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- Eriksson Ström, Jonas
(författare)
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Epigenetic changes and immunological features of chronic obstructive pulmonary disease
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Chronic obstructive pulmonary disease (COPD) is a heterogenous and chronic inflammatory syndrome with the lungs as its main target organ. Clinically, COPD is characterized by airflow limitation, chronic respiratory symptoms, and many extrapulmonary comorbidities. Tobacco smoke is the main environmental risk factor, but pollutants and smoke from biomass fuel are also major contributors. Why some, but not all, smokers develop the disease is a key but largely unresolved research question. Genetic factors seem to explain 40—60% of COPD susceptibility, but what additional role epigenetic factors such as DNA methylation might play has not been thoroughly investigated.Immune cells are of vital importance in the COPD pathogenesis. Among airway lymphocytes, cytotoxic CD8+ T cells are the ones most often found to be involved in the disease, but other lymphocyte populations are not as well studied.Among patients with manifest COPD, the rate of decline in lung function differs widely. Smoking cessation decreases the rate, but beyond that, it is not well understood why some patients experience a more rapid and some a much slower disease progression. Rapid decline is associated with a poor prognosis and has been recognized as a separate phenotype of COPD. Aim: The overall aim of this thesis was to examine the immunologic and epigenetic features of COPD with a focus on the rapid decline phenotype, using flow cytometry and measurement of DNA methylation in cells from bronchoalveolar lavage (BAL) fluid together with clinical characteristics such as rate of decline in lung function, use of inhaled corticosteroids and smoking status. The studies included in this thesis were all part of the Respiratory and Cardiovascular Effects in COPD (“KOLIN”) study.Methods: The study population was the same for all studies in this thesis. Subjects were recruited from the Obstructive Lung Disease in Northern Sweden (OLIN) COPD study according to predetermined criteria. OLIN COPD also provided the longitudinal data needed for classification of rapid/non-rapid decliners (decline in forced expiratory volume in the first second [FEV1] ≥60 or ≤30 mL/year respectively). BAL fluid was analyzed for cell type composition using flow cytometry. DNA methylation in BAL cells was measured using the Illumina MethylationEPIC BeadChip. In the statistical analysis, flow cytometry data was analyzed using group-wise comparisons and multivariable regression models. DNA methylation data was analyzed for association with COPD and accelerated epigenetic aging (defined as the difference between chronological and epigenetic age) using multilinear regression models. Differentially methylated positions and regions associated with COPD were analyzed for gene association and pathway enrichment and integrated with data from previous gene expression and genome-wide association studies.Results: Paper I: in this first paper based on flow cytometry, we focused on cytotoxic lymphocytes and found that Natural Killer (NK) cells in BAL were increased in COPD while invariant Natural Killer T (iNKT) and Natural Killer T-like (NKT-like) cells increased with smoking but not with COPD. NK cells were also higher when comparing ex-smokers with and without COPD. No significant differences were found between COPD subjects with a rapid vs. a non-rapid decline in lung function.Paper II: regulatory immune cells were investigated in this second flow cytometry-based paper. We found that FoxP3+ regulatory T cells (Tregs) were significantly lower in COPD subjects with a rapid decline in lung function compared to those with a non-rapid decline. This result was significant before as well as after adjustments for inhaled corticosteroids (ICS) usage and smoking. None of the investigated regulatory immune cell populations (T helper cells, activated T helper cells, and FoxP3+ Tregs) displayed significant differences associated with either COPD or smoking.Paper III: measurements of BAL cell DNA methylation revealed epigenome-wide differential methylation in COPD; 1,155 differentially methylated positions (DMPs) and 7,097 differentially methylated regions. Functional analysis using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology databases identified biologically plausible pathways and gene relationships, including enrichment for transcription factor activity. No correlation was found between COPD and accelerated aging. For 79 unique DMPs, DNA methylation correlated significantly with gene expression in BAL. Thirty-nine percent of DMPs were co-located with single nucleotide polymorphisms (SNPs) associated with COPD.Conclusions: Among cytotoxic cell types, the NK cell population stood out as it 1) was increased in COPD; and 2) did not normalize in COPD subjects that had quit smoking. This indicates that NK cells might contribute to the continued disease progression in COPD even after smoking cessation.COPD subjects with a rapid decline in lung function had significantly lower levels of Fox P3+ Tregs in BAL. Further longitudinal research is needed to establish the causal direction of this relationship, but based on the evidence available to date, I deem it more plausible that a low expression of Fox P3+ Tregs would lead to a rapid decline in lung function, than the other way around.Our epigenome-wide association study (EWAS) identified widespread differential methylation in COPD, and many DMPs displayed a strong correlation with gene expression. Somewhat less than half of DMPs were located in close proximity to COPD-associated SNPs, suggesting that these might be sites where genetic factors regulate methylation status. In sum, our findings suggest strong associations between epigenetic factors and COPD. As this was the first ever published EWAS of COPD based on BAL cells, results must be validated in future studies.
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| 2. |
- Melén, Erik
(författare)
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Genetic studies on childhood asthma and allergy : role of interactions
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The occurrence of asthma and allergic diseases is influenced by inherited and environmental factors, and symptoms of asthma and allergy usually begin in early childhood. The overall aim with this thesis was to study the role of genetic factors for the development of childhood asthma and allergy, and to evaluate potential interaction between genetic and environmental factors. Using the BAMSE birth cohort study, children with wheezing episodes up to the age of four were classified into the following groups: transient wheezing (n=266, 8%), persistent wheezing (n=319, 9%) and late-onset wheezing (n=195, 6%). Children with persistent and late onset wheezing had the highest occurrence of sensitisation to inhalant allergens (23% and 30%, respectively), whereas lower mean peak expiratory flow values were seen in children with transient and persistent wheezing (mean difference -8.9 and -8.5 l/min, respectively). Both maternal and paternal allergic disease were of importance for all wheezing outcomes in the children, but the influence of parental allergic disease on the risk of persistent wheezing seemed to be more pronounced in boys than in girls. For the genetic analyses, around 500 children with asthma symptoms up to four years and 500 controls were selected from the BAMSE study. Single nucleotide polymorphisms (SNP) and their corresponding haplotypes, in six candidate genes for asthma and allergy were analysed and their associations with various phenotypes were evaluated. Variations in the IL9R gene seemed to influence the susceptibility to both wheezing and sensitisation, predominantly in boys. No overall effect of the IL4RA SNPs was observed and only weak associations to wheezing and sensitisation were indicated when haplotypes were considered. Variants in the ADRB2 gene showed no overall association to any of the outcomes, whereas the TNF-alpha-308 SNP seemed to affect the risk of sensitisation at the age of four. Ala 1 14Val was the only SNP in the GSTP1 gene that showed any association (particularly to asthma). For the GPRA association analyses, asthma and allergic sensitisation were used as major outcomes and the study was designed to evaluate the role of certain haplotypes on these study subjects both from BAMSE and a multinational European project (PARSIFAL). Both risk haplotypes (H5/H6) and non-risk haplotypes (H1/H3) could be identified, and these haplotypes seemed to predominantly influence the risk of sensitisation, but also asthma and allergic rhinoconjunctivitis. Interaction analyses between the IL9R and IL4RA genes showed that the effect of IL4RA SNPs on wheezing up to the age of four was modified by SNPs in the IL9R gene. Combinations of the IL4RA Gln576Arg variant and an intron IL9R variant seemed to influence the risk of wheezing particularly, and both risk and non-risk combinations were observed. Air pollution from road traffic in the study area was evaluated as nitrogen oxides (traffic-NOx) and inhalable particulate matter (traffic- PM10) using emission databases and dispersion modelling. Individual exposure levels during the first year of life were estimated through geocoding of the children's home addresses. Significant geneenvironment interaction effects were suggested between SNPs in the GSTP1 gene and exposure to traffic-NO, during the first year of life with regard to allergic sensitisation at 4 years. Heterozygous GSTP1 carriers seemed to have the most pronounced risk of disease and this pattern was seen for all GSTP1 SNPs tested. Similar interaction was seen for exposure to traffic- PM10. In summary, we have shown that parental allergic disease is important for development of wheezing up to the age of four, but the hereditary influence seemed to be more pronounced in boys than in girls. Variants in several of the analyzed genes were associated with symptoms of asthma and allergic sensitisation. The association between these genetic variants and allergic diseases are likely to be influenced by other genetic variants, here exemplified by genegene interaction between IL4RA and IL9R variants, and environmental factors, here exemplified by geneenvironment interaction between GSTP1 variants and exposure to traffic-NOx.
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| 3. |
- Melen, Erik, et al.
(författare)
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Spirometric phenotypes from early childhood to young adulthood - A CADSET (Chronic Airway Disease Early Stratification) study
- 2020
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Ingår i: European Respiratory Journal. - : ERS Publications. - 0903-1936 .- 1399-3003. ; 56:Suppl 64
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Results from longitudinal cohort studies show that the lower the lung function in childhood and adulthood, the higher the risk of later chronic airway disease such as COPD. Yet, reliable data is sparse on the prevalence of different types of lung function impairments in the general population of children and young adults, as well as their major determinants.Aim: To report age- and sex-specific prevalences and characteristics of spirometric phenotypes from childhood up to young adulthood.Methods: Lung function data from independent European population-based cohorts involved in the CADSET collaboration were analysed. Pre-bronchodilator FEV1 and FVC data from each cohort were converted into z-scores according to the Global Lung Initiative (GLI) reference system. Overall fit with the GLI spirometry equations was assessed. Airway limitation was defined as a FEV1/FVC z-score < -1.65.Results: Five cohorts provided spirometry data from 10,842 observations in subjects aged 7 to 25 years. Airway limitation was found in around 6-10% across all ages in the cohorts. No evidence of differences between males and females in different age groups were observed. In unadjusted analyses of all cohorts, we found maternal smoking during pregnancy to be associated with airway limitation (p<0.05).Conclusion: Analyses of spirometry data from population-based cohorts in Europe show that the prevalence of airflow limitation according to GLI is substantial (6-10%) and quite similar across cohorts and age groups. These results suggest that airflow limitation can develop early in life and that there are rather small changes in prevalence during childhood.
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| 5. |
- Melén Hånell, Sara, et al.
(författare)
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Going global : a guide to succesful internationalization
- 2023
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Trots att globalisering och digitalisering har gjort det enklare än någonsin tidigare att etablera sig internationellt, så innebär globala affärer fortfarande stora utmaningar och risker. Många viktiga internationaliseringsbeslut fattas ofta på basis av magkänsla eller personliga kontakter på specifika marknader. Även om detta kan fungera i enstaka fall visar forskning att avsaknaden av en robust strategi gör det svårt att åstadkomma positiva resultat i längden.Denna bok utgår från tidlösa principer och forskningsresultat från svenska och internationella strategiforskare för att beskriva vilka faktorer som gör globala affärer mer eller mindre framgångsrika. Särskilt fokus läggs vid Dunningmodellen, ett beprövat forskningsbaserat strategiskt ramverk som kan tillämpas av moderna tillväxtföretag som verkar i en global ekonomi. Dunningmodellens styrka är att den kan hjälpa alla typer av företag att utveckla balanserade insikter och strategier för globala affärer utifrån det enskilda företagets förutsättningar. Insikter och begrepp tydliggörs genom användandet av konkreta exempel från svenska företag från flera olika branscher, exempelvis Annas Pepparkakor, BabyBjörn, auktionshuset Bukowskis, techbolaget Tobii, samt tillväxtföretag inom bioteknik. Boken är skriven av forskare inom strategi och innovation vid Handelshögskolan i Stockholm och syftar till att sammanfatta relevant forskning och nya insikter på ett så praktiskt och lättillgängligt sätt som möjligt. Den är avsedd för alla som arbetar med olika former av globala affärer i strategiska, operativa, eller rådgivande roller.
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| 6. |
- Melén, Sara, et al.
(författare)
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Globala affärer : tidlösa principer och strategiska ramverk
- 2020
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Många viktiga internationaliseringsbeslut fattas ofta på basis av magkänsla eller personliga kontakter på specifika marknader. Boken är skriven av forskare inom strategi och innovation vid Handelshögskolan i Stockholm och syftar till att sammanfatta relevant forskning och nya insikter på ett så praktiskt och lättillgängligt sätt som möjligt.
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| 8. |
- Mitselou, Niki, 1982-
(författare)
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Preterm birth and allergic disease
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Allergic diseases are very common in children and young adults, while there is an ongoing interest worldwide in exploring the early origins of these conditions. The perinatal period is considered crucial as it encompasses the maturation of gut microbiota and the establishment of an efficient immunoregulation. Early-life factors might be the key drivers of an altered immune response, sometimes leading to sensitization and allergic disease. Preterm birth is believed to affect the risk of immune-mediated diseases, while a delayed and altered gut microbiota composition and diversity following caesarean delivery might influence the induction of tolerance.In the first paper, using a large population database, we found that caesarean delivery increased the risk of allergic rhinitis (AR) in offspring, while moderately preterm birth (≥32–36 weeks of gestation) was associated with a slightly elevated risk. No association was observed between post-term birth (≥42 weeks) and AR. There also seems to be a positive association between large for gestational age, low 5-minute Apgar score (<7) and AR. In the second paper, we used data from the BAMSE population-based birth cohort to assess the impact of gestational age at birth on future IgE sensitization. The study concluded that preterm birth (<37 weeks of gestation) was inversely associated with IgE sensitization to common food and/or inhalant allergens up to the age 24 years, while no association was found between postterm birth and IgE sensitization.Uncontrolled asthma and allergic disease in pregnancy are associated with poor pregnancy outcome. Current guidelines recommend against the initiation of allergen-specific immunotherapy (AIT) in pregnant patients, while welltolerated ongoing AIT might be continued. In the third paper, using national health-care registers, we found no association between AIT during pregnancy and risk of congenital malformations, preterm birth, caesarean delivery, stillbirth, or other adverse pregnancy outcomes.
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