Impact of a pediatric primary care health-coaching program on change in health-related quality of life in children with mental health problems: results of the PrimA-QuO cohort study.

Mental health problems (MHP) have a considerable negative impact on health-related quality of life (HRQoL) in children and their families. A low threshold Health Coaching (HC) program has been introduced to bring MH services to primary care and strengthen the role of pediatricians. It comprised training concepts as a hands-on approach for pediatricians, standardization of diagnosis and treatment, and extended consultations. The aim of this study was to evaluate the potential effects of the HC on HRQoL in children with MHP and their parents.We used data from the PrimA-QuO cohort study conducted in Bavaria, Germany from November 2018 until November 2019, with two assessments one year apart. We included children aged 17 years or younger with developmental disorder of speech and language, non-organic enuresis, head and abdominal pain, and conduct disorder. All included children were already part of the Starke Kids (SK) program, a more general preventive care program, which includes additional developmental check-ups for children enrolled in the program. In addition,  treatment according to the HC guidelines can be offered to children and adolescents with mental health problems, who are already enrolled in the SK program. These children form the intervention group; while all others (members of BKK and SK but not HC) served as controls. HRQoL in children was assessed using the KINDL questionnaire. Parental HRQoL was measured by the visual analogue scale. To analyze the effects of the intervention on children´s HRQoL over the 1-year follow-up period, we used linear mixed effects models.We compared 342 children receiving HC with 767 control patients. We could not detect any effects of the HC on HRQoL in children and their parents. This may be attributed to the relatively high levels of children´s HRQoL at baseline, or because of highly motivated pediatricians for the controls because of the selection of only participant within the Starke Kids program. Generally, HRQoL was lower in older children (-0.42 points; 95% CI [-0.73; -0.11]) and in boys (-1.73 points; 95% CI [-3.11; -0.36]) when reported by proxy. Parental HRQoL improved significantly over time (2.59 points; 95% CI [1.29; 3.88]).Although this study was not able to quantitatively verify the positive impact of this HC that had been reported by a qualitative study with parents and other stakeholders, and a cost-effectiveness study, the approach of the HC may still be valid and improve health care of children with MHP and should be evaluated in a more general population.

Serum neurofilament light chain reference database for individual application in paediatric care: a retrospective modelling and validation study.

BACKGROUND: Neurological conditions represent an important driver of paediatric disability burden worldwide. Measurement of serum neurofilament light chain (sNfL) concentrations, a specific marker of neuroaxonal injury, has the potential to contribute to the management of children with such conditions. In this context, the European Medicines Agency recently declared age-adjusted reference values for sNfL a top research priority. We aimed to establish an age-adjusted sNfL reference range database in a population of healthy children and adolescents, and to validate this database in paediatric patients with neurological conditions to affirm its clinical applicability. METHODS: To generate a paediatric sNfL reference dataset, sNfL values were measured in a population of healthy children and adolescents (aged 0-22 years) from two large cohorts in Europe (the Coronavirus Antibodies in Kids from Bavaria study, Germany) and North America (a US Network of Paediatric Multiple Sclerosis Centers paediatric case-control cohort). Children with active or previous COVID-19 infection or SARS-CoV-2 antibody positivity at the time of sampling, or a history of primary systemic or neurological conditions were excluded. Linear models were used to restrospectively study the effect of age and weight on sNfL concentrations. We modelled the distribution of sNfL concentrations as a function of age-related physiological changes to derive reference percentile and Z score values via a generalised additive model for location, scale, and shape. The clinical utility of the new reference dataset was assessed in children and adolescents (aged 1-19 years) with neurological diseases (epilepsy, traumatic brain injury, bacterial CNS infections, paediatric-onset multiple sclerosis, and myelin oligodendrocyte glycoprotein antibody-associated disease) from the paediatric neuroimmunology clinic at the University of California San Francisco (San Francisco, CA, USA) and the Children's Hospital of the University of Regensburg (Regensburg, Germany). FINDINGS: Samples from 2667 healthy children and adolescents (1336 [50·1%] girls and 1331 [49·9%] boys; median age 8·0 years [IQR 4·0-12·0]) were used to generate the reference database covering neonatal age to adolescence (target age range 0-20 years). In the healthy population, sNfL concentrations decreased with age by an estimated 6·8% per year until age 10·3 years (estimated multiplicative effect per 1 year increase 0·93 [95% CI 0·93-0·94], p<0·0001) and was mostly stable thereafter up to age 22 years (1·00 [0·52-1·94], p>0·99). Independent of age, the magnitude of the effect of weight on sNfL concentrations was marginal. Samples from 220 children with neurological conditions (134 [60·9%] girls and 86 [39·1%] boys; median age 14·7 years [IQR 10·8-16·5]) were used to validate the clinical utility of the reference Z scores. In this population, age-adjusted sNfL Z scores were higher than in the reference population of healthy children and adolescents (p<0·0001) with higher effect size metrics (Cohen's d=1·56) compared with the application of raw sNfL concentrations (d=1·28). INTERPRETATION: The established normative sNfL values in children and adolescents provide a foundation for the clinical application of sNfL in the paediatric population. Compared with absolute sNfL values, the use of sNfL Z score was associated with higher effect size metrics and allowed for more accurate estimation of the extent of ongoing neuroaxonal damage in individual patients. FUNDING: Swiss National Science Foundation, US National Institutes of Health, and the National Multiple Sclerosis Society.

Longitudinal changes of mental health problems in children and adolescents treated in a primary care-based health-coaching programme - results of the PrimA-QuO cohort study.

BACKGROUND: In Germany, 19.1% of boys and 14.5% of girls are affected by mental health problems (MHP). Paediatricians are usually the first in line to be contacted but they often do not feel adequately trained to diagnose and treat MHP in primary care. A major statutory health insurance fund introduced a health coaching (HC) programme to strengthen primary care consultation for MHP. The HC includes a training concept for paediatricians, standardised guidelines for actions and additional payments. The aim of this study was to investigate the potential effects of the HC programme on the change of MHP in children and adolescents. METHODS: A prospective cohort study was conducted in Bavaria, Germany, in 2018 and 2019. Data were collected at 2 points 1 year apart using an online questionnaire. Parents of patients with developmental disorder of speech and language, head/abdominal pain, conduct disorder or non-organic enuresis were approached by their health insurance. Families treated according to the HC programme form the intervention group while all others serve as controls. MHP was assessed using the Strengths and Difficulties Questionnaire (SDQ) as a child self-assessment (SDQ-S)/or external assessment by parents (SDQ-P). Determinants of SDQ total score were analysed using linear mixed effects models. RESULTS: Cross-sectional (n = 1090) and longitudinal analyses (n = 599) were performed. At baseline, a total of 23.5% had an SDQ total score "at risk" (SDQ-S > 15/SDQ-P > 13). There were no significant differences between intervention and controls. After full adjustment for all potential confounders, higher SDQ scores indicating more problems were significantly associated with male sex (2.000, p < 0.001) whereas a high parental education level was significantly associated with decreased SDQ scores (-2.127, p =0.034). There was a significant improvement in the control group over time (-0.814, p = 0.001) while the SDQ scores in the intervention group remained stable (-0.012, p = 0.020). CONCLUSION: This evaluation of the HC programme could not prove a clinically relevant intervention's effect on the MHP developmental course. Nevertheless, (HC) paediatricians have crucial potential to improve the care of MHP patients. Targeting families with less access to support measures might help reduce the burden of MHP and be a step towards continuous improvement of care.

Cost Effects of a Health Coaching in Children and Adolescents With Mental Health and Developmental Disorders.

OBJECTIVE: Health coaching (HC) aims to strengthen the role of primary care pediatricians in the treatment of children and adolescents with mental health and developmental disorders by extending consultation time and using disease-specific manuals. We evaluated the effect of HC on costs of specialized, pediatrician, and overall care. METHODS: In a retrospective cohort study based on German health insurance claims data, we identified children aged up to 17 years with a newly diagnosed mental health and/or developmental disorder between 2013 and 2015. Patients getting HC were matched to patients receiving usual care. Costs were calculated for 1 year following the start of the treatment and compared by 2-part and gamma models. Absolute costs and cost differences were calculated with bootstrapped 95% confidence intervals (CI). RESULTS: We compared 5597 patients receiving HC with 5597 control patients. The probability of incurring specialized care costs was similar between the groups (0.96, 95% CI: 0.88; 1.05). However, for those who did incur costs, specialized care costs were significantly lower for HC-treated patients (0.77, 95% CI: 0.63; 0.93). Accordingly, specialized care costs were lower by €-94 (95% CI: €-175; €-18), while pediatrician care costs were higher for HC-treated patients by €57 (95% CI: €49; €64). Hence, overall costs did not differ between the groups (€-59, 95% CI: €-191; €71). CONCLUSION: Provision of HC has the potential to lower the costs of specialized care, while increasing the costs of pediatrician care. Overall costs did not differ, suggesting that the additional costs incurred by the HC were offset.

Symptoms, SARS-CoV-2 Antibodies, and Neutralization Capacity in a Cross Sectional-Population of German Children.

Background: Children and youth are affected rather mildly in the acute phase of COVID-19 and thus, SARS-CoV-2 infection infection may easily be overlooked. In the light of current discussions on the vaccinations of children it seems necessary to better identify children who are immune against SARS-CoV-2 due to a previous infection and to better understand COVID-19 related immune reactions in children. Methods: In a cross-sectional design, children aged 1-17 were recruited through primary care pediatricians for the study (a) randomly, if they had an appointment for a regular health check-up or (b) if parents and children volunteered and actively wanted to participate in the study. Symptoms were recorded and two antibody tests were performed in parallel directed against S (in house test) and N (Roche Elecsys) viral proteins. In children with antibody response in either test, neutralization activity was determined. Results: We identified antibodies against SARS-CoV-2 in 162 of 2,832 eligible children (5.7%) between end of May and end of July 2020 in three, in part strongly affected regions of Bavaria in the first wave of the pandemic. Approximately 60% of antibody positive children (n = 97) showed high levels (>97th percentile) of antibodies against N-protein, and for the S-protein, similar results were found. Sufficient neutralizing activity was detected for only 135 antibody positive children (86%), irrespective of age and sex. Initial COVID-19 symptoms were unspecific in children except for the loss of smell and taste and unrelated to antibody responses or neutralization capacity. Approximately 30% of PCR positive children did not show seroconversion in our small subsample in which PCR tests were performed. Conclusions: Symptoms of SARS-CoV-2 infections are unspecific in children and antibody responses show a dichotomous structure with strong responses in many and no detectable antibodies in PCR positive children and missing neutralization activity in a relevant proportion of the young population.

Mixed-methods evaluation of a structured primary care programme for children and adolescents with mental health problems (PrimA-QuO): a study protocol.

INTRODUCTION: More than 17% of German children and adolescents have clinically relevant mental health problems (MHP). Typically, general paediatricians are often the first contact for children with MHP, and referrals to specialised care tend to be the standard approach. A statutory health insurance fund developed a programme for children with MHP (Health Coaching (HC)) aiming to offer targeted but low-threshold services. However, little is known about whether HC has the potential for optimising patient care. The aim of the PrimA-QuO study is to examine the effectiveness and the acceptance, barriers and facilitators of all stakeholders of this structured primary care programme for children affected by the most frequently encountered MHP in paediatric practice. METHODS AND ANALYSIS: In this mixed-methods approach, children (n=800; aged 0-17 years) with MHP meeting all inclusion criteria will be identified in the health insurance database according to International Classification of Diseases, 10th Revision diagnoses between 2018 and 2019. The qualitative component uses a series of semistructured interviews with programme developers, paediatricians trained in HC, adolescents with MHP treated according to the programme guidelines and their parents. In addition, a prospective, pragmatic, parallel-group cohort study will be conducted using an online questionnaire to examine the effects of HC on health-related quality of life of affected children and their families as well as on change in MHP. Children treated according to the HC guidelines form the intervention group, whereas all others serve as controls. Primary data from the cohort study are linked to children's health insurance claims data to calculate the costs of care as proxies for healthcare utilisation. The hypothesis is that HC is an effective and efficient primary care programme with the potential to improve patients' and their families' health outcomes. ETHICS AND DISSEMINATION: The study was approved by the Ethical Committee of Ludwig-Maximilians-Universität München. Grant number 01VSF16032 (funded by the German Innovationsfonds).

Serum neurofilament light chain (sNfL) values in a large cross-sectional population of children with asymptomatic to moderate COVID-19.

BACKGROUND: Serum neurofilament light chain (sNfL) is an established biomarker of neuro-axonal damage in multiple neurological disorders. Raised sNfL levels have been reported in adults infected with pandemic coronavirus disease 2019 (COVID-19). Levels in children infected with COVID-19 have not as yet been reported. OBJECTIVE: To evaluate whether sNfL is elevated in children contracting COVID-19. METHODS: Between May 22 and July 22, 2020, a network of outpatient pediatricians in Bavaria, Germany, the Coronavirus antibody screening in children from Bavaria study network (CoKiBa), recruited healthy children into a cross-sectional study from two sources: an ongoing prevention program for 1-14 years, and referrals of 1-17 years consulting a pediatrician for possible infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We determined sNfL levels by single molecule array immunoassay and SARS-CoV-2 antibody status by two independent quantitative methods. RESULTS: Of the 2652 included children, 148 (5.6%) were SARS-CoV-2 antibody positive with asymptomatic to moderate COVID-19 infection. Neurological symptoms-headache, dizziness, muscle aches, or loss of smell and taste-were present in 47/148 cases (31.8%). Mean sNfL levels were 5.5 pg/ml (SD 2.9) in the total cohort, 5.1 (SD 2.1) pg/ml in the children with SARS-CoV-2 antibodies, and 5.5 (SD 3.0) pg/ml in those without. Multivariate regression analysis revealed age-but neither antibody status, antibody levels, nor clinical severity-as an independent predictor of sNfL. Follow-up of children with pediatric multisystem inflammatory syndrome (n = 14) showed no association with sNfL. CONCLUSIONS: In this population study, children with asymptomatic to moderate COVID-19 showed no neurochemical evidence of neuronal damage.

"We're in good hands there." - Acceptance, barriers and facilitators of a primary care-based health coaching programme for children and adolescents with mental health problems: a qualitative study (PrimA-QuO).

BACKGROUND: 11.5 % of girls and 17.8 % of boys are affected by a mental health problem (MHP). The most prevalent problem areas are behavioural problems (girls/boys in %: 11.9/17.9), emotional problems (9.7/8.6) and hyperactivity problems (4.8/10.8). Primary care paediatricians are the first in line to be contacted. Nevertheless, even for less severely affected patients, referral rates to specialised care are constantly high. Therefore, a major statutory health insurance fund introduced a Health Coaching (HC) programme, including a training concept for paediatricians, standardised guidelines for actions and additional payments to strengthen primary care consultation for MHP and to decrease referrals to specialised care. The aim of this study was to examine how the HC is perceived and implemented in daily practice to indicate potential strengths and challenges. METHODS: During a one-year period starting in November 2017, a series of guideline-based interviews were conducted by phone with HC-developers, HC-qualified paediatricians, parents and patients (≥14 years) treated according to the HC programme. Paediatricians were selected from a Bavarian practice network with a total of 577 HC qualified paediatricians. Parents of patients with the four most common MHP diagnoses were approached by their health insurance: [World Health Organization, 2013] developmental disorder of speech and language [Wille N, et al., 2008] head/abdominal pain (somatoform) [Holling H, et al., 2003-2006 and 2009-2012] conduct disorder [Plass-Christl A, et al., 2018] non-organic enuresis. 23 paediatricians, 314 parents and 10 adolescents consented to be interviewed. Potential participants were selected based on purposeful sampling, according to principles of maximum variance. All interviews were recorded and transcribed verbatim. Two researchers analysed the transcripts independently of each other. Structuring content analysis derived from Mayring was used for analysis. RESULTS: 11 paediatricians, 3 co-developers, 22 parents and 4 adolescents were included. Families were generally satisfied with paediatric care received in the programme's context. The HC supported paediatricians' essential role as consultants and improved their diagnostic skills. Lack of time, financial restrictions and patients' challenging family structures were reported as major barriers to success. CONCLUSION: The HC programme is perceived as a facilitator for more patient-centred care. However, structural barriers remain. Starting points for improvement are further options to strengthen families' resources and expanded interdisciplinary networking.

Yield of a Public Health Screening of Children for Islet Autoantibodies in Bavaria, Germany.

IMPORTANCE: Public health screening for type 1 diabetes in its presymptomatic stages may reduce disease severity and burden on a population level. OBJECTIVE: To determine the prevalence of presymptomatic type 1 diabetes in children participating in a public health screening program for islet autoantibodies and the risk for progression to clinical diabetes. DESIGN, SETTING, AND PARTICIPANTS: Screening for islet autoantibodies was offered to children aged 1.75 to 5.99 years in Bavaria, Germany, between 2015 and 2019 by primary care pediatricians during well-baby visits. Families of children with multiple islet autoantibodies (presymptomatic type 1 diabetes) were invited to participate in a program of diabetes education, metabolic staging, assessment of psychological stress associated with diagnosis, and prospective follow-up for progression to clinical diabetes until July 31, 2019. EXPOSURES: Measurement of islet autoantibodies. MAIN OUTCOMES AND MEASURES: The primary outcome was presymptomatic type 1 diabetes, defined by 2 or more islet autoantibodies, with categorization into stages 1 (normoglycemia), 2 (dysglycemia), or 3 (clinical) type 1 diabetes. Secondary outcomes were the frequency of diabetic ketoacidosis and parental psychological stress, assessed by the Patient Health Questionnaire-9 (range, 0-27; higher scores indicate worse depression; ≤4 indicates no to minimal depression; >20 indicates severe depression). RESULTS: Of 90 632 children screened (median [interquartile range {IQR}] age, 3.1 [2.1-4.2] years; 48.5% girls), 280 (0.31%; 95% CI, 0.27-0.35) had presymptomatic type 1 diabetes, including 196 (0.22%) with stage 1, 17 (0.02%) with stage 2, 26 (0.03%) with stage 3, and 41 who were not staged. After a median (IQR) follow-up of 2.4 (1.0-3.2) years, another 36 children developed stage 3 type 1 diabetes. The 3-year cumulative risk for stage 3 type 1 diabetes in the 280 children with presymptomatic type 1 diabetes was 24.9% ([95% CI, 18.5%-30.7%]; 54 cases; annualized rate, 9.0%). Two children had diabetic ketoacidosis. Median (IQR) psychological stress scores were significantly increased at the time of metabolic staging in mothers of children with presymptomatic type 1 diabetes (3 [1-7]) compared with mothers of children without islet autoantibodies (2 [1-4]) (P = .002), but declined after 12 months of follow-up (2 [0-4]) (P < .001). CONCLUSIONS AND RELEVANCE: Among children aged 2 to 5 years in Bavaria, Germany, a program of primary care-based screening showed an islet autoantibody prevalence of 0.31%. These findings may inform considerations of population-based screening of children for islet autoantibodies.

Nocturnal asthma is affected by genetic interactions between RORA and NPSR1.

BACKGROUND: Neuropeptide S Receptor 1 ( NPSR1) and Retinoid Acid Receptor-Related Orphan Receptor Alpha (RORA ) interact biologically, are both known candidate genes for asthma, and are involved in controlling circadian rhythm. Thus, we assessed (1) whether interactions between RORA and NPSR1 specifically affect the nocturnal asthma phenotype and (2) how this may differ from other asthma phenotypes. METHODS: Interaction effects between 24 single-nucleotide polymorphisms (SNPs) in RORA and 35 SNPs in NPSR1 on asthma and nocturnal asthma symptoms were determined in 1432 subjects (763 asthmatics [192 with nocturnal asthma symptoms]; 669 controls) from the Multicenter Asthma Genetic in Childhood/International Study of Asthma and Allergies in Childhood studies. The results were validated and extended in children from the Manchester Asthma and Allergy Study (N = 723) and the Children Allergy Milieu Stockholm and Epidemiological cohort (N = 1646). RESULTS: RORA* NPSR1 interactions seemed to affect both asthma and nocturnal asthma. In stratified analyses, however, interactions mainly affected nocturnal asthma and less so asthma without nocturnal symptoms or asthma severity. Results were replicated in two independent cohorts and seemed to remain constant over time throughout youth. CONCLUSION: RORA* NPSR1 interactions appear to be involved in mechanisms specific for nocturnal asthma. In contrast to previous studies focusing on the role of beta 2 receptor polymorphisms in nocturnal asthma as a feature of asthma control or severity in general, our data suggest that changes in circadian rhythm control are associated with nighttime asthma symptoms.

Capillary blood islet autoantibody screening for identifying pre-type 1 diabetes in the general population: design and initial results of the Fr1da study.

INTRODUCTION: Type 1 diabetes can be diagnosed at an early presymptomatic stage by the detection of islet autoantibodies. The Fr1da study aims to assess whether early staging of type 1 diabetes (1) is feasible at a population-based level, (2) prevents severe metabolic decompensation observed at the clinical manifestation of type 1 diabetes and (3) reduces psychological distress through preventive teaching and care. METHODS AND ANALYSIS: Children aged 2-5 years in Bavaria, Germany, will be tested for the presence of multiple islet autoantibodies. Between February 2015 and December 2016, 100 000 children will be screened by primary care paediatricians. Islet autoantibodies are measured in capillary blood samples using a multiplex three-screen ELISA. Samples with ELISA results >97.5th centile are retested using reference radiobinding assays. A venous blood sample is also obtained to confirm the autoantibody status of children with at least two autoantibodies. Children with confirmed multiple islet autoantibodies are diagnosed with pre-type 1 diabetes. These children and their parents are invited to participate in an education and counselling programme at a local diabetes centre. Depression and anxiety, and burden of early diagnosis are also assessed. RESULTS: Of the 1027 Bavarian paediatricians, 39.3% are participating in the study. Overall, 26 760 children have been screened between February 2015 and November 2015. Capillary blood collection was sufficient in volume for islet autoantibody detection in 99.46% of the children. The remaining 0.54% had insufficient blood volume collected. Of the 26 760 capillary samples tested, 0.39% were positive for at least two islet autoantibodies. DISCUSSION: Staging for early type 1 diabetes within a public health setting appears to be feasible. The study may set new standards for the early diagnosis of type 1 diabetes and education. ETHICS DISSEMINATION: The study was approved by the ethics committee of Technische Universität München (Nr. 70/14).

Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages.

BACKGROUND: Asthma is a disease affecting more boys than girls in childhood and more women than men in adulthood. The mechanisms behind these sex-specific differences are not yet understood. OBJECTIVE: We analyzed whether and how genetic factors contribute to sex-specific predisposition to childhood-onset asthma. METHODS: Interactions between sex and polymorphisms on childhood asthma risk were evaluated in the Multicentre Asthma Genetics in Childhood Study (MAGICS)/Phase II International Study of Asthma and Allergies in Childhood (ISAAC II) population on a genome-wide level, and findings were validated in independent populations. Genetic fine mapping of sex-specific asthma association signals was performed, and putatively causal polymorphisms were characterized in vitro by using electrophoretic mobility shift and luciferase activity assays. Gene and protein expression of the identified gene doublesex and mab-3 related transcription factor 1 (DMRT1) were measured in different human tissues by using quantitative real-time PCR and immunohistochemistry. RESULTS: Polymorphisms in the testis-associated gene DMRT1 displayed interactions with sex on asthma status in a population of primarily clinically defined asthmatic children and nonasthmatic control subjects (lowest P = 5.21 × 10(-6)). Replication of this interaction was successful in 2 childhood populations clinically assessed for asthma but showed heterogeneous results in other population-based samples. Polymorphism rs3812523 located in the putative DMRT1 promoter was associated with allele-specific changes in transcription factor binding and promoter activity in vitro. DMRT1 expression was observed not only in the testis but also in lung macrophages. CONCLUSION: DMRT1 might influence sex-specific patterns of childhood asthma, and its expression in testis tissue and lung macrophages suggests a potential involvement in hormone or immune cell regulation.

Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in TH2 cytokine levels.

BACKGROUND: Chromosome 17q21, harboring the orosomucoid 1-like 3 (ORMDL3) gene, has been consistently associated with childhood asthma in genome-wide association studies. OBJECTIVE: We investigated genetic variants in and around ORMDL3 that can change the function of ORMDL3 and thus contribute to asthma susceptibility. METHODS: We performed haplotype analyses and fine mapping of the ORMDL3 locus in a cross-sectional (International Study of Asthma and Allergies in Childhood Phase II, n = 3557 total subjects, n = 281 asthmatic patients) and case-control (Multicenter Asthma Genetics in Childhood Study/International Study of Asthma and Allergies in Childhood Phase II, n = 1446 total subjects, n = 763 asthmatic patients) data set to identify putative causal single nucleotide polymorphisms (SNPs) in the locus. Top asthma-associated polymorphisms were analyzed for allele-specific effects on transcription factor binding and promoter activity in vitro and gene expression in PBMCs after stimulation ex vivo. RESULTS: Two haplotypes (H1 and H2) were significantly associated with asthma in the cross-sectional (P = 9.9 × 10(-5) and P = .0035, respectively) and case-control (P = 3.15 × 10(-8) and P = .0021, respectively) populations. Polymorphisms rs8076131 and rs4065275 were identified to drive these effects. For rs4065275, a quantitative difference in transcription factor binding was found, whereas for rs8076131, changes in upstream stimulatory factor 1 and 2 transcription factor binding were observed in vitro by using different cell lines and PBMCs. This might contribute to detected alterations in luciferase activity paralleled with changes in ORMDL3 gene expression and IL-4 and IL-13 cytokine levels ex vivo in response to innate and adaptive stimuli in an allele-specific manner. Both SNPs were in strong linkage disequilibrium with asthma-associated 17q21 SNPs previously related to altered ORMDL3 gene expression. CONCLUSION: Polymorphisms in a putative promoter region of ORMDL3, which are associated with childhood asthma, alter transcriptional regulation of ORMDL3, correlate with changes in TH2 cytokines levels, and therefore might contribute to the childhood asthma susceptibility signal from 17q21.

Different FCER1A polymorphisms influence IgE levels in asthmatics and non-asthmatics.

BACKGROUND: Recently, three genome-wide association studies (GWAS) demonstrated FCER1A, the gene encoding a ligand-binding subunit of the high-affinity IgE receptor, to be a major susceptibility locus for serum IgE levels. The top association signal differed between the two studies from the general population and the one based on an asthma case-control design. In this study, we investigated whether different FCER1A polymorphisms are associated with total serum IgE in the general population and asthmatics specifically. METHODS: Nineteen polymorphisms were studied in FCER1A based on a detailed literature search and a tagging approach. Polymorphisms were genotyped by the Illumina HumanHap300Chip (6 polymorphisms) or MALDI-TOF MS (13 polymorphisms) in at least 1303 children (651 asthmatics) derived from the German International Study of Asthma and Allergies in Childhood II and Multicentre Asthma Genetics in Childhood Study. RESULTS: Similar to two population-based GWAS, the peak association with total serum IgE was observed for SNPs rs2511211, rs2427837, and rs2251746 (mean r(2) > 0.8), with the lowest p-value of 4.37 × 10(-6). The same 3 polymorphisms showed the strongest association in non-asthmatics (lowest p = 0.0003). While these polymorphisms were also associated with total serum IgE in asthmatics (lowest p = 0.003), additional polymorphisms (rs3845625, rs7522607, and rs2427829) demonstrated associations with total serum IgE in asthmatics only (lowest p = 0.01). CONCLUSIONS: These data suggest that FCER1A polymorphisms not only drive IgE levels in the general population but that specific polymorphisms may also influence IgE in association with asthma, suggesting that disease-specific mechanisms in IgE regulation exist.

Genetic variants in Protocadherin-1, bronchial hyper-responsiveness, and asthma subphenotypes in German children.

BACKGROUND: Recently, Protocadherin-1 (PCDH1) was reported as a novel susceptibility gene for bronchial hyper-responsiveness (BHR) and asthma. PCDH1 is located on chromosome 5q31-33, in the vicinity of several known candidate genes for asthma and allergy. To exclude that the associations observed for PCDH1 originate from the nearby cytokine cluster, an extensive linkage disequilibrium (LD) analysis was performed. Effects of polymorphisms in PCDH1 on asthma, BHR, and related phenotypes were studied comprehensively. METHODS: Genotype information was acquired from Illumina HumanHap300Chip genotyping, MALDI-TOF MS genotyping, and imputation. LD was assessed by Haploview 4.2 software. Associations were investigated in a population of 1454 individuals (763 asthmatics) from two German study populations [MAGICS and International Study of Asthma and Allergies in Childhood phase II (ISAAC II)] using logistic regression to model additive effects. RESULTS: No relevant LD between PCDH1 tagging polymorphisms and 98 single nucleotide polymorphisms within the cytokine cluster was detected. While BHR was not associated with PCDH1 polymorphisms, significant associations with subphenotypes of asthma were observed. CONCLUSION: Protocadherin-1 polymorphisms may specifically affect the development of non-atopic asthma in children. Functional studies are needed to further investigate the role of PCDH1 in BHR and asthma development.