Transmitted and acquired determinants for childhood asthma : from genes to teens

The interplay between genetic and environmental factors is central to childhood asthma and allergic disease. Transmitted and acquired risk factors collaborate to produce the phenotypic variation of a trait within the population. In this work, we have employed studies of twins to illustrate the relationship between twinship itself, early growth, and genetic and epigenetic factors with childhood asthma. Twins have been suggested to be a high risk group for asthma. Study I was a large population-based register study of twinship in itself as a risk factor for childhood asthma. Asthma diagnoses and medication use among Swedish twins and singletons born 1993-2001 and 2005-2009 were compared before and after controlling for birth weight and gestational age. In the younger group, twins were at higher risk of developing asthma before controlling for perinatal factors – afterwards, twins were at lower risk of asthma in both age groups. This suggests that important mechanisms for asthma are shared between twins and singletons. Low birth weight and rapid early growth have been shown to increase the risk of asthma. The aim of Study II was to describe the association between early growth and asthma in twins. Height and weight from 0 to 3 years of age were modelled in 2,874 twins. There was an association between later timing of maximum growth velocity and asthma both in terms of weight and height, although this relationship did not remain after controlling for birth weight or gestational age, which indicates that early postnatal growth may primarily be of interest as an extension of preceding foetal growth. There is significant comorbidity between asthma and other allergic diseases. In Study III, we studied the influence of genetic factors on childhood asthma, hay fever, atopic eczema and food allergy. Using twin models and data from 25,306 twins, we concluded that asthma and all of the other allergic phenotypes were highly influenced by additive genetic effects. A preselected set of high-risk genetic variants were primarily associated with asthma or both asthma and hay fever (rs3771180 in IL1RL1). Epigenetic factors have been suggested as a potential explanation for disease discordance within identical twin pairs. In Study IV, we analysed DNA methylation in whole blood of 708 twins with and without asthma using the Illumina 450k Beadchip. On the group level, 340 CpG sites were significantly associated with current asthma at 9-14 years of age, but these associations were not replicated within asthma-discordant pairs. Confounding by genetic factors or cell type composition in the samples seemed to be of importance, and should be considered as influences of potential importance in future epigenetic studies. In conclusion, the work described in this thesis has combined the unique qualities of twin studies with data from population-based registers, interviews, and clinical examinations. The influences of transmitted (genetic) and acquired (twinship, early growth, and epigenetics) on childhood asthma were evaluated. From this selection, the transmitted factors proved to be of most importance to childhood asthma

Twins' risk of childhood asthma mediated by gestational age and birthweight

Background: Children born with low gestational age (GA) or low birth weight (BW) are at increased risk of asthma. Twins as compared to singletons are on average more likely to be born with lower GA and BW, and have been hypothesized to comprise a high risk population for asthma. Many previous studies have not accounted for potential confounders or mediators. Objective: To investigate the association between twinship and childhood asthma or early life wheeze and identify potential mediators, such as GA/BW. Methods: The study population consisted of two cohorts including all children born in Sweden from January 1st 1993 to June 1st 2001 (n=756,363 singletons, n=22,478 twins) and July 1st 2005 to December 31st 2009 (n=456,239 singletons, n=12,872 twins). Asthma was defined using validated register-based outcomes of diagnosis or medication. The data were analysed using logistic (older cohort) and Cox regression (younger cohort). Adjusted models incorporated potential confounding or mediating factors including gestational age and birth weight. Results: In the younger cohort, the crude hazard ratio (HR) of asthma medication after 1.5 years of age was 1.12 (95% CI 1.01-1.23), and fully adjusted HR 0.80, 95% CI 0.72-0.89. Crude HR of asthma diagnosis in the same age group was 1.14 (95% CI 0.99-1.30), fully adjusted 0.78 (0.68-0.98). Adjusted analyses in the older group yielded similar results. Conclusions: Twins were at significantly higher unadjusted risk of asthma or early life wheeze compared to singletons in the younger, but not in the older cohort. Associations attenuated following adjustment for GA/BW suggesting that GA/BW mediates the effect of twinship on asthma risk. After adjustments twins were at lower risk of asthma outcomes, possibly due to unmeasured confounding.NonePublishe

Association between parental age and asthma in a population-based register study

In a nationwide population-based study with family design, we found an association between decreasing parental age and asthma in early childhood. The effect was independent of familial and potentially confounding factors.NoneAccepte

Cohort profile : Swedish Twin Study on Prediction and Prevention of Asthma (STOPPA)

Asthma is a common childhood disease and several risk factors have been identified, however the impact of genes and environment is not fully understood. The aim of the Swedish Twin study On Prediction and Prevention of Asthma (STOPPA) is to identify environmental (birth characteristics and early life) and genetic (including epigenetic) factors as determinants for asthmatic disease. Based on the Child and Adolescent Twin Study in Sweden (parental interview at 9 or 12 years, N~23,900) and an asthma and/or wheezing algorithm, we identified a sample of monozygotic (MZ) and dizygotic (DZ) same-sexed twin pairs. The twin pairs were identified as asthma concordant (ACC), asthma discordant (ADC) and healthy concordant (HCC). A sample of 9- to 14-year-old twins and their parents were invited to participate in a clinical examination. Background characteristics were collected in questionnaires and obtained from the National Health Registers. A clinical examination was performed to test lung function and capacity (spirometry with reversibility test and exhaled nitric oxide) and collect blood (serology and DNA), urine (metabolites), feces (microbiota) and saliva (cortisol). In total, 376 twin pairs (752 individual twins) completed the study, response rate 52%. All participating twins answered the questionnaire and >90% participated in lung function testing, blood and saliva sampling. This article describes the design, recruitment, data collection, measures, background characteristics as well as ongoing and planned analyses in STOPPA. Potential gains of the study include the identification of biomarkers, the emergence of candidates for drug development and new leads for prevention of asthma and allergic disease.NonePublishe

Limited association between markers of stress during pregnancy and fetal growth in “Born into Life”, a new prospective birth cohort

AIMS: We aimed to investigate the associations between perceived maternal stress or salivary cortisol levels during pregnancy and birth weight. METHODS: In 2010-2012 we recruited 92 women living in Stockholm, Sweden, and followed them from before conception and through pregnancy and childbirth. Their Perceived Stress Scale (PSS) scores and salivary cortisol levels were collected at 26-28 gestational weeks. Birth weight was collected from medical records. Linear regression analyses and Pearson correlations were performed between the PSS scores or cortisol levels and birth weight respectively, adjusted for gestational age. RESULTS: No significant associations were found between PSS scores or cortisol levels and birth weight. There was a trend towards higher salivary cortisol levels among infants with lower birth weights and this effect was attenuated after adjusting for gestational age. Morning cortisol levels (r=-0.31, p=0.01), the decline in cortisol levels (r=-0.26, p=0.03) and evening cortisol levels (r=-0.21, p=0.09) were negatively correlated with PSS scores. CONCLUSION: Maternal stress during pregnancy was not associated to birth weight. The inverse correlation between PSS scores and cortisol levels may indicate other mechanisms for maternal stress on child outcomes than the previous explanation of hypothalamic-pituitary-adrenal axis activity.Swedish Initiative for Research on Microdata in the Social and Medical Sciences (SIMSAM) framework grant no 340-2013-5867, as well as the Swedish Heart Lung Foundation, the Swedish Asthma and Allergy Association’s Research Foundation, grants provided by the Stockholm County Council (ALF project), FORTE, and the Strategic Research Program in Epidemiology at Karolinska Institutet.Accepte

Limited association between markers of stress during pregnancy and fetal growth in 'Born into Life' : a new prospective birth cohort

Aims: We aimed to investigate the associations between perceived maternal stress or salivary cortisol levels during pregnancy and birthweight. Methods: In 2010-2012, we recruited 92 women living in Stockholm, Sweden, and followed them from before conception and through pregnancy and childbirth. Their Perceived Stress Scale (PSS) scores and salivary cortisol levels were collected at 26-28 gestational weeks. Birthweight was collected from medical records. Linear regression analyses and Pearson correlations were performed between the PSS scores or cortisol levels and birthweight, respectively, adjusted for gestational age. Results: No significant associations were found between PSS scores or cortisol levels and birthweight. There was a trend towards higher salivary cortisol levels among infants with lower birthweights, and this effect was attenuated after adjusting for gestational age. Morning cortisol levels (r = -0.31, p = 0.01), the decline in cortisol levels (r = -0.26, p = 0.03) and evening cortisol levels (r = -0.21, p = 0.09) were negatively correlated with PSS scores. Conclusion: Maternal stress during pregnancy was not associated with birthweight. The inverse correlation between PSS scores and cortisol levels may indicate other mechanisms for maternal stress on child outcomes than the previous explanation of hypothalamic-pituitary-adrenal axis activity.Swedish Research CouncilSwedish Initiative for Research on Microdata in the Social and Medical Sciences framework (grant no 340-2013-5867)Swedish Heart Lung FoundationSwedish Asthma and Allergy Association's Research FoundationStockholm County Council ALF-projectsFORTEFORMASStrategic Research Program in Epidemiology at Karolinska InstitutetAccepte

Effects of inhaled corticosteroids on DNA methylation in peripheral blood cells in children with asthma

Non peer reviewe

Heritability and confirmation of genetic association studies for childhood asthma in twins.

BACKGROUND: Although the genetics of asthma has been extensively studied using both quantitative and molecular genetic analysis methods, both approaches lack studies specific to the childhood phenotype and including other allergic diseases. This study aimed to give specific estimates for the heritability of childhood asthma and other allergic diseases, to attempt to replicate findings from genomewide association studies (GWAS) for childhood asthma and to test the same variants against other allergic diseases. METHODS: In a cohort of 25 306 Swedish twins aged 9 or 12 years, data on asthma were available from parental interviews and population-based registers. The interviews also inquired about wheeze, hay fever, eczema, and food allergy. Through structural equation modeling, the heritability of all phenotypes was calculated. A subset of 10 075 twins was genotyped for 16 single nucleotide polymorphisms (SNPs) selected from previous GWAS; these were first tested for association with asthma and significant findings also against the other allergic diseases. RESULTS: The heritability of any childhood asthma was 0.82 (95% CI 0.79-0.85). For the other allergic diseases, the range was approximately 0.60-0.80. Associations for six SNPs with asthma were replicated, including rs2305480 in the GSDMB gene (OR 0.80, 95% CI 0.74-0.86, P = 1.5*10(-8) ; other significant associations all below P = 3.5*10(-4) ). Of these, only rs3771180 in IL1RL1 was associated with any other allergic disease (for hay fever, OR 0.64, 95% CI 0.53-0.77, P = 2.5*10(-6) ). CONCLUSION: Asthma and allergic diseases of childhood are highly heritable, and these high-risk genetic variants associated specifically with childhood asthma, except for one SNP shared with hay fever.The Swedish Research CouncilThe Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM)The Stockholm County Council (ALF project)The Strategic Research Program in Epidemiology at Karolinska InstitutetThe Swedish Heart-Lung FoundationThe Swedish Asthma and Allergy Association’s Research FoundationManuscrip

DNA Methylation Trajectories During Pregnancy

There is emerging evidence on DNA methylation (DNAm) variability over time; however, little is known about dynamics of DNAm patterns during pregnancy. We performed an epigenome-wide longitudinal DNAm study of a well-characterized sample of young women from the Swedish Born into Life study, with repeated blood sampling before, during and after pregnancy (n = 21), using the Illumina Infinium MethylationEPIC array. We conducted a replication in the Isle of Wight third-generation birth cohort (n = 27), using the Infinium HumanMethylation450k BeadChip. We identified 196 CpG sites displaying intra-individual longitudinal change in DNAm with a false discovery rate (FDR) P 3 differentially methylated CpGs: HOXB3, AVP, LOC100996291, and MicroRNA 10a. Of 36 CpGs available in the replication cohort, 17 were replicated, all but 2 with the same direction of association (replication P <.05). Biological pathway analysis demonstrated that FDR-significant CpGs belong to genes overrepresented in metabolism-related pathways, such as adipose tissue development, regulation of insulin receptor signaling, and mammary gland fat development. These results contribute to a better understanding of the biological mechanisms underlying important physiological alterations and adaptations for pregnancy and lactation.Peer reviewe

Birth size and gestational age in opposite-sex twins as compared to same-sex twins: An individual-based pooled analysis of 21 cohorts

It is well established that boys are born heavier and longer than girls, but it remains unclear whether birth size in twins is affected by the sex of their co-twin. We conducted an individual-based pooled analysis of 21 twin cohorts in 15 countries derived from the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), including 67,850 dizygotic twin individuals. Linear regression analyses showed that boys having a co-twin sister were, on average, 31&thinsp;g (95% CI 18 to 45) heavier and 0.16&thinsp;cm (95% CI 0.045 to 0.274) longer than those with a co-twin brother. In girls, birth size was not associated (5&thinsp;g birth weight; 95% CI &minus;8 to &minus;18 and &minus;0.089&thinsp;cm birth length; 95% CI &minus;0.202 to 0.025) with the sex of the co-twin. Gestational age was slightly shorter in boy-boy pairs than in boy-girl and girl-girl pairs. When birth size was standardized by gestational age, the magnitude of the associations was attenuated in boys, particularly for birth weight. In conclusion, boys with a co-twin sister are heavier and longer at birth than those with a co-twin brother. However, these differences are modest and partly explained by a longer gestation in the presence of a co-twin sister