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BACKGROUND: Given the profound impact of tuberculosis (TB) on immunity and given murine studies suggesting that infections may influence immunity across generations, we hypothesize that parental TB might impact health and disease in future offspring.OBJECTIVE: This study investigated the impact of maternal and paternal TB on offspring asthma and respiratory symptoms.METHODS: We included data from the third follow-up of the Respiratory Health in Northern Europe study (RHINE). Information on own asthma status, asthma-like symptoms and other respiratory symptoms, as well as information about parental TB and asthma, were collected using standardized questionnaires. The associations between parental TB and RHINE participants' asthma and respiratory symptoms were analyzed using multiple logistic regression, with adjustment for parental education, smoking habits and asthma.RESULTS: Of 8,323 study participants, 227 (2.7%) reported only paternal TB, 282 (3.4%) only maternal TB, and 33 (0.4%) reported that both parents had TB. We found a higher risk of asthma (aOR: 1.29, 95% CI: 1.05-1.57) in offspring with a history of parental TB as compared to offspring without parental TB., Parental TB was significantly associated with allergic asthma in offspring (aOR: 1.58, 95% CI: 1.29-2.05), while no significant association between parental TB and asthma without allergy (aOR: 1.00, 95% CI: 0.76-1.32) in offspring was observed.CONCLUSION: Results from this study indicate that parental TB might be a risk factor for offspring's asthma and respiratory symptoms. We raise the hypothesis that the immunological impact of infections might be transmitted to influence offspring phenotype in humans.

Johanna Heldin,1 Andrei Malinovschi,2 Ane Johannessen,3 Kjell Alving,4 Mathias Holm,5 Karl A Franklin,6 Bertil Forsberg,7 Vivi Schlünssen,8,9 Rain Jögi,10 Thorarinn Gislason,11,12 Bryndis Benediktsdottir,11,12 Cecilie Svanes,3,13 Christer Janson1 1Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 2Department of Medical Sciences: Clinical Physiology, Uppsala University, Uppsala, Sweden; 3Centre for International Health, Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; 4Department of Women’s and Children’s Health, Paediatric Research, Uppsala University, Uppsala, Sweden; 5Occupational and Environmental Medicine, School of Public Health and Community Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; 6Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden; 7Department of Public Health and Clinical Medicine, Section of Sustainable Health, Umeå University, Umeå, Sweden; 8Department of Public Health, Unit for Environment, Occupation and Health, Danish Ramazzini Centre, Aarhus University, Aarhus, Denmark; 9National Research Center for the Working Environment, Copenhagen, Denmark; 10Tartu University Hospital, Lung Clinic, Tartu, Estonia; 11The Medical Faculty, University of Iceland, Reykjavik, Iceland; 12Department of Sleep, Landspitali University Hospital Reykjavik, Reykjavik, Iceland; 13Department of Occupational Medicine, Haukeland University Hospital, Bergen, NorwayCorrespondence: Christer Janson, Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden, Email christer.janson@medsci.uu.seBackground: Although asthma and allergic rhinitis are chronic diseases, some patients experience periods of remission. Information on prognostic factors associated with the remission of asthma and allergic rhinitis is valuable in resource prioritization. This study investigated factors associated with the clinical remission of asthma and allergic rhinitis.Methods: In the Respiratory Health In Northern Europe (RHINE) study, data was collected with questionnaires in stage one (RHINE I, 1989– 1992) and two follow-ups (RHINE II, 1999– 2001 and RHINE III, 2010– 2012) from Sweden, Norway, Denmark, Iceland and Estonia. Clinical remission was defined as having reported asthma or allergic rhinitis in RHINE I or RHINE II but not in RHINE III.Results: Of 13,052 participants, 975 (7.5%) reported asthma in RHINE I or RHINE II, and 3379 (25.9%) allergic rhinitis. Clinical remission of asthma and allergic rhinitis was found in 46.4% and 31.8%, respectively. Living in Estonia (OR (95% CI) 2.44 (1.22– 4.85)) and living in an apartment (1.45 (1.06– 1.98)) were related to remission of asthma, while subjects reporting allergic rhinitis (0.68 (0.51– 0.90)), asthma onset ≤ 12 years of age (0.49 (0.35– 0.68)), receiving treatment with antibiotics for respiratory illness (0.64 (0.47– 0.87)) were less likely to have asthma remission. Factors related to a higher likelihood of remission of allergic rhinitis were no asthma at baseline, age ≥ 58 years in RHINE III, allergic rhinitis onset after 12 years of age, living in rural areas as a child, having only a primary school education and not being pregnant.Conclusion: Clinical remission was found in almost one-half of those with asthma and one-third of persons with allergic rhinitis. Coexisting allergic symptoms were associated with less clinical asthma remission. Age, asthma symptoms and environmental factors in childhood, such as living in a rural area, were found to influence the clinical remission of allergic rhinitis.Keywords: asthma, allergic rhinitis, remission, epidemiology

Mechanistic research suggests that lifestyle and environmental factors impact respiratory health across generations by epigenetic changes transmitted through male germ cells. Evidence from studies on humans is very limited.We investigated multigeneration causal associations to estimate the causal effects of tobacco smoking on lung function within the paternal line. We analysed data from 383 adult offspring (age 18-47 years; 52.0% female) and their 274 fathers, who had participated in the European Community Respiratory Health Survey (ECRHS)/Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) generation study and had provided valid measures of pre-bronchodilator lung function. Two counterfactual-based, multilevel mediation models were developed with: paternal grandmothers' smoking in pregnancy and fathers' smoking initiation in prepuberty as exposures; fathers' forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), or FEV1/FVC z-scores as potential mediators (proxies of unobserved biological mechanisms that are true mediators); and offspring's FEV1 and FVC, or FEV1/FVC z-scores as outcomes. All effects were summarised as differences (Δ) in expected z-scores related to fathers' and grandmothers' smoking history.Fathers' smoking initiation in prepuberty had a negative direct effect on both offspring's FEV1 (Δz-score -0.36, 95% CI -0.63- -0.10) and FVC (-0.50, 95% CI -0.80- -0.20) compared with fathers' never smoking. Paternal grandmothers' smoking in pregnancy had a negative direct effect on fathers' FEV1/FVC (-0.57, 95% CI -1.09- -0.05) and a negative indirect effect on offspring's FEV1/FVC (-0.12, 95% CI -0.21- -0.03) compared with grandmothers' not smoking before fathers' birth nor during fathers' childhood.Fathers' smoking in prepuberty and paternal grandmothers' smoking in pregnancy may cause lower lung function in offspring. Our results support the concept that lifestyle-related exposures during these susceptibility periods influence the health of future generations.

Table S1. Sensitivity, specificity and Cohen’s Kappa estimate of smoking status during offspring’s childhood by sex. (DOCX 14 kb)

Table S2. Sensitivity, specificity and Cohen’s Kappa estimate of smoking status during offspring’s childhood by centre (DOCX 15 kb)

Table S1. Response rates of the offspring population, RHINESSA. Table S2a and 2b. Parameter estimates and 95% confidence intervals for Cohen’s kappa, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for offspring-reported parental asthma and parent- reported offspring asthma, stratified by study centers. Table S3. Parameter estimates and 95% confidence intervals for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for offspring-reported parental asthma and parent-reported offspring asthma, according to timing of parental asthma onset. Table S4. Frequency (absolute and relative) of discrepant asthma reports according to fathers/mothers, and current smoking parents/never-smoking parents. (DOCX 36 kb)

Background: Mothers’ smoking during pregnancy increases asthma risk in their offspring. There is some evidence that grandmothers’ smoking may have a similar effect, and biological plausibility that fathers’ smoking during adolescence may influence offspring’s health through transmittable epigenetic changes in sperm precursor cells. We evaluated the three-generation associations of tobacco smoking with asthma. Methods: Between 2010 and 2013, at the European Community Respiratory Health Survey III clinical interview, 2233 mothers and 1964 fathers from 26 centres reported whether their offspring (aged ≤51 years) had ever had asthma and whether it had coexisted with nasal allergies or not. Mothers and fathers also provided information on their parents’ (grandparents) and their own asthma, education and smoking history. Multilevel mediation models within a multicentre three-generation framework were fitted separately within the maternal (4666 offspring) and paternal (4192 offspring) lines. Results: Fathers’ smoking before they were 15 [relative risk ratio (RRR) = 1.43, 95% confidence interval (CI): 1.01–2.01] and mothers’ smoking during pregnancy (RRR = 1.27, 95% CI: 1.01-1.59) were associated with asthma without nasal allergies in their offspring. Grandmothers’ smoking during pregnancy was associated with asthma in their daughters [odds ratio (OR) = 1.55, 95% CI: 1.17-2.06] and with asthma with nasal allergies in their grandchildren within the maternal line (RRR = 1.25, 95% CI: 1.02-1.55). Conclusions: Fathers’ smoking during early adolescence and grandmothers’ and mothers’ smoking during pregnancy may independently increase asthma risk in offspring. Thus, risk factors for asthma should be sought in both parents and before conception.