Cohort profile: the multigeneration Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) cohort

Purpose: The Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) cohort was established to (1) investigate how exposures before conception and in previous generations influence health and disease, particularly allergies and respiratory health, (2) identify susceptible time windows and (3) explore underlying mechanisms. The ultimate aim is to facilitate efficient intervention strategies targeting multiple generations. Participants: RHINESSA includes study participants of multiple generations from ten study centres in Norway (1), Denmark (1), Sweden (3), Iceland (1), Estonia (1), Spain (2) and Australia (1). The RHINESSA core cohort, adult offspring generation 3 (G3), was first investigated in 2014-17 in a questionnaire study (N=8818, age 18-53 years) and a clinical study (subsample, n=1405). Their G2 parents participated in the population-based cohorts, European Community Respiratory Heath Survey and Respiratory Health In Northern Europe, followed since the early 1990s when they were 20-44 years old, at 8-10 years intervals. Study protocols are harmonised across generations. Findings to date Collected data include spirometry, skin prick tests, exhaled nitric oxide, anthropometrics, bioimpedance, blood pressure; questionnaire/interview data on respiratory/ general/reproductive health, indoor/outdoor environment, smoking, occupation, general characteristics and lifestyle; biobanked blood, urine, gingival fluid, skin swabs; measured specific and total IgE, DNA methylation, sex hormones and oral microbiome. Research results: suggest that parental environment years before conception, in particular, father’s exposures such as smoking and overweight, may be of key importance for asthma and lung function, and that there is an important susceptibility window in male prepuberty. Statistical analyses developed to approach causal inference suggest that these associations may be causal. DNA methylation studies suggest a mechanism for transfer of father’s exposures to offspring health and disease through impact on offspring DNA methylation. Future plans: Follow-up is planned at 5–8 years intervals, first in 2021-2023. Linkage with health registries contributes to follow-up of the cohort.Coordination of the RHINESSA study has received funding from the Research Council of Norway (Grants No. 274767, 214123, 228174, 230 827 and 273838), ERC StG project BRuSH #804199, the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 633 212 (the ALEC Study WP2), the Bergen Medical Research Foundation, and the Western Norwegian Regional Health Authorities (Grants No. 912011, 911 892 and 911631). Study centres have further received local funding from the following: Bergen: the above grants for study establishment and co- ordination, and, in addition, World University Network (REF and Sustainability grants), Norwegian Labour Inspection, the Norwegian Asthma and Allergy Association and Trond Mohn Foundation (Grant ID BFS2017TMT02). Albacete and Huelva: Sociedad Española de Patología Respiratoria (SEPAR) Fondo de Investigación Sanitaria (FIS PS09). Gøteborg, Umeå and Uppsala: the Swedish Heart and Lung Foundation, the Swedish Asthma and Allergy Association. Reykjavik: Iceland University. Melbourne: Australian National Health and Medical Research Council (NHMRC) Project Grant ID1128450. Tartu: the Estonian Research Council (Grant No. PUT562). Århus: The Danish Wood Foundation (Grant No. 444508795), the Danish Working Environment Authority (Grant No. 20150067134), Aarhus University (PhD scholarship).The RHINE study received funding by Norwegian Research Council, Norwegian Asthma and Allergy Association, Danish Lung Association, Swedish Heart and Lung Foundation, Vårdal Foundation for Health CareHealthcare Science and Allergy Research, Swedish Asthma and Allergy Association, Icelandic Research Council, and Estonian Science Foundation. The RHINE IV ongoing study has received funding from the Research Council of Norway project Life- GAP grant No. 300 765.Co- ordination of the ECRHS study has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 633 212 (the ALEC study), the Medical Research Council (ECRHS III) and the European Commission FP5 and FP7 (ECRHS I and II). The ECRHS IV ongoing study in the ten RHINESSA study centres has received funding from the European Union’s Horizon 2020 research and innovation programme projects EPHOR under grant agreement No. 874 703 and European Research Council (ERC) project BRuSH under grant agreement No. 804199, and from the Research Council of Norway grant No. 273 838. Funding agencies for ECRHS I, II and III are reported in online supplement.Coordination of the RHINESSA study has received funding from the Research Council of Norway (Grants No. 274767, 214123, 228174, 230 827 and 273838), ERC StG project BRuSH #804199, the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 633 212 (the ALEC Study WP2), the Bergen Medical Research Foundation, and the Western Norwegian Regional Health Authorities (Grants No. 912011, 911 892 and 911631). Study centres have further received local funding from the following: Bergen: the above grants for study establishment and co-ordination, and, in addition, World University Network (REF and Sustainability grants), Norwegian Labour Inspection, the Norwegian Asthma and Allergy Association and Trond Mohn Foundation (Grant ID BFS2017TMT02). Albacete and Huelva: Sociedad Española de Patología Respiratoria (SEPAR) Fondo de Investigación Sanitaria (FIS PS09). Gøteborg, Umeå and Uppsala: the Swedish Heart and Lung Foundation, the Swedish Asthma and Allergy Association. Reykjavik: Iceland University. Melbourne: Australian National Health and Medical Research Council (NHMRC) Project Grant ID1128450. Tartu: the Estonian Research Council (Grant No. PUT562). Århus: The Danish Wood Foundation (Grant No. 444508795), the Danish Working Environment Authority (Grant No. 20150067134), Aarhus University (PhD scholarship).The RHINE study received funding by Norwegian Research Council, Norwegian Asthma and Allergy Association, Danish Lung Association, Swedish Heart and Lung Foundation, Vårdal Foundation for Health CareHealthcare Science and Allergy Research, Swedish Asthma and Allergy Association, Icelandic Research Council, and Estonian Science Foundation. The RHINE IV ongoing study has received funding from the Research Council of Norway project Life-GAP grant No. 300 765.Co-ordination of the ECRHS study has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 633 212 (the ALEC study), the Medical Research Council (ECRHS III) and the European Commission FP5 and FP7 (ECRHS I and II). The ECRHS IV ongoing study in the ten RHINESSA study centres has received funding from the European Union’s Horizon 2020 research and innovation programme projects EPHOR under grant agreement No. 874 703 and European Research Council (ERC) project BRuSH under grant agreement No. 804199, and from the Research Council of Norway grant No. 273 838. Funding agencies for ECRHS I, II and III are reported in online supplement

Transgenerational and intergenerational epigenetic inheritance in allergic diseases

It has become clear that early life (including in utero exposures) is a key window of vulnerability during which environmental exposures can alter developmental trajectories and initiate allergic disease development. However, recent evidence suggests that there might be additional windows of vulnerability to environmental exposures in the parental generation before conception or even in previous generations. There is evidence suggesting that information of prior exposures can be transferred across generations, and experimental animal models suggest that such transmission can be conveyed through epigenetic mechanisms. Although the molecular mechanisms of intergenerational and transgenerationational epigenetic transmission have yet to be determined, the realization that environment before conception can alter the risks of allergic diseases has profound implications for the development of public health interventions to prevent disease. Future research in both experimental models and in multigenerational human cohorts is needed to better understand the role of intergenerational and transgenerational effects in patients with asthma and allergic disease. This will provide the knowledge basis for a new approach to efficient intervention strategies aimed at reducing the major public health challenge of these conditions.publishedVersio

Airway symptoms and lung function in the local population after the oil tank explosion in Gulen, Norway

Background: Oil tanks containing a mixture of hydrocarbons, including sulphuric compounds, exploded and caught fire in an industrial harbour. This study assesses airway symptoms and lung function in the nearby population 1½ years after the explosion. Methods: A cross-sectional study included individuals ≥18 years old. Individuals living 20 km away formed a control group. A questionnaire and spirometry tests were completed by 223 exposed individuals (response rate men 70%, women 75%) and 179 control individuals (response rate men 51%, women 65%). Regression analyses included adjustment for smoking, occupational exposure, atopy, infection in the preceding month and age. Analyses of symptoms were also adjusted for stress reactions related to the accident. Results: Exposed individuals experienced significantly more blocked nose (odds ratio 1.7 [95% confidence interval 1.0, 2.8]), rhinorrhoea (1.6 [1.1, 3.3]), nose irritation (3.4 [2.0, 5.9]), sore throat (3.1 [1.8, 5.5]), morning cough (3.5 [2.0, 5.5]), daily cough (2.2 [1.4, 3.7]), cough >3 months a year (2.9 [1.5, 5.3]) and cough with phlegm (1.9 [1.2, 3.1]) than control individuals. A significantly increasing trend was found for nose symptoms and cough, depending on the proximity of home address to explosion site (daily cough, 3-6km 1.8 [1.0, 3.1], <3km 3.0 [1.7, 6.4]). Lung function measurements were significantly lower in the exposed group than in the control group, FEV1 adjusted mean difference −123 mL [95% confidence interval −232, -14]), FEV1% predicted −2.5 [−5.5, 0.5], FVC −173 mL [− 297, -50], FVC% predicted −3.1 [− 5.9, -0.4], and airway obstruction (GOLD II/III). Conclusions: Based on cross sectional analyses, individuals living in an area with air pollution from an oil tank explosion had more airway symptoms and lower lung function than a control group 1½ years after the incident

Airway symptoms and lung function in the local population after the oil tank explosion in Gulen, Norway

Background: Oil tanks containing a mixture of hydrocarbons, including sulphuric compounds, exploded and caught fire in an industrial harbour. This study assesses airway symptoms and lung function in the nearby population 1½ years after the explosion. Methods: A cross-sectional study included individuals ≥18 years old. Individuals living 20 km away formed a control group. A questionnaire and spirometry tests were completed by 223 exposed individuals (response rate men 70%, women 75%) and 179 control individuals (response rate men 51%, women 65%). Regression analyses included adjustment for smoking, occupational exposure, atopy, infection in the preceding month and age. Analyses of symptoms were also adjusted for stress reactions related to the accident. Results: Exposed individuals experienced significantly more blocked nose (odds ratio 1.7 [95% confidence interval 1.0, 2.8]), rhinorrhoea (1.6 [1.1, 3.3]), nose irritation (3.4 [2.0, 5.9]), sore throat (3.1 [1.8, 5.5]), morning cough (3.5 [2.0, 5.5]), daily cough (2.2 [1.4, 3.7]), cough >3 months a year (2.9 [1.5, 5.3]) and cough with phlegm (1.9 [1.2, 3.1]) than control individuals. A significantly increasing trend was found for nose symptoms and cough, depending on the proximity of home address to explosion site (daily cough, 3-6km 1.8 [1.0, 3.1], <3km 3.0 [1.7, 6.4]). Lung function measurements were significantly lower in the exposed group than in the control group, FEV1 adjusted mean difference −123 mL [95% confidence interval −232, -14]), FEV1% predicted −2.5 [−5.5, 0.5], FVC −173 mL [− 297, -50], FVC% predicted −3.1 [− 5.9, -0.4], and airway obstruction (GOLD II/III). Conclusions: Based on cross sectional analyses, individuals living in an area with air pollution from an oil tank explosion had more airway symptoms and lower lung function than a control group 1½ years after the incident.publishedVersio

Exposure to environmental phenols and parabens, and relation to body mass index, eczema and respiratory outcomes in the Norwegian RHINESSA study

Background Many phenols and parabens are applied in cosmetics, pharmaceuticals and food, to prevent growth of bacteria and fungi. Whether these chemicals affect inflammatory diseases like allergies and overweight is largely unexplored. We aimed to assess the associations of use of personal care products with urine biomarkers levels of phenols and paraben exposure, and whether urine levels (reflecting body burden of this chemical exposures) are associated with eczema, rhinitis, asthma, specific IgE and body mass index. Methods Demographics, clinical variables, and self-report of personal care products use along with urine samples were collected concurrently from 496 adults (48% females, median age: 28 years) and 90 adolescents (10–17 years of age) from the RHINESSA study in Bergen, Norway. Urine biomarkers of triclosan (TCS), triclocarban (TCC), parabens and benzophenone-3, bisphenols and dichlorophenols (DCP) were quantified by mass spectrometry. Results Detection of the urine biomarkers varied according to chemical type and demographics. TCC was detected in 5% of adults and in 45% of adolescents, while propyl (PPB) and methyl (MPB) parabens were detected in 95% of adults and in 94% (PPB) and 99% (MPB) of adolescents. Women had higher median urine concentrations of phenolic chemicals and reported a higher frequency of use of personal care products than men. Urine concentration of MPB increased in a dose-dependent manner with increased frequency of use of several cosmetic products. Overall, urinary biomarker levels of parabens were lower in those with current eczema. The biomarker concentrations of bisphenol S was higher in participants with positive specific IgE and females with current asthma, but did not differ by eczema or rhinitis status. MPB, ethylparaben (EPB), 2,4-DCP and TCS were inversely related to BMI in adults; interaction by gender were not significant. Conclusions Reported frequency of use of personal care products correlated very well with urine biomarker levels of paraben and phenols. Several chemicals were inversley related to BMI, and lower levels of parabens was observed for participants with current eczema. There is a need for further studies of health effects of chemicals from personal care products, in particular in longitudinally designed studies.publishedVersio

Association of oral bacteria with oral hygiene habits and self-reported gingival bleeding

Aim To describe associations of gingival bacterial composition and diversity with self-reported gingival bleeding and oral hygiene habits in a Norwegian regional-based population. Materials and Methods We examined the microbiome composition of the gingival fluid (16S amplicon sequencing) in 484 adult participants (47% females; median age 28 years) in the Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) study in Bergen, Norway. We explored bacterial diversity and abundance differences by the community periodontal index score, self-reported frequency of gingival bleeding, and oral hygiene habits. Results Gingival bacterial diversity increased with increasing frequency of self-reported gingival bleeding, with higher Shannon diversity index for “always” β = 0.51 and “often” β = 0.75 (p < .001) compared to “never” gingival bleeding. Frequent gingival bleeding was associated with higher abundance of several bacteria such as Porphyromonas endodontalis, Treponema denticola, and Fretibacterium spp., but lower abundance of bacteria within the gram-positive phyla Firmicutes and Actinobacteria. Flossing and rinsing with mouthwash twice daily were associated with higher total abundance of bacteria in the Proteobacteria phylum but with lower bacterial diversity compared to those who never flossed or never used mouthwash. Conclusions A high frequency of self-reported gingival bleeding was associated with higher bacterial diversity than found in participants reporting no gingival bleeding and with higher total abundance of known periodontal pathogens such as Porphyromonas spp., Treponema spp., and Bacteroides spp.publishedVersio

Epigenome-wide association of father's smoking with offspring DNA methylation: a hypothesis-generating study

Epidemiological studies suggest that father’s smoking might influence their future children’s health, but few studies have addressed whether paternal line effects might be related to altered DNA methylation patterns in the offspring. To investigate a potential association between fathers’ smoking exposures and offspring DNA methylation using epigenome-wide association studies. We used data from 195 males and females (11–54 years) participating in two population-based cohorts. DNA methylation was quantified in whole blood using Illumina Infinium MethylationEPIC Beadchip. Comb-p was used to analyse differentially methylated regions (DMRs). Robust multivariate linear models, adjusted for personal/maternal smoking and cell-type proportion, were used to analyse offspring differentially associated probes (DMPs) related to paternal smoking. In sensitivity analyses, we adjusted for socio-economic position and clustering by family. Adjustment for inflation was based on estimation of the empirical null distribution in BACON. Enrichment and pathway analyses were performed on genes annotated to cytosine-phosphate-guanine (CpG) sites using the gometh function in missMethyl. We identified six significant DMRs (Sidak-corrected P values: 0.0006–0.0173), associated with paternal smoking, annotated to genes involved in innate and adaptive immunity, fatty acid synthesis, development and function of neuronal systems and cellular processes. DMP analysis identified 33 CpGs [false discovery rate (FDR)  < 0.05]. Following adjustment for genomic control (λ = 1.462), no DMPs remained epigenome-wide significant (FDR < 0.05). This hypothesis-generating study found that fathers’ smoking was associated with differential methylation in their adolescent and adult offspring. Future studies are needed to explore the intriguing hypothesis that fathers’ exposures might persistently modify their future offspring’s epigenome.publishedVersio

Prevalence of allergic sensitization to storage mites in Northern Europe.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadBACKGROUND: Allergic sensitization to storage mites has mostly been related to occupational exposures like farming, grain/cattle handling, whereas for non-occupational settings, storage mite sensitization has been attributed to cross-reactivity with house dust mite (HDM) allergens. OBJECTIVE: We aimed to describe the prevalence of allergic sensitization to storage mites, co-sensitization to HDM allergens and respiratory symptoms in Denmark, Iceland, Norway and Sweden. METHODS: The population comprised of 1180 participants born 1945-1972 of the third follow-up of the population-based cohort European Community Respiratory Health Survey (ECRHS) in Aarhus, Bergen, Reykjavik and Uppsala. A clinical examination included skin prick tests (SPT) to Lepidoglyphus destructor, Tyrophagus putrescentiae, Acarus siro and common inhalant allergens, as well as standardized interviews. RESULTS: 8% were sensitized to HDM and 10% to storage mite, with some variation by study centre: Reykjavik 13%, Bergen 8% and Aarhus 7%. In Uppsala, only L destructor (3%) was measured. Storage mite sensitization was higher among men (11%) than women (8%). Among storage mite sensitized, 44% were also sensitized to HDM. Storage mite sensitization was associated with asthma and nasal allergies, but not with age, education, pet keeping or place of upbringing. CONCLUSIONS AND CLINICAL RELEVANCE: In this Northern European population-based study, allergic sensitization to storage mite was as common as HDM sensitization. Storage mite sensitization was, independently of HDM sensitization, associated with respiratory symptoms and asthma. Our findings suggest that storage mite sensitization should be evaluated with regard to inclusion into the common inhalant allergen panel in Northern Europe.Landspitali University Hospital Research Fund University of Iceland Research Fund ResMed Foundation, California, USA Orkuveita Reykjavikur (Geothermal plant) Vegageroin (The Icelandic Road Administration (ICERA)) Swedish Heart-Lung Foundation Swedish Asthma and Allergy Association Swedish Association against Lung and Heart Disease Swedish Research Council for health, working life and welfare (FORTE) Research Council of Norway Western Norway Regional Health Authorities grant Bergen Medical Research Foundation Faculty of Health, Aarhus University Wood Dust Foundatio

Associations of preconception exposure to air pollution and greenness with offspring asthma and hay fever

We investigated if greenness and air pollution exposure in parents’ childhood affect offspring asthma and hay fever, and if effects were mediated through parental asthma, pregnancy greenness/pollution exposure, and offspring exposure. We analysed 1106 parents with 1949 offspring (mean age 35 and 6) from the Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) generation study. Mean particulate matter (PM2.5 and PM10), nitrogen dioxide (NO2), black carbon (BC), ozone (O3) (µg/m3) and greenness (normalized difference vegetation index (NDVI)) were calculated for parents 0-18 years old and offspring 0-10 years old, and were categorised in tertiles. We performed logistic regression and mediation analyses for two-pollutant models (clustered by family and centre, stratified by parental lines, and adjusted for grandparental asthma and education). Maternal medium PM2.5 and PM10 exposure was associated with higher offspring asthma risk (odds ratio (OR) 2.23, 95%CI 1.32-3.78, OR 2.27, 95%CI 1.36-3.80), and paternal high BC exposure with lower asthma risk (OR 0.31, 95%CI 0.11-0.87). Hay fever risk increased for offspring of fathers with medium O3 exposure (OR 4.15, 95%CI 1.28-13.50) and mothers with high PM10 exposure (OR 2.66, 95%CI 1.19-5.91). The effect of maternal PM10 exposure on offspring asthma was direct, while for hay fever, it was mediated through exposures in pregnancy and offspring’s own exposures. Paternal O3 exposure had a direct effect on offspring hay fever. To conclude, parental exposure to air pollution appears to influence the risk of asthma and allergies in future offspring