Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

Allergic disease trajectories up to adolescence: Characteristics, early-life, and genetic determinants.

BACKGROUND: Allergic diseases often develop jointly during early childhood but differ in timing of onset, remission, and progression. Their disease course over time is often difficult to predict and determinants are not well understood. OBJECTIVES: We aimed to identify trajectories of allergic diseases up to adolescence and to investigate their association with early-life and genetic determinants and clinical characteristics. METHODS: Longitudinal k-means clustering was used to derive trajectories of allergic diseases (asthma, atopic dermatitis, and rhinitis) in two German birth cohorts (GINIplus/LISA). Associations with early-life determinants, polygenic risk scores, food and aeroallergen sensitization, and lung function were estimated by multinomial models. The results were replicated in the independent Swedish BAMSE cohort. RESULTS: Seven allergic disease trajectories were identified: "Intermittently allergic," "rhinitis," "early-resolving dermatitis," "mid-persisting dermatitis," "multimorbid," "persisting dermatitis plus rhinitis," and "early-transient asthma." Family history of allergies was more prevalent in all allergic disease trajectories compared the non-allergic controls with stronger effect sizes for clusters comprising more than one allergic disease (e.g., RRR = 5.0, 95% CI = [3.1-8.0] in the multimorbid versus 1.8 [1.4-2.4] in the mild intermittently allergic cluster). Specific polygenic risk scores for single allergic diseases were significantly associated with their relevant trajectories. The derived trajectories and their association with genetic effects and clinical characteristics showed similar results in BAMSE. CONCLUSION: Seven robust allergic clusters were identified and showed associations with early life and genetic factors as well as clinical characteristics.

Methylation risk scores for childhood aeroallergen sensitization: Results from the LISA birth cohort.

BACKGROUND: Epigenomic (e.g., DNA methylation [DNAm]) changes have been hypothesized as intermediate step linking environmental exposures with allergic disease. Associations between individual DNAm at CpGs and allergic diseases have been reported, but their joint predictive capability is unknown. METHODS: Data were obtained from 240 children of the German LISA cohort. DNAm was measured in blood clots at 6 (N = 234) and 10 years (N = 227) using the Illumina EPIC chip. Presence of aeroallergen sensitization was measured in blood at 6, 10, and 15 years. We calculated six methylation risk scores (MRS) for allergy-related phenotypes, like total and specific IgE, asthma, or any allergies, based on available publications and assessed their performances both cross-sectionally (biomarker) and prospectively (predictor of the disease). Dose-response associations between aeroallergen sensitization and MRS were evaluated. RESULTS: All six allergy-related MRS were highly correlated (r > .86), and seven CpGs were included in more than one MRS. Cross-sectionally, we observed an 81% increased risk for aeroallergen sensitization at 6 years with an increased MRS by one standard deviation (best-performing MRS, 95% confidence interval = [43%; 227%]). Significant associations were also seen cross-sectionally at 10 years and prospectively, though the effect of the latter was attenuated when restricted to participants not sensitized at baseline. A clear dose-response relationship with levels of aeroallergen sensitization could be established cross-sectionally, but not prospectively. CONCLUSION: We found good classification and prediction capabilities of calculated allergy-related MRS cross-sectionally, underlining the relevance of altered gene-regulation in allergic diseases and providing insights into potential DNAm biomarkers of aeroallergen sensitization.

Genome-wide associations for birth weight and correlations with adult disease.

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.

Air pollution and IgE sensitization in 4 European birth cohorts-the MeDALL project.

BACKGROUND: Whether long-term exposure air to pollution has effects on allergic sensitization is controversial. OBJECTIVE: Our aim was to investigate associations of air pollution exposure at birth and at the time of later biosampling with IgE sensitization against common food and inhalant allergens, or specific allergen molecules, in children aged up to 16 years. METHODS: A total of 6163 children from 4 European birth cohorts participating in the Mechanisms of the Development of ALLergy [MeDALL] consortium were included in this meta-analysis of the following studies: Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) (Sweden), Influences of Lifestyle-Related Factors on the Human Immune System and Development of Allergies in Childhood (LISA)/German Infant Study on the Influence of Nutrition Intervention PLUS Environmental and Genetic Influences on Allergy Development (GINIplus) (Germany), and Prevention and Incidence of Asthma and Mite Allergy (PIAMA) (The Netherlands). The following indicators were modeled by land use regression: individual residential outdoor levels of particulate matter with aerodynamic diameters less than 2.5 µm, less than 10 µm, and between 2.5 and 10 µm; PM2.5 absorbance (a measurement of the blackness of PM2.5 filters); and nitrogen oxides levels. Blood samples drawn at ages 4 to 6 (n = 5989), 8 to 10 (n = 6603), and 15 to 16 (n = 5825) years were analyzed for IgE sensitization to allergen extracts by ImmunoCAP. Additionally, IgE against 132 allergen molecules was measured by using the MedALL microarray chip (n = 1021). RESULTS: Air pollution was not consistently associated with IgE sensitization to any common allergen extract up to age 16 years. However, allergen-specific analyses suggested increased risks of sensitization to birch (odds ratio [OR] = 1.12 [95% CI = 1.01-1.25] per 10-µg/m3 increase in NO2 exposure). In a subpopulation with microarray data, IgE to the major timothy grass allergen Phleum pratense 1 (Phl p 1) and the cat allergen Felis domesticus 1 (Fel d 1) greater than 3.5 Immuno Solid-phase Allergen Chip standardized units for detection of IgE antibodies were related to PM2.5 exposure at birth (OR = 3.33 [95% CI = 1.40-7.94] and OR = 4.98 [95% CI = 1.59-15.60], respectively, per 5-µg/m3 increase in exposure). CONCLUSION: Air pollution exposure does not seem to increase the overall risk of allergic sensitization; however, sensitization to birch as well as grass pollen Phl p 1 and cat Fel d 1 allergen molecules may be related to specific pollutants.

A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity.

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.

Consortium-based genome-wide meta-analysis for childhood dental caries traits.

Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from nine contributing centres. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage and the results were combined using fixed-effects meta-analysis. Analysis included up to 19 003 individuals (7530 affected) for primary teeth and 13 353 individuals (5875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth [intronic within ALLC, odds ratio (OR) 0.85, effect allele frequency (EAF) 0.60, P 4.13e-8] and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, P 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low [h2 of 1% (95% CI: 0%: 7%) and 6% (95% CI 0%: 13%) for primary and permanent dentitions, respectively] compared with corresponding within-study estimates [h2 of 28% (95% CI: 9%: 48%) and 17% (95% CI: 2%: 31%)] or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.

A novel whole blood gene expression signature for asthma, dermatitis, and rhinitis multimorbidity in children and adolescents.

BACKGROUND: Allergic diseases often occur in combination (multimorbidity). Human blood transcriptome studies have not addressed multimorbidity. Large-scale gene expression data were combined to retrieve biomarkers and signaling pathways to disentangle allergic multimorbidity phenotypes. METHODS: Integrated transcriptomic analysis was conducted in 1233 participants with a discovery phase using gene expression data (Human Transcriptome Array 2.0) from whole blood of 786 children from three European birth cohorts (MeDALL), and a replication phase using RNA Sequencing data from an independent cohort (EVA-PR, n = 447). Allergic diseases (asthma, atopic dermatitis, rhinitis) were considered as single disease or multimorbidity (at least two diseases), and compared with no disease. RESULTS: Fifty genes were differentially expressed in allergic diseases. Thirty-two were not previously described in allergy. Eight genes were consistently overexpressed in all types of multimorbidity for asthma, dermatitis, and rhinitis (CLC, EMR4P, IL5RA, FRRS1, HRH4, SLC29A1, SIGLEC8, IL1RL1). All genes were replicated the in EVA-PR cohort. RT-qPCR validated the overexpression of selected genes. In MeDALL, 27 genes were differentially expressed in rhinitis alone, but none was significant for asthma or dermatitis alone. The multimorbidity signature was enriched in eosinophil-associated immune response and signal transduction. Protein-protein interaction network analysis identified IL5/JAK/STAT and IL33/ST2/IRAK/TRAF as key signaling pathways in multimorbid diseases. Synergistic effect of multimorbidity on gene expression levels was found. CONCLUSION: A signature of eight genes identifies multimorbidity for asthma, rhinitis, and dermatitis. Our results have clinical and mechanistic implications, and suggest that multimorbidity should be considered differently than allergic diseases occurring alone.

Ambient air pollution and diabetes: A systematic review and meta-analysis.

BACKGROUND: Air pollutants are suggested to be related to type 2 diabetes (T2D). Since several high quality papers on air pollutants and T2D have been published beyond the last reviews, an extended systematic review is highly warranted. We review epidemiological studies to quantify the association between air pollutants and T2D, and to answer if diabetes patients are more vulnerable to air pollutants. METHODS: We systematically reviewed the databases of PubMed and Web of Science based on the guidelines of the Preferred Reporting Items for Systematic review and Meta-analysis (PRISMA). We calculated odds ratios (OR) or hazard ratios (HR) and their 95% confidence intervals (CI) to assess the strength of the associations between air pollutants [e.g., particulate matter with diameter ≤ 2.5 µm (PM2.5), particulate matter with diameter ≤ 10 µm (PM10), and nitrogen dioxide (NO2)] and T2D. We evaluated the quality and risk of bias of the included studies and graded the credibility of the pooled evidence using several recommended tools. We also performed sensitivity analysis, meta-regression analysis, and publication bias test. RESULTS: Out of 716 articles identified, 86 were used for this review and meta-analysis. Meta-analyses showed significant associations of PM2.5 with T2D incidence (11 studies; HR = 1.10, 95% CI = 1.04-1.17 per 10 µg/m3 increment; I2 = 74.4%) and prevalence (11 studies; OR = 1.08; 95% CI = 1.04-1.12 per 10 µg/m3 increment; I2 = 84.3%), of PM10 with T2D prevalence (6 studies; OR = 1.10; 95% CI = 1.03-1.17 per 10 µg/m3 increment; I2 = 89.5%) and incidence (6 studies; HR = 1.11; 95% CI = 1.00-1.22 per µg/m3 increment; I2 = 70.6%), and of NO2 with T2D prevalence (11 studies; OR = 1.07; 95% CI = 1.04-1.11 per 10 µg/m3 increment; I2 = 91.1%). The majority of studies on glucose-homoeostasis markers also showed increased risks with higher air pollutants levels, but the studies were too heterogeneous for meta-analysis. Overall, patients with diabetes might be more vulnerable to PM. CONCLUSIONS: Recent publications strengthened the evidence for adverse effects of ambient air pollutants exposure (especially for PM) on T2D and that diabetic patients might be more vulnerable to air pollutants exposure.

Association of sugar-sweetened drinks with caries in 10- and 15-year-olds.

BACKGROUND: Sugar-sweetened drinks (SSDs) are known to be cariogenic, but this association has not been well investigated in population-based repeated cross-sectional studies in recent years. Therefore, this study examined whether SSD intake is associated with higher caries experience in 10- and 15-year-olds. METHODS: The study sample included participants from the Munich study centre of two birth cohorts with data on non-cavitated caries lesions (NCCL/S), caries experience (DMF/S index), overall caries burden (DMF + NCCL/S) and SSD intake. In total, 915 and 996 children were included from the 10- and 15-year follow-ups, respectively. Intake (g/day) of SSDs, comprising cola, lemonade, ice-tea, sport/energy drinks, fruit squashes and nectars, was calculated from food frequency questionnaires. For analyses, the SSD intake was converted into portions (250 ml/day). Multiple logistic regression and prospective analysis models were performed to test associations between SSD intake and various definitions of caries, adjusting for sex, parental education, body mass index (BMI) categories, study cohort, plaque-affected sextants, mode of SSD consumption, energy content of SSDs, and total energy intake. RESULTS: The mean overall caries burden at 10 and 15 years of age was 1.81 (SD: 2.71) and 6.04 (SD: 8.13), respectively. The average consumption of SSDs at the 10- and 15-year follow-ups was 0.48 (SD: 0.85) and 0.83 (SD 1.40) portions/day, respectively. After adjusting for confounders, in 10-year-olds, SSD intake was significantly associated with higher caries experience based on the indices DMF/S (adjusted odds ratio: 1.29; 95% CI: 1.06-1.57), NCCL/S (1.24; 1.03-1.49) and DMF + NCCL/S (1.27; 1.05-1.55). At the 15-year follow-up, SSD consumption was significantly associated with increased DMF/S index (1.12; 1.01-1.25) only. Prospective model associating 10-year SSD intake with 15-year caries experience was not significant. CONCLUSIONS: SSD intake significantly increases the caries burden in 10-year-olds, with attenuated effects in 15-year-olds. To prevent caries, SSD consumption should be reduced, especially in children and adolescents.

A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways.

More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N = 5758) followed by replication (N = 3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.

Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.

Maternal smoking during pregnancy and offspring overweight: is there a dose-response relationship? An individual patient data meta-analysis.

BACKGROUND/OBJECTIVES: A number of meta-analyses suggest an association between any maternal smoking in pregnancy and offspring overweight obesity. Whether there is a dose-response relationship across number of cigarettes and whether this differs by sex remains unclear. SUBJECT/METHODS: Studies reporting number of cigarettes smoked during pregnancy and offspring BMI published up to May 2015 were searched. An individual patient data meta-analysis of association between the number of cigarettes smoked during pregnancy and offspring overweight (defined according to the International Obesity Task Force reference) was computed using a generalized additive mixed model with non-linear effects and adjustment for confounders (maternal weight status, breastfeeding, and maternal education) and stratification for sex. RESULTS: Of 26 identified studies, 16 authors provided data on a total of 238,340 mother-child-pairs. A linear positive association was observed between the number of cigarettes smoked and offspring overweight for up to 15 cigarettes per day with an OR increase per cigarette of 1.03, 95% CI = [1.02-1.03]. The OR flattened with higher cigarette use. Associations were similar in males and females. Sensitivity analyses supported these results. CONCLUSIONS: A linear dose-response relationship of maternal smoking was observed in the range of 1-15 cigarettes per day equally in boys and girls with no further risk increase for doses above 15 cigarettes.

A novel common variant in DCST2 is associated with length in early life and height in adulthood.

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; ß = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

Higher serum 25(OH)D concentrations are associated with improved FEV1 and FVC in adolescence.

Vitamin D plays a role in the development of the immune system and the lung, as well as in airway remodelling. Therefore, this study investigated the association between serum 25-hydroxyvitamin D (25(OH)D) concentrations and spirometric lung function parameters at age 15 years.In the German birth cohorts GINIplus and LISAplus, lung function testing by spirometry and 25(OH)D measurements were performed during the 15-year follow-up examinations. Valid lung function measurements pre- and/or post-bronchodilation and serum 25(OH)D concentrations, which were adjusted for the date of blood sampling to account for seasonal variability, were available for 2607 adolescents. Associations between 25(OH)D concentrations and spirometric parameters were analysed using generalised additive models adjusted for confounding factors.Serum 25(OH)D concentrations were significantly associated with forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC measured before bronchodilation after adjustment for potential confounders: FEV1 increased by 10 mL (95% CI 2-17), FVC by 20 mL (95% CI 12-28) and FEV1/FVC decreased by 0.177% (95% CI -0.286 to -0.067) per 10 nmol·L-1 increase in 25(OH)D concentrations. Flow rates (forced expiratory flow rates at 25, 50 and 75% of exhaled FVC (FEF25, FEF50, FEF75) and mean flow rate between 25 and 75% of FVC (FEF25-75)) were not associated with vitamin D. Similar associations were observed for lung function parameters measured after bronchodilation.Vitamin D concentrations are positively associated with volume-related lung function parameters pre- and post-bronchodilation, suggesting structural changes in peripheral airways.

Gingivitis and lifestyle influences on high-sensitivity C-reactive protein and interleukin 6 in adolescents.

AIM: This cross-sectional study was repeated at two time points and investigated the influence of gingivitis, smoking and body mass index (BMI) on the systemic inflammatory markers high-sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL6) in 10- and 15-year-olds. MATERIALS AND METHODS: The study sample of two birth cohorts, i.e. GINIplus and LISAplus, from the Munich centre consisted of 806 and 846 subjects who were evaluated at 10- and 15-year follow-ups respectively. Children and their parents completed questionnaires on participant-related lifestyle information. Gingivitis was measured at the sextant level using a simplified sulcus-bleeding index. Serum hs-CRP and IL6 levels were obtained from blood samples. Multiple logistic regressions adjusting for lifestyle-related factors and other confounders were performed to assess associations between the specified variables. RESULTS: There were no associations between gingivitis and the inflammatory markers hs-CRP and IL6 in 10-year-olds. In 15-year-olds, gingivitis (aOR: 2.17; 95% CI: 1.25-3.77); daily smoking (aOR: 6.27; 95% CI: 1.39-28.39); and being overweight/obese (aOR: 4.95; 95% CI: 0.73-33.68) were identified as significantly influencing factors for elevated hs-CRP values. Oral hygiene did not influence hs-CRP. CONCLUSION: In this study, hs-CRP was positively associated with gingivitis, smoking daily and overweight/obesity among 15-year-olds.

Fluoride/vitamin D tablet supplementation in infants-effects on dental health after 10 years.

OBJECTIVE: We examined whether fluoride/vitamin D supplementation in the first year of life is associated with caries or molar incisor hypomineralization (MIH) at 10 years of age. METHODS: The study population consisted of 406 children for whom information on fluoride/vitamin D supplementation during the first year of life was available. Dental examination at the age of 10 included caries and MIH registration. The results of logistic regression models were adjusted for gender, age, BMI, parental education, and equivalent income. RESULTS: Children receiving supplementation during the entire first year of life had a significantly lower probability of having caries-related restorations in primary teeth in comparison to those who received supplementation for less than 6 months (fluoride supplementation: odds ratio (OR) for d3-4mfs 2.47 (1.32-4.63), for fs 2.70 (1.43-5.10); vitamin D supplementation: OR for d3-4mfs 2.08 (1.00-4.32), fs 2.50 (1.19-5.25)). The majority of logistic regression analyses indicated no association between supplementation and MIH. CONCLUSIONS: It was found a consistent significant caries-preventive effect in the primary dentition of children who received fluoride (256/372)/vitamin D supplementation (274/376) in all 12 months over the first year of life; no effects were observed for permanent dentition. The high parental interest in supplementation is linked to an imbalance of the study groups. Furthermore, tooth brushing frequency, use of fluoride toothpastes and/or other oral hygiene products were not recorded during the observation period which may also confound the results. CLINICAL RELEVANCE: Fluoride/vitamin D supplementation can be used in children for preventing caries in the primary dentition.

A genome-wide approach to children's aggressive behavior: The EAGLE consortium.

Individual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest sample exploring children's aggressive behavior to date (N = 18,988), with measures in two developmental stages (N = 15,668 early childhood and N = 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children's aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed sample and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total sample. GCTA quantified variance tagged by common SNPs (10-54%). The meta-analysis of the total sample identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P = 5.30 × 10(-8) ). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning. © 2015 Wiley Periodicals, Inc.

Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity.

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.

Early exposure to bio-contaminants and asthma up to 10 years of age: results of the HITEA study.

Inverse associations have been found between exposure to bio-contaminants and asthma and allergies. The aim of this study was to prospectively assess whether early exposure to bio-contaminants in dust is associated with asthma and allergy later in childhood among children from (sub)-urban areas. In subsets of three European birth cohorts (PIAMA: n=553; INMA: n=481; and LISAplus: n=395), endotoxin, (1,3,)-ß-d-glucan and extracellular polysaccharide were measured in dust from living rooms shortly after birth. Current asthma at 6 years and 10 years of age and ever asthma up to 10 years of age were assessed by parental questionnaires. Specific IgE levels at 8 years (PIAMA) and 10 years (LISAplus) were available. Adjusted, cohort-specific logistic regression analyses were performed. Higher endotoxin concentrations were positively associated with current asthma at 6 years of age in PIAMA (adjusted OR 1.96, 95% CI 1.07-3.58), but were inversely related with ever asthma up to 10 years of age in INMA (adjusted OR 0.39, 95% CI 0.16-0.94). No associations with asthma were found for LISAplus. No associations were observed with atopic sensitisation in all cohorts. All associations with (1,3)-ß-d-glucan and extracellular polysaccharide were statistically nonsignificant. The suggested immunological mechanisms of early exposure to bio-contaminants with regards to asthma and allergy might be different for children growing up in (sub)-urban environments.