Publications by authors named "Hans Bisgaard"

279 Publications

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 Jun 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Innate IL-23/Type 17 immune responses mediate the effect of the 17q21 locus on childhood asthma.

Clin Exp Allergy 2021 May 13. Epub 2021 May 13.

COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Gentofte, Denmark.

Background: Several childhood asthma risk loci that relate to immune function have been identified by genome-wide association studies (GWAS), but the underlying mechanisms remain unknown.

Objective: Here, we examined whether perturbed innate immune responses mediate the association between known genetic risk variants and development of childhood asthma.

Methods: Peripheral blood mononuclear cells from 336 six-month-old infants from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC ) cohort were stimulated in vitro with six different innate ligands (LPS, CpG, poly(I:C), R848, HDMAPP and aluminium hydroxide together with low levels of LPS) followed by quantification of 18 released cytokines and chemokines 40 h after the stimulations. The innate immune response profiles were decomposed by principal component (PC) analysis, and PC1-5 were used in mediation analyses of the effect of 25 known genetic risk variants on childhood asthma until age 7.

Results: The effects of two variants from the 17q21 locus (rs7216389, rs2305480) on asthma and exacerbation risk were significantly mediated by immune parameters induced in response to ligands mimicking intracellular colonization; bacterial DNA (CpG) and double-stranded viral RNA (poly(I:C)). The Th17 and innate lymphoid cell type 3-amplifying cytokine IL-23 was the most prominent cytokine involved.

Conclusion: The 17q21 effect on childhood asthma and exacerbations was partly mediated by deregulation of IL-23 in response to intracellular microbial ligands, which may suggest ineffective clearance of intracellular pathogens in the lungs.
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http://dx.doi.org/10.1111/cea.13900DOI Listing
May 2021

Associations between Inhaled Corticosteroid in the First 6 Years of Life and Obesity Related Traits.

Am J Respir Crit Care Med 2021 May 11. Epub 2021 May 11.

University of Copenhagen, 4321, COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, Kobenhavn, Denmark;

Rationale Infants and young children might be particularly susceptible to the potential clinical side effects of inhaled corticosteroids (ICS) on body mass index (BMI), adiposity rebound and body composition, but this has rarely been studied in long-term studies in this age-group. Objective To determine the association between ICS exposure in the first 6 years of life on BMI, adiposity rebound, body composition and blood lipid levels. Methods Children from the two Copenhagen Prospective Studies on Asthma in Childhood mother-child cohorts were included. ICS use was registered prospectively to age 6 and the cumulative dose was calculated. Multiple linear regression models were used for analysis. Measurements and Main Results A total of 932 (84%) of the 1111 children from the COPSAC cohorts had data on BMI, 786 (71%) had DXA scan data at age 6 years, and 815 (73%) had adiposity rebound age calculated. 291 children (31%) received a cumulative ICS dose > 10 weeks of standard treatment before age 6. ICS treatment during 0-6 years of age was associated with an increased BMI z-score; 0.05 SD [95% CI: 0.005 to 0.09] per one-year standard treatment, p=0.03, an earlier age at adiposity rebound; -0.18 year [95% CI: -0.28 to -0.08], p=0.0006, and a 2 % increased geometric mean android fat percentage, p=0.05. ICS exposure and DXA scan data were not associated. Conclusions ICS use in early childhood was associated with increased BMI z-score at age six, an earlier adiposity rebound and a trend of association with increased android body fat percentage.
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http://dx.doi.org/10.1164/rccm.202009-3537OCDOI Listing
May 2021

The infant gut resistome associates with E. coli, environmental exposures, gut microbiome maturity, and asthma-associated bacterial composition.

Cell Host Microbe 2021 06 21;29(6):975-987.e4. Epub 2021 Apr 21.

Department of Biology, Section of Microbiology, University of Copenhagen, 2100 Copenhagen, Denmark. Electronic address:

Antimicrobial resistance (AMR) is an accelerating global threat, yet the nature of AMR in the gut microbiome and how AMR is acquired during early life remain largely unknown. In a cohort of 662 Danish children, we characterized the antibiotic resistance genes (ARGs) acquired during the first year of life and assessed the impacts of diverse environmental exposures on ARG load. Our study reveals a clear bimodal distribution of ARG richness that is driven by the composition of the gut microbiome, especially E. coli. ARG profiles were significantly affected by various environmental factors. Among these factors, the importance of antibiotics diminished with time since treatment. Finally, ARG load and ARG clusters were also associated with the maturity of the gut microbiome and a bacterial composition associated with increased risk of asthma. These findings broaden our understanding of AMR in early life and have critical implications for efforts to mitigate its spread.
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http://dx.doi.org/10.1016/j.chom.2021.03.017DOI Listing
June 2021

Neonatal airway immune profiles and asthma and allergy endpoints in childhood.

Allergy 2021 Apr 16. Epub 2021 Apr 16.

COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Background: The immune system plays a key role in the pathogenesis of asthma and allergy, but the role of the airway cytokine and chemokine composition in vivo in early life prior to symptom development has not been described previously. Here, we aimed to examine whether the neonatal airway immune composition associates with development of allergy and asthma in childhood.

Methods: We measured unstimulated levels of 20 immune mediators related to the Type 1, Type 2, Type 17, or regulatory immune pathways in the airway mucosal lining fluid of 620 one-month-old healthy neonates from the COPSAC birth cohort. Allergy and asthma were diagnosed at our research clinic by predefined algorithms and objective assessments at age 6 years. Principal component analyses were used to describe the airway cytokine and chemokine composition.

Results: A neonatal airway immune profile particularly characterized by enhanced IL-1β and reduced CCL26 was significantly associated with later development of elevated specific IgE to inhaled allergens, a positive skin prick test, and allergic rhinitis, but not with food sensitization. Conversely, reduced Type 17 immune-associated markers, including IL-1β and CXCL8, showed trend of association with development of early asthma endpoints.

Conclusions: Development of early asthma endpoints and inhalant allergy during the first 6 years of life seems associated with distinctly perturbed airway immune profiles in neonatal life, which is suggestive of an early origin and different pathogenesis of childhood asthma and allergy. These exploratory findings suggest pre- and perinatal life as an important window of opportunity for prevention of asthma and inhalant allergy.
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http://dx.doi.org/10.1111/all.14862DOI Listing
April 2021

The Airway Microbiota Modulates Effect of Azithromycin Treatment for Episodes of Recurrent Asthma-like Symptoms in Preschool Children: A Randomized Clinical Trial.

Am J Respir Crit Care Med 2021 Mar 17. Epub 2021 Mar 17.

Gentofte Hospital, 53147, COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Hellerup, Denmark;

Rationale Childhood asthma is often preceded by recurrent episodes of asthma-like symptoms, which can be triggered by both viral and bacterial agents. Recent randomized controlled trials have shown that azithromycin treatment reduces episode duration and severity through yet undefined mechanisms. Objectives Here, we studied the influence of the airway microbiota on the effect of azithromycin treatment during acute episodes of asthma-like symptoms. Methods Children from the Copenhagen Studies on Asthma in Childhood 2010 (COPSAC2010) cohort with recurrent asthma-like symptoms aged 12-36 months were randomized during acute episodes to azithromycin or placebo as previously reported. Prior to randomization, hypopharyngeal aspirates were collected and examined by 16S rRNA gene amplicon sequencing. Measurements and Main Results In 139 airway samples from 68 children, episode duration after randomization was associated with microbiota richness (7.5% increased duration per 10 additional Operational Taxonomic Units (OTUs), 95% confidence interval [1%;14%], p=0.025), with 15 individual OTUs (including several Neisseria and Veillonella), and with microbial pneumotypes defined from weighted UniFrac distances (longest durations in a Neisseria-dominated pneumotype). Microbiota richness before treatment increased the effect of azithromycin by 10% per 10 additional OTUs, and more OTUs were positively vs. negatively associated with increased azithromycin effect (82 vs. 58, p=0.0032). Furthermore, effect modification of azithromycin was found for 5 individual OTUs (3 increased and 2 decreased the effect, q<0.05). Conclusions The airway microbiota in acute episodes of asthma-like symptoms is associated with episode duration and modifies the effect of azithromycin treatment of the episodes in preschool children with recurrent asthma-like symptoms. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT01233297.
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http://dx.doi.org/10.1164/rccm.202008-3226OCDOI Listing
March 2021

Cost of Illness in Young Children: A Prospective Birth Cohort Study.

Children (Basel) 2021 Feb 24;8(3). Epub 2021 Feb 24.

Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, 2820 Gentofte, Denmark.

Childhood illness is extremely common and imposes a considerable economic burden on society. We aimed to quantify the overall economic burden of childhood illness in the first three years of life and the impact of environmental risk factors. The study is based on the prospective, clinical mother-child cohort Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) of 700 children with embedded randomized trials of fish-oil and vitamin D supplementations during pregnancy. First, descriptive analyses were performed on the total costs of illness, defined as both the direct costs (hospitalizations, outpatient visits, visit to the practitioner) and the indirect costs (lost earnings) collected from the Danish National Health Registries. Thereafter, linear regression analyses on log-transformed costs were used to investigate environmental determinants of the costs of illness. The median standardized total cost of illness at age 0-3 years among the 559 children eligible for analyses was EUR 14,061 (IQR 9751-19,662). The exposures associated with reduced costs were fish-oil supplementation during pregnancy (adjusted geometric mean ratio (GMR) 0.89 (0.80; 0.98), = 0.02), gestational age in weeks (aGMR = 0.93 (0.91; 0.96), < 0.0001), and birth weight per 100 g (aGMR 0.98 (0.97; 0.99), = 0.0003), while cesarean delivery was associated with higher costs (aGMR = 1.30 (1.15; 1.47), < 0.0001). In conclusion, common childhood illnesses are associated with significant health-related costs, which can potentially be reduced by targeting perinatal risk factors, including maternal diet during pregnancy, cesarean delivery, preterm birth and low birth weight.
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http://dx.doi.org/10.3390/children8030173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996350PMC
February 2021

Maternal 17q21 genotype influences prenatal vitamin D effects on offspring asthma/recurrent wheeze.

Eur Respir J 2021 Mar 2. Epub 2021 Mar 2.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.

Background: Prenatal vitamin D supplementation has been linked to reduced risk of early life asthma/recurrent wheeze. This protective effect appears to be influenced by variations in the 17q21 functional SNP rs12936231 of the child, which regulates the expression of and for which the high-risk CC-genotype is associated with early-onset asthma. However, this does not fully explain the differential effects of supplementation. We investigated the influence of maternal rs12936231 genotype variation on the protective effect of prenatal vitamin D supplementation against offspring asthma/recurrent wheeze.

Methods: We determined the rs12936231 genotype of mother-child pairs from two randomised-controlled trials: the Vitamin D Antenatal Asthma Reduction Trial (VDAART, n=613) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC, n=563) to examine the effect of maternal genotype variation on offspring asthma/recurrent wheeze at age 0-3 years between groups who received high-dose prenatal vitamin D supplementation placebo.

Results: Offspring of mothers with low-risk GG-genotype or GC-genotype who received high-dose vitamin D supplementation had a significantly reduced risk of asthma/recurrent wheeze when compared to the placebo group (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.37-0.77; p<0.001 for VDAART and HR, 0.56; 95% CI, 0.35-0.92; p=0.021 for COPSAC), whereas no difference was observed among the offspring of mothers with high-risk CC-genotype (HR, 1.05; 95% CI, 0.61-1.84; p=0.853 for VDAART and HR, 1.11; 95% CI, 0.54-2.28; p=0.785 for COPSAC).

Conclusion: Maternal 17q21 genotype has an important influence on the protective effects of prenatal vitamin D supplementation against offspring asthma/recurrent wheeze.
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http://dx.doi.org/10.1183/13993003.02012-2020DOI Listing
March 2021

Characteristics and Mechanisms of a Sphingolipid-associated Childhood Asthma Endotype.

Am J Respir Crit Care Med 2021 04;203(7):853-863

Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital-University of Copenhagen, Gentofte, Denmark.

A link among sphingolipids, 17q21 genetic variants, and childhood asthma has been suggested, but the underlying mechanisms and characteristics of such an asthma endotype remain to be elucidated. To study the sphingolipid-associated childhood asthma endotype using multiomic data. We used untargeted liquid chromatography-mass spectrometry plasma metabolomic profiles at the ages of 6 months and 6 years from more than 500 children in the COPSAC (Copenhagen Prospective Studies on Asthma in Childhood) birth cohort focusing on sphingolipids, and we integrated the 17q21 genotype and nasal gene expression of SPT (serine palmitoyl-CoA transferase) (i.e., the rate-limiting enzyme in sphingolipid synthesis) in relation to asthma development and lung function traits from infancy until the age 6 years. Replication was sought in the independent VDAART (Vitamin D Antenatal Asthma Reduction Trial) cohort. Lower concentrations of ceramides and sphingomyelins at the age of 6 months were associated with an increased risk of developing asthma before age 3, which was also observed in VDAART. At the age of 6 years, lower concentrations of key phosphosphingolipids (e.g., sphinganine-1-phosphate) were associated with increased airway resistance. This relationship was dependent on the 17q21 genotype and nasal SPT gene expression, with significant interactions occurring between the genotype and the phosphosphingolipid concentrations and between the genotype and SPT expression, in which lower phosphosphingolipid concentrations and reduced SPT expression were associated with increasing numbers of at-risk alleles. However, the findings did not pass the false discovery rate threshold of <0.05. This exploratory study suggests the existence of a childhood asthma endotype with early onset and increased airway resistance that is characterized by reduced sphingolipid concentrations, which are associated with 17q21 genetic variants and expression of the SPT enzyme.
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http://dx.doi.org/10.1164/rccm.202008-3206OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017574PMC
April 2021

Fish Oil Supplementation in Pregnancy and Neurodevelopment in Childhood-A Randomized Clinical Trial.

Child Dev 2021 Jan 28. Epub 2021 Jan 28.

University of Copenhagen.

A double-blind randomized controlled trial of n-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) supplementation or matching placebo during third trimester of pregnancy was conducted within the COPSAC mother-child cohort consisting of 736 women and their children. The objective was to determine if maternal n-3 LCPUFA pregnancy supplementation affects offspring neurodevelopment until 6 years. Neurodevelopment was evaluated in 654 children assessing age of motor milestone achievement, language development, cognitive development, general neurodevelopment, and emotional and behavioral problems. Maternal n-3 LCPUFA supplementation during pregnancy improved early language development and reduced the impact of emotional and behavioral problems. The n-3 LCPUFA supplementation was in boys associated with the earlier achievement of gross motor milestones, improved cognitive development, and a reduced impact of emotional and behavioral problems.
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http://dx.doi.org/10.1111/cdev.13541DOI Listing
January 2021

Maternal Metabolome in Pregnancy and Childhood Asthma or Recurrent Wheeze in the Vitamin D Antenatal Asthma Reduction Trial.

Metabolites 2021 Jan 23;11(2). Epub 2021 Jan 23.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

The in utero environment during pregnancy has important implications for the developing health of the child. We aim to examine the potential impact of maternal metabolome at two different timepoints in pregnancy on offspring respiratory health in early life. In 685 mother-child pairs from the Vitamin D Antenatal Asthma Reduction Trial, we assessed the prospective associations between maternal metabolites at both baseline (10-18 weeks gestation) and third trimester (32-38 weeks gestation) and the risk of child asthma or recurrent wheeze by age three using logistic regression models accounting for confounding factors. Subgroup analyses were performed by child sex. Among 632 metabolites, 19 (3.0%) and 62 (9.8%) from baseline and third trimester, respectively, were associated with the outcome (-value < 0.05). Coffee-related metabolites in the maternal metabolome appeared to be of particular importance. Caffeine, theophylline, trigonelline, quinate, and 3-hydroxypyridine sulfate were inversely associated with asthma risk at a minimum of one timepoint. Additional observations also highlight the roles of steroid and sphingolipid metabolites. Overall, there was a stronger relationship between the metabolome in later pregnancy and offspring asthma risk. Our results suggest that alterations in prenatal metabolites may act as drivers of the development of offspring asthma.
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http://dx.doi.org/10.3390/metabo11020065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910853PMC
January 2021

Large-scale association analyses identify host factors influencing human gut microbiome composition.

Nat Genet 2021 02 18;53(2):156-165. Epub 2021 Jan 18.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10 < P < 5 × 10) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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http://dx.doi.org/10.1038/s41588-020-00763-1DOI Listing
February 2021

High-dose vitamin D during pregnancy and pathway gene polymorphisms in prevention of offspring persistent wheeze.

Pediatr Allergy Immunol 2021 May 20;32(4):679-689. Epub 2021 Feb 20.

COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Background: Randomized controlled trials (RCTs) suggest a protective effect of high-dose vitamin D supplementation in pregnancy on offspring risk of persistent wheeze, but only in some individuals, which might be explained by variations in vitamin D pathway genes. This study aimed to investigate the effect of vitamin D supplementation by maternal and offspring vitamin D receptor (VDR) genotype and GC genotype, encoding vitamin D binding protein (VDBP), in two RCTs.

Methods: In the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC ) RCT, we analyzed the effect of high-dose vitamin D during pregnancy on the risk of persistent wheeze age 0-3 years by variants in single nucleotide polymorphisms (SNPs) in VDR (rs1544410, rs2228570, rs7975128, rs7975232) and GC (rs4588, rs7041). Replication was sought in the Vitamin D Antenatal Asthma Reduction Trial (VDAART).

Results: In COPSAC , VDR SNP rs1544410 influenced the effect of high-dose vitamin D: maternal P  = .049 and child P  = .001, with the largest effect in offspring from mothers with TT genotype: hazard ratio (95% CI), 0.26 (0.10-0.68), P = .006, and no effect among CT or CC genotypes: 0.85 (0.48-1.51), P = .58 and 0.94 (0.47-1.89), P = .87, respectively. However, these findings were not replicated in VDAART. There was no significant effect modification from maternal or offspring GC genotype in either COPSAC or VDAART: all P  ≥ .17.

Conclusions: We found that the effect of high-dose vitamin D supplementation during pregnancy on offspring risk of persistent wheeze was significantly influenced by VDR genotype in the COPSAC RCT, but not VDAART, which may be due to population differences.
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http://dx.doi.org/10.1111/pai.13453DOI Listing
May 2021

Modeling transfer of vaginal microbiota from mother to infant in early life.

Elife 2021 Jan 15;10. Epub 2021 Jan 15.

Section of Microbiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.

Early-life microbiota has been linked to the development of chronic inflammatory diseases. It has been hypothesized that maternal vaginal microbiota is an important initial seeding source and therefore might have lifelong effects on disease risk. To understand maternal vaginal microbiota's role in seeding the child's microbiota and the extent of delivery mode-dependent transmission, we studied 665 mother-child dyads from the COPSAC cohort. The maternal vaginal microbiota was evaluated twice in the third trimester and compared with the children's fecal (at 1 week, 1 month, and 1 year of age) and airway microbiota (at 1 week, 1 month, and 3 months). Based on the concept of weighted transfer ratios (WTRs), we have identified bacterial orders for which the WTR displays patterns indicate persistent or transient transfer from the maternal vaginal microbiome, as well as orders that are shared at later time points independent of delivery mode, indicating a common reservoir.
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http://dx.doi.org/10.7554/eLife.57051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810462PMC
January 2021

Urbanized microbiota in infants, immune constitution, and later risk of atopic diseases.

J Allergy Clin Immunol 2020 Dec 15. Epub 2020 Dec 15.

Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Gentofte, Denmark.

Background: Urbanization is linked with an increased burden of asthma and atopic traits. A putative mechanism is insufficient exposure to beneficial microbes early in life, leading to immune dysregulation, as was previously shown for indoor microbial exposures.

Objective: Our aim was to investigate whether urbanization is associated with the microbiota composition in the infants' body and early immune function, and whether these contribute to the later risk of asthma and atopic traits.

Methods: We studied the prospective Copenhagen Prospective Studies on Asthma in Childhood 2010 mother-child cohort of 700 children growing up in areas with different degrees of urbanization. During their first year of life, airway and gut microbiotas, as well as immune marker concentrations, were defined. When the children were 6 years of age, asthma and atopic traits were diagnosed by pediatricians.

Results: In adjusted analyses, the risk of asthma and aeroallergen sensitization were increased in urban infants. The composition of especially airway but also gut microbiotas differed between urban and rural infants. The living environment-related structure of the airway microbiota was already associated with immune mediator concentrations at 1 month of age. An urbanized structure of the airway and gut microbiotas was associated with an increased risk of asthma coherently during multiple time points and also with the risks of eczema and sensitization.

Conclusion: Our findings suggest that urbanization-related changes in the infant microbiota may elevate the risk of asthma and atopic traits, probably via cross talk with the developing immune system. The airways may facilitate this effect, as they are open for colonization by environmental airborne microbes and serve as an immune interface.
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http://dx.doi.org/10.1016/j.jaci.2020.12.621DOI Listing
December 2020

FUT2-ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses.

Nat Commun 2020 12 16;11(1):6398. Epub 2020 Dec 16.

Department of Human Genetics, University of Chicago, Chicago, IL, USA.

Asthma with severe exacerbation is the most common cause of hospitalization among young children. We aim to increase the understanding of this clinically important disease entity through a genome-wide association study. The discovery analysis comprises 2866 children experiencing severe asthma exacerbation between ages 2 and 6 years, and 65,415 non-asthmatic controls, and we replicate findings in 918 children from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) birth cohorts. We identify rs281379 near FUT2/MAMSTR on chromosome 19 as a novel risk locus (OR = 1.18 (95% CI = 1.11-1.25), P = 2.6 × 10) as well as a biologically plausible interaction between functional variants in FUT2 and ABO. We further discover and replicate a potential causal mechanism behind this interaction related to S. pneumoniae respiratory illnesses. These results suggest a novel mechanism of early childhood asthma and demonstrates the importance of phenotype-specificity for discovery of asthma genes and epistasis.
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http://dx.doi.org/10.1038/s41467-020-19814-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744576PMC
December 2020

High-Dose Vitamin D Supplementation in Pregnancy and Neurodevelopment in Childhood: A Prespecified Secondary Analysis of a Randomized Clinical Trial.

JAMA Netw Open 2020 12 1;3(12):e2026018. Epub 2020 Dec 1.

Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Importance: Observational studies have reported an association between high maternal vitamin D levels and improved neurodevelopment in offspring, but no randomized clinical trial (RCT) has investigated these observations.

Objective: To determine whether high-dose vitamin D supplementation during pregnancy improves offspring neurodevelopment from birth to age 6 years.

Design, Setting, And Participants: This prespecified secondary analysis of a double-blinded, placebo-controlled RCT of high-dose vitamin D3 supplementation vs standard dose during the third trimester of pregnancy was conducted in the unselected prospective mother-child birth cohort at a single-center research unit in Denmark as part of the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC-2010). Participants included pregnant women; women with vitamin D intake greater than 600 IU/d or an endocrine, heart, or kidney disorder, and those who did not speak Danish fluently were excluded. Neurodevelopmental assessments for offspring of these women were performed at ages 0 to 6 years. Children born prematurely (gestational week <37), with low birth weight (<2500 g), or with a neurological disease affecting neurodevelopment were excluded. Data were analyzed from August 2019 to February 2020.

Interventions: High-dose (ie, 2800 IU/d) vs standard dose (ie, 400 IU/d) vitamin D3 supplementation from pregnancy week 24 until 1 week after birth.

Main Outcomes And Measures: The primary outcome of interest was cognitive development assessed at 2.5 years using the Bayley Scales of Infant and Toddler Development. Other neurodevelopmental outcomes included age of motor milestone achievement (Denver Developmental Index and World Health Organization milestone registration), language development (MacArthur-Bates Communicative Development Inventories), general neurodevelopment at age 3 years (Ages and Stages Questionnaire), and emotional and behavioral problems at age 6 years (Strengths and Difficulties Questionnaire).

Results: Among 623 women randomized, 315 were randomized to high-dose vitamin D3 and 308 were randomized to standard dose placebo. A total of 551 children were evaluated from birth to age 6 years, (282 [51.2%] boys; 528 [95.8%] White), with 277 children in the high-dose vitamin D3 group and 274 children in the standard dose group. There was no effect of the high-dose compared with standard dose of vitamin D3 supplementation during pregnancy on offspring achievement of motor milestones (β = 0.08 [95% CI, -0.26 to 0.43]; P = .64), cognitive development (score difference: 0.34 [95% CI, -1.32 to 1.99]; P = .70), general neurodevelopment (median [IQR] communication score: 50 [50-55] vs 50 [50-55]; P = .62), or emotional and behavioral problems (odds ratio, 0.76 [95% CI, 0.53 to 1.09]; P = .14). There was no effect on language development expressed by the word production at 1 year (median [IQR], 2 [0-6] words vs 3 [1-6] words; P = .16), although a decreased word production was apparent at 2 years in children in the high-dose vitamin D3 group (median [IQR], 232 [113-346] words vs 253 [149-382.5] words; P = .02).

Conclusions And Relevance: In this prespecified secondary analysis of an RCT, maternal high-dose vitamin D3 supplementation during the third trimester of pregnancy did not improve neurodevelopmental outcomes in the offspring during the first 6 years of life. These findings contribute essential information clarifying the effects of prenatal exposure to vitamin D on neurodevelopment in childhood.

Trial Registration: ClinicalTrials.gov Identifier: NCT00856947.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.26018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724557PMC
December 2020

Delivery mode and gut microbial changes correlate with an increased risk of childhood asthma.

Sci Transl Med 2020 11;12(569)

COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, 2820 Copenhagen, Denmark.

There have been reports of associations between cesarean section delivery and the risk of childhood asthma, potentially mediated through changes in the gut microbiota. We followed 700 children in the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) cohort prospectively from birth. We examined the effects of cesarean section delivery on gut microbial composition by 16 rRNA gene amplicon sequencing during the first year of life. We then explored whether gut microbial perturbations due to delivery mode were associated with a risk of developing asthma in the first 6 years of life. Delivery by cesarean section was accompanied by marked changes in gut microbiota composition at one week and one month of age, but by one year of age only minor differences persisted compared to vaginal delivery. Increased asthma risk was found in children born by cesarean section only if their gut microbiota composition at 1 year of age still retained a cesarean section microbial signature, suggesting that appropriate maturation of the gut microbiota could mitigate against the increased asthma risk associated with gut microbial changes due to cesarean section delivery.
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http://dx.doi.org/10.1126/scitranslmed.aax9929DOI Listing
November 2020

Airway immune mediator levels during asthma-like symptoms in young children and their possible role in response to azithromycin.

Allergy 2021 Jun 20;76(6):1754-1764. Epub 2020 Nov 20.

COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Background: Asthma-like symptoms in young children are orchestrated by the local airway immune response, but current knowledge largely relies on in vitro airway models. Azithromycin has been shown to reduce the duration of episodes with asthma-like symptoms, but efficacy may depend on the individual child's immune response.

Objectives: To investigate in vivo upper airway immune mediator levels during episodes with asthma-like symptoms in young children and their ability to predict the clinical response to azithromycin treatment.

Methods: A total of 535 children aged 0-3 years from the Copenhagen Prospective Studies of Asthma in Childhood-2010 mother-child cohort were examined for immune mediator levels in samples of nasal epithelial lining fluid during episodes with asthma-like symptoms as well as in the asymptomatic state. In a sub-study, children with recurrent asthma-like symptoms were randomized to either a 3-day course of oral azithromycin (10 mg/kg; n = 32) or placebo (n = 38). In the current study, we compared the pretreatment immune mediator levels with the clinical response to treatment with azithromycin in an exploratory post hoc analysis.

Results: The immune mediator concentrations during vs outside episodes were significantly upregulated for IFN-ɣ (ratio 1.73), TNF-α (ratio 2.05), IL-1β (ratio 1.45), IL-10 (ratio 1.97), while CCL22 (ratio 0.65) was downregulated. Low levels of TNF-α and IL-10 and high levels of CCL22 predicted better treatment response to azithromycin (P-values < .05).

Conclusion: Upper airway immune mediator levels were altered during episodes of asthma-like symptoms, and levels of TNF-α, CCL22, and IL-10 may predict the response to azithromycin treatment.
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http://dx.doi.org/10.1111/all.14651DOI Listing
June 2021

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

PLoS Genet 2020 10 12;16(10):e1008718. Epub 2020 Oct 12.

Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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http://dx.doi.org/10.1371/journal.pgen.1008718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581004PMC
October 2020

[Allergitest hos børn: flere spørgsmål end svar].

Authors:
Hans Bisgaard

Ugeskr Laeger 2020 09;182(38)

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September 2020

Association between childhood asthma and attention deficit hyperactivity or autism spectrum disorders: A systematic review with meta-analysis.

Clin Exp Allergy 2021 Feb 13;51(2):228-252. Epub 2020 Oct 13.

COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Background: Children with asthma are at risk of depression and anxiety and growing evidence suggest they may also be at risk of attention deficit hyperreactivity disorder (ADHD) and autism spectrum disorder (ASD). Here, we conducted a systematic review with meta-analysis of studies investigating association between asthma and ADHD or ASD in children.

Methods: A comprehensive search using PubMed, EMBASE and Cochrane Library databases was completed in March 2019. Observational human studies published in English, clinic-based or population-based with a healthy comparator group, evaluating asthma-ADHD or asthma-ASD overlap in children 18 years or younger using categorical diagnoses (yes/no) were considered for inclusion. Random effects meta-analysis models were used to analyse data. The Newcastle Ottawa Scale was used to evaluate risk of bias.

Results: A total of 25 asthma-ADHD studies were included of which 17 showed significant positive associations and one a negative association: 17/25 studies were population-based, 19/25 were cross-sectional or cohort studies and 7/25 had a low risk of bias. We performed a meta-analysis of 23 of the studies, which showed a significant association between asthma and ADHD: odds ratio (OR) 1.52 (1.42-1.63), P < .001, I2 = 60%. All studies were adjusted for age and sex and a large proportion; that is, 19/23 were further adjusted for relevant confounders. Seventeen asthma-ASD studies were included, whereof 7 showed a positive association and 3 a negative association; 8/17 were population-based with a cross-sectional study design and 4/17 had a low risk of bias. We performed a meta-analysis of 14 of the studies, which did not show a significant association between asthma and ASD: OR 1.12 (0.93-1.34), P = .24, I2 = 89%. All studies were adjusted for age and sex and 10/14 were further adjusted for relevant confounders.

Conclusions: This systematic review with meta-analyses shows a significant overlap between asthma and ADHD, but not between asthma and ASD in children. Clinicians taking care of children with asthma or ADHD should be aware of such association to aid an early diagnosis and treatment of such comorbidity.
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http://dx.doi.org/10.1111/cea.13750DOI Listing
February 2021

Symptom burden of atopic dermatitis in early childhood assessed from daily monitoring of symptoms and topical steroid use.

J Am Acad Dermatol 2021 Mar 18;84(3):725-734. Epub 2020 Sep 18.

Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health and Medical Sciences and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Background: To our knowledge, disease burden of atopic dermatitis (AD) as number of days with symptoms and medical treatment has never been studied as measure of severity.

Objectives: To investigate risk factors for AD burden in the first 3 years of life.

Methods: The Copenhagen Prospective Studies on Asthma in Childhood included 700 children. AD burden was assessed by daily diary entries with information on AD and steroid days measuring 18 possible heritable, prenatal, and postnatal environmental exposures.

Results: The children with AD had a median (interquartile range) of 136 symptom days (61-294 days) and 72 steroid days (27-145 days) during the first 3 years of life, with the highest disease burden in the second year of life. The multivariable risk factor analysis showed that maternal AD and childhood allergic sensitization were associated with a higher number of AD days and maternal AD, filaggrin mutation, and allergic sensitization were associated with a higher number of steroid days.

Limitations: Participants with a personal interest in atopic diseases could be more likely to participate.

Conclusion: Children's burden of AD, assessed quantitatively as AD and steroid days, demonstrated positive associations with maternal AD, filaggrin mutation, and early-life allergic sensitization, with the highest disease burden in the second year of life.
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http://dx.doi.org/10.1016/j.jaad.2020.09.038DOI Listing
March 2021

Delayed Motor Milestones Achievement in Infancy Associates with Perturbations of Amino Acids and Lipid Metabolic Pathways.

Metabolites 2020 Aug 19;10(9). Epub 2020 Aug 19.

COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, 1017 Copenhagen, Denmark.

The relationship between developmental milestone achievement in infancy and later cognitive function and mental health is well established, but underlying biochemical mechanisms are poorly described. Our study aims to discover pathways connected to motor milestone achievement during infancy by using untargeted plasma metabolomic profiles from 571 six-month-old children in connection with age of motor milestones achievement (Denver Developmental Index) in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) mother-child cohort. We used univariate regression models and multivariate modelling (Partial Least Squares Discriminant Analysis: PLS-DA) to examine the associations and the VDAART (Vitamin D Antenatal Asthma Reduction Trial) cohort for validation. The univariate analyses showed 62 metabolites associated with gross-motor milestone achievement ( < 0.05) as well as the PLS-DA significantly differentiated between slow and fast milestone achievers (AUC = 0.87, = 0.01). Higher levels of tyramine-O-sulfate in the tyrosine pathway were found in the late achievers in COPSAC ( = 0.0002) and in VDAART ( = 0.02). Furthermore, we observed that slow achievers were characterized by higher levels of fatty acids and products of fatty acids metabolism including acyl carnitines. Finally, we also observed changes in the lysine, histidine, glutamate, creatine and tryptophan pathways. Observing these metabolic changes in relation to gross-motor milestones in the first year of life, may be of importance for later cognitive function and mental health.
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http://dx.doi.org/10.3390/metabo10090337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570268PMC
August 2020

Maternal High-Dose Vitamin D Supplementation and Offspring Bone Mineralization Until Age 6 Years-Reply.

JAMA Pediatr 2021 Jan;175(1):104

Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

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http://dx.doi.org/10.1001/jamapediatrics.2020.2017DOI Listing
January 2021

Environmental shaping of the bacterial and fungal community in infant bed dust and correlations with the airway microbiota.

Microbiome 2020 08 7;8(1):115. Epub 2020 Aug 7.

Section of Microbiology, Department of Biology, University of Copenhagen, Universitetsparken 15, bldg. 1, DK2100, Copenhagen, Denmark.

Background: From early life, children are exposed to a multitude of environmental exposures, which may be of crucial importance for healthy development. Here, the environmental microbiota may be of particular interest as it represents the interface between environmental factors and the child. As infants in modern societies spend a considerable amount of time indoors, we hypothesize that the indoor bed dust microbiota might be an important factor for the child and for the early colonization of the airway microbiome. To explore this hypothesis, we analyzed the influence of environmental exposures on 577 dust samples from the beds of infants together with 542 airway samples from the Copenhagen Prospective Studies on Asthma in Childhood cohort.

Results: Both bacterial and fungal community was profiled from the bed dust. Bacterial and fungal diversity in the bed dust was positively correlated with each other. Bacterial bed dust microbiota was influenced by multiple environmental factors, such as type of home (house or apartment), living environment (rural or urban), sex of siblings, and presence of pets (cat and/or dog), whereas fungal bed dust microbiota was majorly influenced by the type of home (house or apartment) and sampling season. We further observed minor correlation between bed dust and airway microbiota compositions among infants. We also analyzed the transfer of microbiota from bed dust to the airway, but we did not find evidence of transfer of individual taxa.

Conclusions: Current study explores the influence of environmental factors on bed dust microbiota (both bacterial and fungal) and its correlation with airway microbiota (bacterial) in early life using high-throughput sequencing. Our findings demonstrate that bed dust microbiota is influenced by multiple environmental exposures and could represent an interface between environment and child. Video Abstract.
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http://dx.doi.org/10.1186/s40168-020-00895-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414761PMC
August 2020

Epigenetic landscape links upper airway microbiota in infancy with allergic rhinitis at 6 years of age.

J Allergy Clin Immunol 2020 12 18;146(6):1358-1366. Epub 2020 Jul 18.

Departments of Human Genetics, The University of Chicago, Chicago, Ill. Electronic address:

Background: The upper airways present a barrier to inhaled allergens and microbes, which alter immune responses and subsequent risk for diseases, such as allergic rhinitis (AR).

Objective: We tested the hypothesis that early-life microbial exposures leave a lasting signature in DNA methylation that ultimately influences the development of AR in children.

Methods: We studied upper airway microbiota at 1 week, 1 month, and 3 months of life, and measured DNA methylation and gene expression profiles in upper airway mucosal cells and assessed AR at age 6 years in children in the Copenhagen Prospective Studies on Asthma in Childhood birth cohort.

Results: We identified 956 AR-associated differentially methylated CpGs in upper airway mucosal cells at age 6 years, 792 of which formed 3 modules of correlated differentially methylated CpGs. The eigenvector of 1 module was correlated with the expression of genes enriched for lysosome and bacterial invasion of epithelial cell pathways. Early-life microbial diversity was lower at 1 week (richness P = .0079) in children with AR at age 6 years, and reduced diversity at 1 week was also correlated with the same module's eigenvector (ρ = -0.25; P = 3.3 × 10). We show that the effect of microbiota richness at 1 week on risk for AR at age 6 years was mediated in part by the epigenetic signature of this module.

Conclusions: Our results suggest that upper airway microbial composition in infancy contributes to the development of AR during childhood, and this trajectory is mediated, at least in part, through altered DNA methylation patterns in upper airway mucosal cells.
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http://dx.doi.org/10.1016/j.jaci.2020.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821422PMC
December 2020

Effect of prenatal bisphenol A exposure on early childhood body mass index through epigenetic influence on the insulin-like growth factor 2 receptor (IGF2R) gene.

Environ Int 2020 10 6;143:105929. Epub 2020 Jul 6.

Institute of Environmental Medicine, Seoul National University Medical Research Center, Seoul 03080, Republic of Korea; Section of Environmental Epidemiology, Department of Public Health, University of Copenhagen, Copenhagen 1014, Denmark. Electronic address:

Objectives: Epigenetic mechanisms have been suggested to play a role in the link between in utero exposure to bisphenol A (BPA) and pediatric obesity; however, there is little evidence regarding this mechanism in humans. We obtained data on obesity-associated CpG sites from a previous epigenome-wide association study, and then examined whether methylation at those CpG sites was influenced by prenatal BPA exposure. We then evaluated the relationship between CpG methylation status and body mass index (BMI) in a prospective children's cohort at ages 2, 4, 6, and 8 years.

Methods: Methylation profiles of 59 children were longitudinally analyzed at ages 2 and 6 years using the Infinium Human Methylation BeadChip. A total of 594 CpG sites known to be BMI or obesity-associated sites were tested for an association with prenatal BPA levels, categorized into low and high exposure groups based on the 80th percentile of maternal BPA levels (2.68 μg/g creatinine), followed by an analysis of the association between DNA methylation and BMI from ages 2-8.

Results: There was a significant increase in the methylation levels of cg19196862 (IGF2R) in the high BPA group at age 2 years (p = 0.00030, false discovery rate corrected p < 0.10) but not at age 6. With one standard deviation increase of methylation at cg19196862 (IGF2R) at age 2 years, the linear mixed model analysis revealed that BMI during ages 2-8 years significantly increased by 0.49 (95% confidence interval; 0.08, 0.90) in girls, but not in boys. The indirect effect of prenatal BPA exposure on early childhood BMI through methylation at cg19196862 (IGF2R) at age 2 years was marginally significant.

Conclusions: Prenatal exposure to BPA may influence differential methylation of IGF2R at age 2. This result indicates that a possible sensitive period of DNA methylation occurs earlier during development, which may affect BMI until later childhood in a sex-specific manner.
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http://dx.doi.org/10.1016/j.envint.2020.105929DOI Listing
October 2020

Parent-specific effects on risk of developing allergic sensitization and asthma in childhood.

Clin Exp Allergy 2020 08 7;50(8):915-921. Epub 2020 Jul 7.

COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

Background: Parent's history of atopic traits increases the risk of the same traits in their children, but mother's history may confer an increased risk compared to father's history.

Objective: To investigate parent-specific effects on risk of developing allergic sensitization and asthma in childhood.

Methods: We included 685 parent-child trios from the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) cohort. Parent's asthma was assessed by structured interviews and child's asthma was diagnosed prospectively at regular visits to the COPSAC clinic until age 6. Specific IgE and total IgE levels were measured in parents and children by age 0.5, 1.5 and 6 years. Associations between parent and child disease traits were analyzed using general estimating equations model adjusted for breastfeeding and maternal smoking during 3rd trimester.

Results: Maternal compared to paternal elevated specific IgE increased the child's risk of elevated specific IgE from 0-6 years: adjusted odds ratio (aOR)mother = 1.49 [1.09-2.03], P = .01 and aORfather = 1.32 [0.96-1.82], P = .08. Maternal elevated total IgE also increased the child's risk of elevated total IgE: adjusted relative risk (aOR)mother = 4.32 [1.51-10.8], P < .01, while a trend was observed for paternal total IgE: aORfather = 2.01 [0.76-4.82], P = .13. Individual time point analyses showed that the maternal effect was strongest in early life, whereas the parental effects were comparable by age 6. A similar parent-specific pattern was observed for the child's risk of asthma.

Conclusions And Clinical Relevance: The effect of mother's history of atopic traits on the child's risk of developing the same traits in early childhood was stronger than the effect from father's history, which was not evident before age 6. This suggests that maternal non-genetic factors seem to confer an added disease risk to the child, particularly in early life.
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http://dx.doi.org/10.1111/cea.13670DOI Listing
August 2020