as CAM, 53.7% were homeopathic remedies, and 30.8% were herbal drugs.
Factors associated with higher medicinal CAM use were female gender, residing in Munich, and higher maternal education.
A homeopathy user utilized on average homeopathic remedies worth EUR 15.28. The corresponding figure for herbal drug users was EUR 16.02, and EUR 18.72 for overall medicinal CAM users.
Compared with the 10-year follow-up, the prevalence of homeopathy use was more than halved (−52%) and dropped substantially for herbal drug use (−36%) and overall CAM use (−38%) as well.
CAM use among 15-year-old children in the GINIplus cohort is popular, but decreased noticeably compared with children from the same cohort at the age of 10 years. This is possibly mainly because German health legislation normally covers CAM for children younger than 12 years only.
PMCID: PMC4364567  PMID: 25885673
Complementary therapies; CAM; Homeopathy; Phytotherapy; Child; Germany; Drug utilization; Socioeconomic factors; Trends
8.  A nested case-control study indicating heavy metal residues in meconium associate with maternal gestational diabetes mellitus risk 
Environmental Health  2015;14:19.
Environmental pollutant exposure may play certain roles in the pathogenesis and progression of diabetes mellitus including gestational diabetes mellitus (GDM). We hypothesize that heavy metal exposure may trigger GDM during pregnancy. The objective of this study was to investigate the possible associations between selected heavy metal exposure and GDM risk.
This investigation is a retrospective case–control study nested within a cohort of 1359 pregnant women. These participants were recruited in Xiamen Maternity and Child Care Hospital, China, during June to July, 2012. All their newborns’ meconium samples were collected. By reviewing the antenatal care records, 166 GDM mothers were screened out from the 1359 participants; 137 of 166 GDM mothers offered their newborns’ meconium samples for the metal analysis. Those 137 mothers were set as the case group. Similarly, 294 healthy mothers without any gestational complication were initially screened out from the rest 1193 non-GDM mothers. 190 of the 294 healthy mothers offered their newborns’ meconium samples for the metal analysis. Those 190 mothers were set as the control group. Arsenic (As), mercury (Hg), lead (Pb), cadmium (Cd), and chromium (Cr) levels in these case–control meconium samples were measured by inductively coupled plasma mass spectrometry. The possible association between the metal levels and maternal GDM risk of studied subjects was assessed by binary logistic regression.
GDM prevalence of 12.21% was observed in the investigated 1359 participants. The concentrations of As, Hg, Cr and Cd in studied cases were significantly higher (p < 0.05) than those of controls. After adjustments for maternal age, pre-pregnant body mass index, gravidity, parity, hepatitis B virus infection, and newborn sex, As, Cd and Cr were found to be positively associated with GDM prevalence in dose-dependent manners. Among them, As was detected in all samples and its levels associated the maternal GDM with the adjusted odds ratios of 3.28 [95% CI 1.24, 8.71], 3.35 [95% CI 1.28, 8.75] and 5.25 [95% CI 1.99, 13.86] for the 2nd, 3rd and 4th quartiles, respectively.
The present work implies that exposure to some of the selected metals (noticeably As) may contribute to maternal GDM risk during pregnancy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12940-015-0004-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4357163  PMID: 25888735
Heavy metals; Meconium; Gestational diabetes mellitus; China
9.  A Network-Based Kernel Machine Test for the Identification of Risk Pathways in Genome-Wide Association Studies 
Human heredity  2014;76(2):64-75.
Biological pathways provide rich information and biological context on the genetic causes of complex diseases. The logistic kernel machine test integrates prior knowledge on pathways in order to analyze data from genome-wide association studies (GWAS). Here, the kernel converts genomic information of two individuals to a quantitative value reflecting their genetic similarity. With the selection of the kernel one implicitly chooses a genetic effect model. Like many other pathway methods, none of the available kernels accounts for topological structure of the pathway or gene-gene interaction types. However, evidence indicates that connectivity and neighborhood of genes are crucial in the context of GWAS, because genes associated with a disease often interact. Thus, we propose a novel kernel that incorporates the topology of pathways and information on interactions. Using simulation studies, we demonstrate that the proposed method maintains the type I error correctly and can be more effective in the identification of pathways associated with a disease than non-network-based methods. We apply our approach to genome-wide association case control data on lung cancer and rheumatoid arthritis. We identify some promising new pathways associated with these diseases, which may improve our current understanding of the genetic mechanisms.
PMCID: PMC4026009  PMID: 24434848
Kernel Machine Test; Pathways; Networks; Gene-Gene Interactions; Score Test; Generalized Linear Model; Lung Cancer; Rheumatoid Arthritis; Disease Association; Genetic Association Studies
10.  Genome-wide association analysis identifies six new loci associated with forced vital capacity 
Loth, Daan W. | Artigas, María Soler | Gharib, Sina A. | Wain, Louise V. | Franceschini, Nora | Koch, Beate | Pottinger, Tess | Smith, Albert Vernon | Duan, Qing | Oldmeadow, Chris | Lee, Mi Kyeong | Strachan, David P. | James, Alan L. | Huffman, Jennifer E. | Vitart, Veronique | Ramasamy, Adaikalavan | Wareham, Nicholas J. | Kaprio, Jaakko | Wang, Xin-Qun | Trochet, Holly | Kähönen, Mika | Flexeder, Claudia | Albrecht, Eva | Lopez, Lorna M. | de Jong, Kim | Thyagarajan, Bharat | Alves, Alexessander Couto | Enroth, Stefan | Omenaas, Ernst | Joshi, Peter K. | Fall, Tove | Viňuela, Ana | Launer, Lenore J. | Loehr, Laura R. | Fornage, Myriam | Li, Guo | Wilk, Jemma B. | Tang, Wenbo | Manichaikul, Ani | Lahousse, Lies | Harris, Tamara B. | North, Kari E. | Rudnicka, Alicja R. | Hui, Jennie | Gu, Xiangjun | Lumley, Thomas | Wright, Alan F. | Hastie, Nicholas D. | Campbell, Susan | Kumar, Rajesh | Pin, Isabelle | Scott, Robert A. | Pietiläinen, Kirsi H. | Surakka, Ida | Liu, Yongmei | Holliday, Elizabeth G. | Schulz, Holger | Heinrich, Joachim | Davies, Gail | Vonk, Judith M. | Wojczynski, Mary | Pouta, Anneli | Johansson, Åsa | Wild, Sarah H. | Ingelsson, Erik | Rivadeneira, Fernando | Völzke, Henry | Hysi, Pirro G. | Eiriksdottir, Gudny | Morrison, Alanna C. | Rotter, Jerome I. | Gao, Wei | Postma, Dirkje S. | White, Wendy B. | Rich, Stephen S. | Hofman, Albert | Aspelund, Thor | Couper, David | Smith, Lewis J. | Psaty, Bruce M. | Lohman, Kurt | Burchard, Esteban G. | Uitterlinden, André G. | Garcia, Melissa | Joubert, Bonnie R. | McArdle, Wendy L. | Musk, A. Bill | Hansel, Nadia | Heckbert, Susan R. | Zgaga, Lina | van Meurs, Joyce B.J. | Navarro, Pau | Rudan, Igor | Oh, Yeon-Mok | Redline, Susan | Jarvis, Deborah | Zhao, Jing Hua | Rantanen, Taina | O’Connor, George T. | Ripatti, Samuli | Scott, Rodney J. | Karrasch, Stefan | Grallert, Harald | Gaddis, Nathan C. | Starr, John M. | Wijmenga, Cisca | Minster, Ryan L. | Lederer, David J. | Pekkanen, Juha | Gyllensten, Ulf | Campbell, Harry | Morris, Andrew P. | Gläser, Sven | Hammond, Christopher J. | Burkart, Kristin M. | Beilby, John | Kritchevsky, Stephen B. | Gudnason, Vilmundur | Hancock, Dana B. | Williams, O. Dale | Polasek, Ozren | Zemunik, Tatijana | Kolcic, Ivana | Petrini, Marcy F. | Wjst, Matthias | Kim, Woo Jin | Porteous, David J. | Scotland, Generation | Smith, Blair H. | Viljanen, Anne | Heliövaara, Markku | Attia, John R. | Sayers, Ian | Hampel, Regina | Gieger, Christian | Deary, Ian J. | Boezen, H. Marike | Newman, Anne | Jarvelin, Marjo-Riitta | Wilson, James F. | Lind, Lars | Stricker, Bruno H. | Teumer, Alexander | Spector, Timothy D. | Melén, Erik | Peters, Marjolein J. | Lange, Leslie A. | Barr, R. Graham | Bracke, Ken R. | Verhamme, Fien M. | Sung, Joohon | Hiemstra, Pieter S. | Cassano, Patricia A. | Sood, Akshay | Hayward, Caroline | Dupuis, Josée | Hall, Ian P. | Brusselle, Guy G. | Tobin, Martin D. | London, Stephanie J.
Nature genetics  2014;46(7):669-677.
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
PMCID: PMC4140093  PMID: 24929828
11.  Serum 25(OH)D concentrations and atopic diseases at age 10: results from the GINIplus and LISAplus birth cohort studies 
BMC Pediatrics  2014;14:286.
Vitamin D is well recognized for its role in skeletal health and its involvement in the modulation of the immune system. In the literature, controversial results are reported for atopic diseases. Thus, we investigated the association between vitamin D status and the prevalence of atopic diseases.
Serum 25-hydroxy-vitamin D (25(OH)D) concentrations were measured in a sample of 2815 10-years old children from two German birth cohort studies. Self-reported physician-diagnosed eczema, hay fever or allergic rhinitis, and asthma were used as outcome variables as well as specific IgE positivity against common allergens. We applied logistic regression models, deriving adjusted odds ratio estimates (aOR) and 95% confidence intervals (CI).
For asthma and hay fever or allergic rhinitis, no associations existed with serum 25(OH)D concentrations. We observed a significant positive relationship between serum 25(OH)D levels and eczema at age 10 (aOR = 1.09, CI = 1.01-1.17, per 10 nmol/l increase in serum 25(OH)D levels) and for the lifetime prevalence of eczema (aOR = 1.05, CI = 1.01-1.09). Specific IgE positivity for food allergens (aOR = 1.07, CI = 1.02-1.11) and aeroallergens (aOR = 1.05, CI = 1.01-1.08) at age 10, as well as lifetime prevalence, was significantly related to the vitamin D status.
In this study we found no indication that higher blood 25(OH)D levels are associated with decreased risk for any of the atopic outcomes in children. However, we observed a positive association of serum 25(OH)D concentrations with eczema and detectable specific IgE. Due to the given limitations of our study, the clinical relevance of these findings needs further clarification.
Electronic supplementary material
The online version of this article (doi:10.1186/s12887-014-0286-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4251945  PMID: 25421846
Asthma; Atopic diseases; Eczema; Allergic rhinitis; Birth cohort; Hay fever; Sensitization; Vitamin D
12.  Cord blood LC-PUFA composition and allergic diseases during the first 10 yr. Results from the LISAplus study 
Pediatric Allergy and Immunology  2014;25(4):344-350.
It has been suggested that n-6 and n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) in blood are associated with risk of allergic diseases, although results are inconclusive. Low levels of n-6 LC-PUFA and high levels of n-3 LC-PUFA are anticipated to have beneficial effects. Pregnancy is considered a critical time period for imprinting the developing immune system. We examined whether n-6 LC-PUFA, n-3 LC-PUFA concentrations or the n-6/n-3 ratio in cord blood (CB) serum are associated with allergic diseases up to the age of 10 yr.
This analysis included 436 children from the Munich LISAplus birth cohort study. Information on doctor-diagnosed asthma, hay fever/allergic rhinitis, and eczema was collected using questionnaires completed at the ages 6 and 10 yr, and for eczema additionally at 2 yr. Specific immunoglobulin E (IgE) against inhalant allergens was measured at 6 and 10 yr. Fatty acid composition was measured by gas chromatography in serum from CB and from blood collected at 2, 6, and 10 yr. Associations between n-3, n-6 LC-PUFA concentrations, and the n-6/n-3 ratio in CB serum and allergic diseases or atopy were assessed using generalized estimating equations (GEE) considering the longitudinal structure. Models were adjusted for LC-PUFA concentrations at follow-up and potential confounding factors.
There was no significant association between n-3 LC-PUFA, n-6 LC-PUFA, or the n-6/n-3 ratio in CB serum with eczema, asthma, hay fever/allergic rhinitis, or aeroallergen sensitization.
There is no indication of a beneficial effect of increased n-3 LC-PUFA in CB serum on the development of any of the disease entities.
PMCID: PMC4238817  PMID: 24576150
allergies; asthma; atopy; children; cord blood; eczema; epidemiology; fatty acids; polyunsaturated fatty acids; rhinitis
13.  Prenatal nicotine exposure and child behavioural problems 
In utero exposure to tobacco smoke has been related to numerous adverse health effects in new-borns, infants, children, adolescents and adults. The aim of this review was to summarise findings on prenatal nicotine exposure and its relationship with behavioural problems in the offspring. The majority of studies, and especially several recent epidemiological studies, observed a higher likelihood for attention-deficit/hyperactivity disorder (ADHD) or ADHD symptoms in exposed subjects. However, both human and animal studies have failed to provide clear evidence on causality. Existing literature on studies investigating the association between prenatal nicotine exposure and conduct or externalising problems in the offspring suggests a causal effect. The establishment of a final conclusion concerning the relationship between prenatal nicotine exposure and internalising problems in the offspring is complicated by insufficient data and mixed results in epidemiological studies. Prenatal nicotine exposure has been associated with altered brain structure and function in human offspring, and a proposed biological mechanism is related to nicotine’s adverse influence on neurotransmitter systems during brain development. In conclusion, establishing a statement on the causality of the relationship between prenatal nicotine exposure and behavioural problems in children remains a challenging task. Nevertheless, considering the results of an increasing number of studies which link prenatal exposure to nicotine to externalising problems applying different methodologies to account for confounding and in view of other adverse health effects known to be caused by this exposure, parents should consider smoking cessation.
PMCID: PMC4186967  PMID: 25241028
Tobacco smoke; Attention-deficit/hyperactivity disorder; Conduct problems; Depression; Anxiety; Brain development
14.  Health-related quality of life and chronic obstructive pulmonary disease in early stages – longitudinal results from the population-based KORA cohort in a working age population 
BMC Pulmonary Medicine  2014;14:134.
It is widely recognized that health-related quality of life (HRQL) is impaired in patients with Chronic Obstructive Pulmonary Disease (COPD), but there is a lack of research on longitudinal associations of COPD and HRQL. This study examined the effects of COPD in early stages of disease on HRQL over ten years in a working-age general population setting in Southern Germany while considering the influence of common comorbidities.
In the population-based KORA F4 study (2006–08) 1,321 participants aged 41–61 years performed spirometry and reported information on HRQL (measured by the generic SF-12) and comorbidities. For the same participants, HRQL information was available seven years before and three years after the lung function test from the previous S4 (1999–2001) and the F4L follow-up study (2010). Using linear mixed models, the physical and mental component summary scores (PCS-12 / MCS-12) of the SF-12 were compared over time between COPD groups.
7.8% of participants were classified as having COPD (according to the LLN definition and the Global Lungs Initiative), 59.4% of them in grade 1. Regression models showed a negative cross-sectional association of COPD grade 2+ with PCS-12 which persisted when comorbidities were considered. Adjusted mean PCS-12 scores for the COPD grade 2+ group were reduced (−3.5 (p = 0.008) in F4, −3.3 (p = 0.014) in S4 and −4.7 (p = 0.003) in F4L) compared to the group without airflow limitation. The size of the COPD effect in grade 2+ was similar to the effect of myocardial infarction and cancer. Over ten years, a small decline in PCS-12 was observed in all groups. This decline was larger in participants with COPD grade 2+, but insignificant. Regarding MCS-12, no significant cross-sectional or longitudinal associations with COPD were found.
Despite small HRQL differences between COPD patients in early disease stages and controls and small changes over ten years, our results indicate that it is important to prevent subjects with airflow limitation from progression to higher grades. Awareness of HRQL impairments in early stages is important for offering early interventions in order to maintain high HRQL in COPD patients.
PMCID: PMC4130122  PMID: 25107380
COPD; Health-related quality of life; SF-12; Comorbidities; General population study; Longitudinal
15.  Performance of Multi-City Land Use Regression Models for Nitrogen Dioxide and Fine Particles 
Environmental Health Perspectives  2014;122(8):843-849.
Background: Land use regression (LUR) models have been developed mostly to explain intraurban variations in air pollution based on often small local monitoring campaigns. Transferability of LUR models from city to city has been investigated, but little is known about the performance of models based on large numbers of monitoring sites covering a large area.
Objectives: We aimed to develop European and regional LUR models and to examine their transferability to areas not used for model development.
Methods: We evaluated LUR models for nitrogen dioxide (NO2) and particulate matter (PM; PM2.5, PM2.5 absorbance) by combining standardized measurement data from 17 (PM) and 23 (NO2) ESCAPE (European Study of Cohorts for Air Pollution Effects) study areas across 14 European countries for PM and NO2. Models were evaluated with cross-validation (CV) and hold-out validation (HV). We investigated the transferability of the models by successively excluding each study area from model building.
Results: The European model explained 56% of the concentration variability across all sites for NO2, 86% for PM2.5, and 70% for PM2.5 absorbance. The HV R2s were only slightly lower than the model R2 (NO2, 54%; PM2.5, 80%; PM2.5 absorbance, 70%). The European NO2, PM2.5, and PM2.5 absorbance models explained a median of 59%, 48%, and 70% of within-area variability in individual areas. The transferred models predicted a modest-to-large fraction of variability in areas that were excluded from model building (median R2: NO2, 59%; PM2.5, 42%; PM2.5 absorbance, 67%).
Conclusions: Using a large data set from 23 European study areas, we were able to develop LUR models for NO2 and PM metrics that predicted measurements made at independent sites and areas reasonably well. This finding is useful for assessing exposure in health studies conducted in areas where no measurements were conducted.
Citation: Wang M, Beelen R, Bellander T, Birk M, Cesaroni G, Cirach M, Cyrys J, de Hoogh K, Declercq C, Dimakopoulou K, Eeftens M, Eriksen KT, Forastiere F, Galassi C, Grivas G, Heinrich J, Hoffmann B, Ineichen A, Korek M, Lanki T, Lindley S, Modig L, Mölter A, Nafstad P, Nieuwenhuijsen MJ, Nystad W, Olsson D, Raaschou-Nielsen O, Ragettli M, Ranzi A, Stempfelet M, Sugiri D, Tsai MY, Udvardy O, Varró MJ, Vienneau D, Weinmayr G, Wolf K, Yli-Tuomi T, Hoek G, Brunekreef B. 2014. Performance of multi-city land use regression models for nitrogen dioxide and fine particles. Environ Health Perspect 122:843–849;
PMCID: PMC4123024  PMID: 24787034
16.  Empirical Hierarchical Bayes Approach to Gene-Environment Interactions: Development and Application to Genome-Wide Association Studies of Lung Cancer in TRICL 
Genetic epidemiology  2013;37(6):551-559.
The analysis of gene-environment (GxE) interactions remains one of the greatest challenges in the post-genome-wide-association-studies (GWAS) era. Recent methods constitute a compromise between the robust but underpowered case-control and powerful case-only methods. Inferences of the latter are biased when the assumption of gene-environment (G-E) independence fails. We propose a novel empirical hierarchical Bayes approach to GxE interaction (EHB-GE), which benefits from greater power while accounting for population-based G-E dependence. Building on Lewinger et al.'s ([2007] Genet Epidemiol 31:871-882) hierarchical Bayes prioritization approach, the method utilizes posterior G-E association estimates in controls based on G-E information across the genome to adjust for it in resulting test statistics. These posteriori estimates are subtracted from the corresponding G-E association coefficients within cases.
We compared EHB-GE with rival methods using simulation. EHB-GE has similar or greater rank power to detect GxE interactions in the presence of large numbers of G-E associations with weak to strong effects or only a low number of such associations with large effect. When there are no or only a few weak G-E associations, Murcray et al.'s method ([2009] Am J Epidemiol 169:219-226) identifies markers with low GxE interaction effects better. We applied EHB-GE and competing methods to four lung cancer case-control GWAS from the TRICL/ILCCO consortium with smoking as environmental factor. Genes identified by the EHB-GE approach are reasonable candidates, suggesting usefulness of the method.
PMCID: PMC4082246  PMID: 23893921
population G-E association; GWAS; rank power; lung cancer
17.  Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity 
Human Molecular Genetics  2013;22(13):2735-2747.
The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10−8) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.
PMCID: PMC3674797  PMID: 23449627
18.  Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function 
Tang, Wenbo | Kowgier, Matthew | Loth, Daan W. | Soler Artigas, María | Joubert, Bonnie R. | Hodge, Emily | Gharib, Sina A. | Smith, Albert V. | Ruczinski, Ingo | Gudnason, Vilmundur | Mathias, Rasika A. | Harris, Tamara B. | Hansel, Nadia N. | Launer, Lenore J. | Barnes, Kathleen C. | Hansen, Joyanna G. | Albrecht, Eva | Aldrich, Melinda C. | Allerhand, Michael | Barr, R. Graham | Brusselle, Guy G. | Couper, David J. | Curjuric, Ivan | Davies, Gail | Deary, Ian J. | Dupuis, Josée | Fall, Tove | Foy, Millennia | Franceschini, Nora | Gao, Wei | Gläser, Sven | Gu, Xiangjun | Hancock, Dana B. | Heinrich, Joachim | Hofman, Albert | Imboden, Medea | Ingelsson, Erik | James, Alan | Karrasch, Stefan | Koch, Beate | Kritchevsky, Stephen B. | Kumar, Ashish | Lahousse, Lies | Li, Guo | Lind, Lars | Lindgren, Cecilia | Liu, Yongmei | Lohman, Kurt | Lumley, Thomas | McArdle, Wendy L. | Meibohm, Bernd | Morris, Andrew P. | Morrison, Alanna C. | Musk, Bill | North, Kari E. | Palmer, Lyle J. | Probst-Hensch, Nicole M. | Psaty, Bruce M. | Rivadeneira, Fernando | Rotter, Jerome I. | Schulz, Holger | Smith, Lewis J. | Sood, Akshay | Starr, John M. | Strachan, David P. | Teumer, Alexander | Uitterlinden, André G. | Völzke, Henry | Voorman, Arend | Wain, Louise V. | Wells, Martin T. | Wilk, Jemma B. | Williams, O. Dale | Heckbert, Susan R. | Stricker, Bruno H. | London, Stephanie J. | Fornage, Myriam | Tobin, Martin D. | O′Connor, George T. | Hall, Ian P. | Cassano, Patricia A.
PLoS ONE  2014;9(7):e100776.
Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10-7). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
PMCID: PMC4077649  PMID: 24983941
19.  A cross-sectional analysis of the effects of residential greenness on blood pressure in 10-year old children: results from the GINIplus and LISAplus studies 
BMC Public Health  2014;14:477.
According to Ulrich’s psychoevolutionary theory, contact with green environments mitigates stress by activating the parasympathetic system, (specifically, by decreasing blood pressure (BP)). Experimental studies have confirmed this biological effect. However, greenness effects on BP have not yet been explored using an observational study design. We assessed whether surrounding residential greenness is associated with BP in 10 year-old German children.
Systolic and diastolic BPs were assessed in 10 year-old children residing in the Munich and Wesel study areas of the German GINIplus and LISAplus birth cohorts. Complete exposure, outcome and covariate data were available for 2,078 children. Residential surrounding greenness was defined as the mean of Normalized Difference Vegetation Index (NDVI) values, derived from Landsat 5 TM satellite images, in circular 500-m buffers around current home addresses of participants. Generalized additive models assessed pooled and area-specific associations between BP and residential greenness categorized into area-specific tertiles.
In the pooled adjusted model, the systolic BP of children living at residences with low and moderate greenness was 0.90 ± 0.50 mmHg (p-value = 0.073) and 1.23 ± 0.50 mmHg (p-value = 0.014) higher, respectively, than the systolic BP of children living in areas of high greenness. Similarly, the diastolic BP of children living in areas with low and moderate greenness was 0.80 ± 0.38 mmHg (p-value = 0.033) and 0.96 ± 0.38 mmHg (p-value = 0.011) higher, respectively, than children living in areas with high greenness. These associations were not influenced by environmental stressors (temperature, air pollution, noise annoyance, altitude and urbanisation level). When stratified by study area, associations were significant among children residing in the urbanised Munich area but null for those in the rural Wesel area.
Lower residential greenness was positively associated with higher BP in 10 year-old children living in an urbanised area. Further studies varying in participants’ age, geographical area and urbanisation level are required.
PMCID: PMC4035901  PMID: 24886243
Greenness; NDVI; Blood pressure; Children; Green spaces
20.  Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls 
Human genetics  2013;132(5):579-589.
Recent evidence suggests that inflammation plays a pivotal role in the development of lung cancer. In this study, we used a two-stage approach to investigate associations between genetic variants in inflammation pathways and lung cancer risk based on genome-wide association study (GWAS) data. A total of 7,650 sequence variants from 720 genes relevant to inflammation pathways were identified using keyword and pathway searches from Gene Cards and Gene Ontology databases. In Stage 1, six GWAS datasets from the International Lung Cancer Consortium were pooled (4,441 cases and 5,094 controls of European ancestry), and a hierarchical modeling (HM) approach was used to incorporate prior information for each of the variants into the analysis. The prior matrix was constructed using (1) role of genes in the inflammation and immune pathways; (2) physical properties of the variants including the location of the variants, their conservation scores and amino acid coding; (3) LD with other functional variants and (4) measures of heterogeneity across the studies. HM affected the priority ranking of variants particularly among those having low prior weights, imprecise estimates and/or heterogeneity across studies. In Stage 2, we used an independent NCI lung cancer GWAS study (5,699 cases and 5,818 controls) for in silico replication. We identified one novel variant at the level corrected for multiple comparisons (rs2741354 in EPHX2 at 8q21.1 with p value = 7.4 × 10−6), and confirmed the associations between TERT (rs2736100) and the HLA region and lung cancer risk. HM allows for prior knowledge such as from bioinformatic sources to be incorporated into the analysis systematically, and it represents a complementary analytical approach to the conventional GWAS analysis.
PMCID: PMC3628758  PMID: 23370545
21.  Associations between Traffic Noise, Particulate Air Pollution, Hypertension, and Isolated Systolic Hypertension in Adults: The KORA Study 
Environmental Health Perspectives  2014;122(5):492-498.
Background: Studies on the association between traffic noise and cardiovascular diseases have rarely considered air pollution as a covariate in the analyses. Isolated systolic hypertension has not yet been in the focus of epidemiological noise research.
Methods: The association between traffic noise (road and rail) and the prevalence of hypertension was assessed in two study populations with a total of 4,166 participants 25–74 years of age. Traffic noise (weighted day–night average noise level; LDN) at the facade of the dwellings was derived from noise maps. Annual average PM2.5 mass concentrations at residential addresses were estimated by land-use regression. Hypertension was assessed by blood pressure readings, self-reported doctor-diagnosed hypertension, and antihypertensive drug intake.
Results: In the Greater Augsburg, Germany, study population, traffic noise and air pollution were not associated with hypertension. In the City of Augsburg population (n = 1,893), where the exposure assessment was more detailed, the adjusted odds ratio (OR) for a 10-dB(A) increase in noise was 1.16 (95% CI: 1.00, 1.35), and 1.11 (95% CI: 0.94, 1.30) after additional adjustment for PM2.5. The adjusted OR for a 1-μg/m3 increase in PM2.5 was 1.15 (95% CI: 1.02, 1.30), and 1.11 (95% CI: 0.98, 1.27) after additional adjustment for noise. For isolated systolic hypertension, the fully adjusted OR for noise was 1.43 (95% CI: 1.10, 1.86) and for PM2.5 was 1.08 (95% CI: 0.87, 1.34).
Conclusions: Traffic noise and PM2.5 were both associated with a higher prevalence of hypertension. Mutually adjusted associations with hypertension were positive but no longer statistically significant.
Citation: Babisch W, Wolf K, Petz M, Heinrich J, Cyrys J, Peters A. 2014. Associations between traffic noise, particulate air pollution, hypertension, and isolated systolic hypertension in adults: the KORA Study. Environ Health Perspect 122:492–498;
PMCID: PMC4014763  PMID: 24602804
22.  Genome-wide association study of body mass index in 23,000 individuals with and without asthma 
Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions.
To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals.
In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23,000 individuals with predominantly European descent, of whom 8,165 are asthmatics.
We report associations between several DENND1B variants (p=2.2×10−7 for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2,691 asthmatic children (screening data). The top DENND1B SNPs were next evaluated in seven independent replication data sets comprising 2,014 asthmatics, and rs4915551 was nominally replicated (p<0.05) in two of the seven studies and of borderline significance in one (p=0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, p=0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m2 (p=0.01 for combined screening and replication data sets, N=4,705) per additional G allele of this DENND1B SNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status.
Conclusions and Clinical Relevance
DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.
PMCID: PMC3608930  PMID: 23517042
Association; Asthma; BMI; Genetics; Genome-wide; Obesity
23.  GSTP1 and TNF Gene Variants and Associations between Air Pollution and Incident Childhood Asthma: The Traffic, Asthma and Genetics (TAG) Study 
Environmental Health Perspectives  2014;122(4):418-424.
Background: Genetics may partially explain observed heterogeneity in associations between traffic-related air pollution and incident asthma.
Objective: Our aim was to investigate the impact of gene variants associated with oxidative stress and inflammation on associations between air pollution and incident childhood asthma.
Methods: Traffic-related air pollution, asthma, wheeze, gene variant, and potential confounder data were pooled across six birth cohorts. Parents reported physician-diagnosed asthma and wheeze from birth to 7–8 years of age (confirmed by pediatric allergist in two cohorts). Individual estimates of annual average air pollution [nitrogen dioxide (NO2), particulate matter ≤ 2.5 μm (PM2.5), PM2.5 absorbance, ozone] were assigned to each child’s birth address using land use regression, atmospheric modeling, and ambient monitoring data. Effect modification by variants in GSTP1 (rs1138272/Ala114Val and rs1695/IIe105Val) and TNF (rs1800629/G-308A) was investigated.
Results: Data on asthma, wheeze, potential confounders, at least one SNP of interest, and NO2 were available for 5,115 children. GSTP1 rs1138272 and TNF rs1800629 SNPs were associated with asthma and wheeze, respectively. In relation to air pollution exposure, children with one or more GSTP1 rs1138272 minor allele were at increased risk of current asthma [odds ratio (OR) = 2.59; 95% CI: 1.43, 4.68 per 10 μg/m3 NO2] and ever asthma (OR = 1.64; 95% CI: 1.06, 2.53) compared with homozygous major allele carriers (OR = 0.95; 95% CI: 0.68, 1.32 for current and OR = 1.20; 95% CI: 0.98, 1.48 for ever asthma; Bonferroni-corrected interaction p = 0.04 and 0.01, respectively). Similarly, for GSTP1 rs1695, associations between NO2 and current and ever asthma had ORs of 1.43 (95% CI: 1.03, 1.98) and 1.36 (95% CI: 1.08, 1.70), respectively, for minor allele carriers compared with ORs of 0.82 (95% CI: 0.52, 1.32) and 1.12 (95% CI: 0.84, 1.49) for homozygous major allele carriers (Bonferroni-corrected interaction p-values 0.48 and 0.09). There were no clear differences by TNF genotype.
Conclusions: Children carrying GSTP1 rs1138272 or rs1695 minor alleles may constitute a susceptible population at increased risk of asthma associated with air pollution.
Citation: MacIntyre EA, Brauer M, Melén E, Bauer CP, Bauer M, Berdel D, Bergström A, Brunekreef B, Chan-Yeung M, Klümper C, Fuertes E, Gehring U, Gref A, Heinrich J, Herbarth O, Kerkhof M, Koppelman GH, Kozyrskyj AL, Pershagen G, Postma DS, Thiering E, Tiesler CM, Carlsten C, TAG Study Group. 2014. GSTP1 and TNF gene variants and associations between air pollution and incident childhood asthma: the traffic, asthma and genetics (TAG) Study. Environ Health Perspect 122:418–424;
PMCID: PMC3984232  PMID: 24465030
24.  Pleiotropic Associations of Risk Variants Identified for Other Cancers With Lung Cancer Risk: The PAGE and TRICL Consortia 
Genome-wide association studies have identified hundreds of genetic variants associated with specific cancers. A few of these risk regions have been associated with more than one cancer site; however, a systematic evaluation of the associations between risk variants for other cancers and lung cancer risk has yet to be performed.
We included 18023 patients with lung cancer and 60543 control subjects from two consortia, Population Architecture using Genomics and Epidemiology (PAGE) and Transdisciplinary Research in Cancer of the Lung (TRICL). We examined 165 single-nucleotide polymorphisms (SNPs) that were previously associated with at least one of 16 non–lung cancer sites. Study-specific logistic regression results underwent meta-analysis, and associations were also examined by race/ethnicity, histological cell type, sex, and smoking status. A Bonferroni-corrected P value of 2.5×10–5 was used to assign statistical significance.
The breast cancer SNP LSP1 rs3817198 was associated with an increased risk of lung cancer (odds ratio [OR] = 1.10; 95% confidence interval [CI] = 1.05 to 1.14; P = 2.8×10–6). This association was strongest for women with adenocarcinoma (P = 1.2×10–4) and not statistically significant in men (P = .14) with this cell type (P het by sex = .10). Two glioma risk variants, TERT rs2853676 and CDKN2BAS1 rs4977756, which are located in regions previously associated with lung cancer, were associated with increased risk of adenocarcinoma (OR = 1.16; 95% CI = 1.10 to 1.22; P = 1.1×10–8) and squamous cell carcinoma (OR = 1.13; CI = 1.07 to 1.19; P = 2.5×10–5), respectively.
Our findings demonstrate a novel pleiotropic association between the breast cancer LSP1 risk region marked by variant rs3817198 and lung cancer risk.
PMCID: PMC3982896  PMID: 24681604
25.  Impact of Ambient Air Pollution on the Differential White Blood Cell Count in Patients with Chronic Pulmonary Disease 
Inhalation toxicology  2010;22(3):10.3109/08958370903207274.
Epidemiologic studies report associations between particulate air pollution and increased mortality from pulmonary diseases.To examine whether the exposure to ambient gaseous and particulate air pollution leads to an alteration of the differential white blood cell count in patients with chronic pulmonary diseases like chronic bronchitis, chronic obstructive pulmonary disease, and asthma.
A prospective panel study was conducted in Erfurt, Eastern Germany, with 12 repeated differential white blood cell counts in 38 males with chronic pulmonary diseases. Hourly particulate and gaseous air pollutants and meteorological data were acquired. Mixed models with a random intercept adjusting for trend, meteorology, weekday, and other risk variables were used.
In this explorative analysis we found an immediate decrease of polymorphonuclear leukocytes in response to an increase of most gaseous and particulate pollutants. Lymphocytes increased within 24 hours in association with all gaseous pollutants but showed no effect in regard to particulate air pollution. Monocytes showed an increase associated with ultrafine particles, and nitrogen monoxide. The effect had two peaks in time, one 0-23 hours before blood withdrawal and a second one with a time lag of 48-71 hours.
The increase of particulate and gaseous air pollution was associated with multiple changes in the differential white blood cell count in patients with chronic pulmonary diseases.
PMCID: PMC3877919  PMID: 20064088
air pollution; C-reactive protein; PM10; differential white blood cell count; ultrafine particles

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