| 1. |
- Acevedo, Nathalie, et al.
(författare)
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DNA Methylation Levels in Mononuclear Leukocytes from the Mother and Her Child Are Associated with IgE Sensitization to Allergens in Early Life
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:2
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Tidskriftsartikel (refereegranskat)abstract
- DNA methylation changes may predispose becoming IgE-sensitized to allergens. We analyzed whether DNA methylation in peripheral blood mononuclear cells (PBMC) is associated with IgE sensitization at 5 years of age (5Y). DNA methylation was measured in 288 PBMC samples from 74 mother/child pairs from the birth cohort ALADDIN (Assessment of Lifestyle and Allergic Disease During INfancy) using the HumanMethylation450BeadChip (Illumina). PBMCs were obtained from the mothers during pregnancy and from their children in cord blood, at 2 years and 5Y. DNA methylation levels at each time point were compared between children with and without IgE sensitization to allergens at 5Y. For replication, CpG sites associated with IgE sensitization in ALADDIN were evaluated in whole blood DNA of 256 children, 4 years old, from the BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology) cohort. We found 34 differentially methylated regions (DMRs) associated with IgE sensitization to airborne allergens and 38 DMRs associated with sensitization to food allergens in children at 5Y (Sidak p <= 0.05). Genes associated with airborne sensitization were enriched in the pathway of endocytosis, while genes associated with food sensitization were enriched in focal adhesion, the bacterial invasion of epithelial cells, and leukocyte migration. Furthermore, 25 DMRs in maternal PBMCs were associated with IgE sensitization to airborne allergens in their children at 5Y, which were functionally annotated to the mTOR (mammalian Target of Rapamycin) signaling pathway. This study supports that DNA methylation is associated with IgE sensitization early in life and revealed new candidate genes for atopy. Moreover, our study provides evidence that maternal DNA methylation levels are associated with IgE sensitization in the child supporting early in utero effects on atopy predisposition.
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| 2. |
- Acevedo, Nathalie, et al.
(författare)
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Epigenetic alterations in skin homing CD4(+)CLA(+) T cells of atopic dermatitis patients
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- T cells expressing the cutaneous lymphocyte antigen (CLA) mediate pathogenic inflammation in atopic dermatitis (AD). The molecular alterations contributing to their dysregulation remain unclear. With the aim to elucidate putative altered pathways in AD we profiled DNA methylation levels and miRNA expression in sorted T cell populations -(CD4(+), -CD4(+)CD45RA(+) naive, -CD4(+)CLA(+), and -CD8(+)) from adult AD patients and healthy controls (HC). Skin homing -CD4(+)CLA(+) T cells from AD patients showed significant differences in DNA methylation in 40 genes compared to HC (p < 0.05). Reduced DNA methylation levels in the upstream region of the interleukin-13 gene (IL13) in -CD4(+)CLA(+) T cells from AD patients correlated with increased IL13 mRNA expression in these cells. Sixteen miRNAs showed differential expression in -CD4(+)CLA(+) T cells from AD patients targeting genes in 202 biological processes (p < 0.05). An integrated network analysis of miRNAs and CpG sites identified two communities of strongly interconnected regulatory elements with strong antagonistic behaviours that recapitulated the differences between AD patients and HC. Functional analysis of the genes linked to these communities revealed their association with key cytokine signaling pathways, MAP kinase signaling and protein ubiquitination. Our findings support that epigenetic mechanisms play a role in the pathogenesis of AD by affecting inflammatory signaling molecules in skin homing -CD4(+)CLA(+) T cells and uncover putative molecules participating in AD pathways.
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| 3. |
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| 4. |
- Färdig, Martin, et al.
(författare)
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Eosinophil-derived neurotoxin levels in early childhood and association with preschool asthma - A prospective observational study
- 2023
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Ingår i: Clinical and Experimental Allergy. - : John Wiley & Sons. - 0954-7894 .- 1365-2222. ; 53:11, s. 1198-1211
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Eosinophil-derived neurotoxin (EDN) is related to childhood asthma, while normal values are lacking. We aimed to document serum EDN levels at 1 and 3 years in general and in non-atopic children, and explore if EDN levels differed by sex or were associated with preschool asthma at 3 years.Methods: From the PreventADALL birth cohort, we included 1233 children with EDN analysed using ImmunoCAP at 1 and/or 3 years. Non-atopic children had no history of wheeze, asthma, allergic sensitization or atopic dermatitis. Preschool asthma was defined as having ≥3 episodes of bronchial obstruction between 2 and 3 years, plus doctor diagnosed asthma and/or asthma medication use by 3 years. The upper limit of normal (ULN) of EDN was defined as the 95th percentile. With Youden Index we calculated EDN cut-off levels for risk of preschool asthma.Results: The overall median (ULN) EDN levels were 27.4 (121) μg/L at 1 year (n = 787), and 20.1 (87.8) μg/L at 3 years (n = 857). Non-atopic children had EDN levels of 24.0 (107) μg/L at 1 year (n = 147), and 17.3 (84.6) μg/L at 3 years (n = 173). EDN levels were higher in boys compared to girls; 32.0 (133) versus 24.5 (97.0) μg/L at 1 year, and 20.9 (96.3) versus 19.0 (72.4) μg/L at 3 years. Preschool asthma was observed in 109/892 (12.2%) children. Higher EDN levels at 1 (>26.7 μg/L) and 3 (≥20.5 μg/L) years were associated with preschool asthma; adjusted OR (95% CI) 2.20 (1.09, 4.41) and 4.68 (2.29, 9.55), respectively.Conclusion and Clinical Relevance: We report EDN values in early childhood, demonstrating higher levels at 1 compared to 3 years and in boys compared to girls at both ages. Higher EDN levels at both ages were associated with preschool asthma. However, EDN cut-off levels for preschool asthma were overall lower than the ULN of non-atopic children, limiting translation into clinical practice.
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| 5. |
- Holmdahl, Idun, et al.
(författare)
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Early Life Wheeze and Risk Factors for Asthma-A Revisit at Age 7 in the GEWAC-Cohort
- 2021
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Ingår i: Children. - : MDPI. - 2227-9067. ; 8:6
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Tidskriftsartikel (refereegranskat)abstract
- One third of all toddlers are in need of medical care because of acute wheeze and many of these children have persistent asthma at school age. Our aims were to assess risk factors for and the prevalence of asthma at age 7 in a cohort of children suffering from an acute wheezing episode as toddlers. A total of 113 children, included during an acute wheezing episode (cases), and 54 healthy controls were followed prospectively from early pre-school age to 7 years. The protocol included questionnaires, ACT, FeNO, nasopharyngeal virus samples, blood sampling for cell count, vitamin D levels, and IgE to food and airborne allergens. The prevalence of asthma at age 7 was 70.8% among cases and 1.9% among controls (p < 0.001). Acute wheeze caused by rhinovirus (RV) infection at inclusion was more common among cases with asthma at age 7 compared to cases without asthma (p = 0.011) and this association remained significant following adjustment for infection with other viruses (OR 3.8, 95% CI 1.4-10.5). Cases with asthma at age 7 had been admitted to hospital more often (p = 0.024) and spent more days admitted (p = 0.01) during the year following inclusion compared to cases without asthma. RV infection stands out as the main associated factor for wheeze evolving to persistent asthma. Cases who developed asthma also had an increased need of hospital time and care for wheeze during the year after inclusion.
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| 6. |
- Holmdahl, Idun, et al.
(författare)
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Inflammatory related plasma proteins involved in acute preschool wheeze
- 2023
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Ingår i: Clinical and Translational Allergy. - : John Wiley & Sons. - 2045-7022 .- 2045-7022. ; 13:11
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPreschool wheeze is a risk factor for asthma development. However, the molecular mechanism behind a wheezing episode is not well understood.ObjectiveOur aims were to assess the association of plasma proteins with acute preschool wheeze and to study the proteins with differential expression at the acute phase at revisit after 3 months. Additionally, to investigate the relationship between protein expression and clinical parameters.MethodWe measured 92 inflammatory proteins in plasma and clinical parameters from 145 children during an episode of preschool wheeze (PW) and at the revisit after 3 months (PW-R, n = 113/145) and 101 healthy controls (HC) aged 6–48 months in the GEWAC cohort using the antibody-mediated proximity extension-based assay (Olink Proteomics, Uppsala).ResultsOf the 74 analysed proteins, 52 were differentially expressed between PW and HC. The expression profiles of the top 10 proteins, Oncostatin M (OSM), IL-10, IL-6, Fibroblast growth factor 21 (FGF21), AXIN1, CXCL10, SIRT2, TNFSF11, Tumour necrosis factor β (TNF-β) and CASP8, could almost entirely separate PW from HC. Five out of 10 proteins were associated with intake of oral corticosteroids (OCS) 24 h preceding blood sampling (OSM, CASP8, IL-10, TNF-β and CXCL10). No differences in protein expression were seen between PWs with or without OCS in comparison to HC. At the revisit after 3 months, differential protein expressions were still seen between PW-R and HC for three (IL-10, SIRT2 and FGF21) of the 10 proteins.ConclusionOur results contribute to unravelling potential immunopathological pathways shared between preschool wheeze and asthma.
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| 7. |
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| 8. |
- Lundin, Johanna, et al.
(författare)
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22q11.2 microduplication in two patients with bladder exstrophy and hearing impairment
- 2010
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Ingår i: European Journal of Medical Genetics. - : Elsevier BV. - 1769-7212 .- 1878-0849. ; 53:2, s. 61-65
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Tidskriftsartikel (refereegranskat)abstract
- Bladder exstrophy is a congenital malformation of the bladder and urethra. The genetic basis of this malformation is unknown however it is well known that chromosomal aberrations can lead to defects in organ development. A few bladder exstrophy patients have been described to carry chromosomal aberrations. Chromosomal rearrangements of 22q11.2 are implicated in several genomic disorders i.e. DiGeorge/velocardiofacial- and cat-eye syndrome. Deletions within this chromosomal region are relatively common while duplications of 22q11.2 are much less frequently observed. An increasing number of reports of microduplications of this region describe a highly variable phenotype. We have performed array-CGH analysis of 36 Swedish bladder exstrophy patients. The analysis revealed a similar and approximately 3 Mb duplication, consistent with the recently described 22q11.2 microduplication syndrome, in two unrelated cases with bladder exstrophy and hearing impairment. This finding was confirmed by multiplex ligation-dependent probe amplification (MLPA) and FISH analysis. Subsequent MLPA analysis of this chromosomal region in 33 bladder exstrophy patients did not reveal any deletion/duplication within this region. MLPA analysis of 171 anonymous control individuals revealed one individual carrying this microduplication. This is the first report of 22q11.2 microduplication associated with bladder exstrophy and hearing impairment. Furthermore the finding of one carrier among a cohort of normal controls further highlights the variable phenotype linked to this microduplication syndrome.
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| 9. |
- Merid, Simon Kebede, et al.
(författare)
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Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age
- 2020
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Ingår i: Genome Medicine. - Stockholm : Karolinska Institutet, Dept of Clinical Science and Education, Södersjukhuset. - 1756-994X.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10- 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.
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| 10. |
- Söderhäll, Cilla
(författare)
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Gene mapping of atopic dermatitis
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atopic dermatitis is a hereditary, pruritic, inflammatory and chronic skin disease that typically presents in early childhood. It is often associated with other atopic manifestations, such as asthma, allergic rhinoconjunctivitis, and elevated total and/or allergen-specific serum lgE levels. In urbanised societies, a marked increase has occurred in its prevalence during the past decades. In Sweden, the prevalence of atopic dermatitis in schoolchildren has more than doubled between 1979 and 1991, and is now one of the highest in the world; approximately 15%. Twin studies support the role of a strong genetic contribution with a concordance rate of 0.86 in monozygotic twins and 0.21 in dizygotic twins. When both parents have atopic dermatitis, children have a risk of up to 75% to develop the disease. This thesis includes studies that aim to identify genetic components contributing to the development of atopic dermatitis. A genome-wide linkage analysis was performed with 367 microsatellite markers in 109 pedigrees forming 193 full-sib pairs and 9 half-sib pairs affected with atopic dermatitis. In total, five chromosome regions reaching the level for suggestive linkage (p<7.4x10-4) were identified. Four of these chromosome regions: 3q, 13q14, 15q14-15 and 17q21 were linked to a severity score of atopic dermatitis. Two other phenotypes: atopic dermatitis combined with allergen-specific serum lgE levels (sp-IgE+) and a more severe form of atopic dermatitis (extreme AD) showed linkage to chromosome region 18q21, reaching the level for suggestive linkage for sp-IgE+. Another region on this chromosome, 18p, showed linkage to extreme AD, while 3p24-22 showed linkage to the phenotype atopic dermatitis (AD). Weaker evidence of linkage was observed to chromosome regions 1p32 (sp-IgE+), 4q24-26 (sp-IgE+), 5p13 (AD), 6p (sp-IgE+), 6q16 (AD), 7p14 (Extreme AD), 10p13-12 (AD), 11q13 (Extreme AD), 21q21 (Extreme AD) and Xp 11 (Extreme AD). In 406 families, 572 sib pairs and 30 half-sib pairs, affected with atopic dermatitis were tested for linkage to genetic markers in seven candidate chromosome regions (2q35, 5q31-33, 6p21, 11q13, 14q11, 16p12 and Xp11). The region on 14q11 showed evidence in favour of linkage, but not association to the phenotype AD (NPL-score 2.36, p<0.009). However, a polymorphism in the candidate gene. CMA1 that previously has been associated to atopic dermatitis was neither linked nor associated in this material. An intragenic marker in the beta subunit of the high-affinity lgE receptor (FCERIbeta) located at 11q13 was associated to sp-IgE+ (p<0.009). No differences could be seen between transmissions of maternal and paternal alleles. Evidence in favour of linkage to chromosome region 5q31-33 for the severity score of atopic dermatitis was obtained. A polymorphism in the promoter region of the IL4 gene at 5q31-33 gave evidence in favour of linkage to this phenotype. We therefore speculate that this chromosome region may contain a gene controlling the severity of atopic dermatitis. For the Wiskott-Aldrich syndrome gene (WAS) at Xp11, weak evidence of linkage was also found to the severity score of atopic dermatitis. For AD and sp-IgE+ the presence of a susceptibility gene with a major effect could be excluded. Neither linkage nor association was seen to the chromosome regions 2q35, 6p21 or 16p12 to any of the phenotypes. This suggests that major effects on the disease development of genes in these chromosome regions could be excluded in this material.
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