The mediating role of self-efficacy in the relationship between past professional training and burnout resilience in medical education: a multicentre cross-sectional study.

BACKGROUND: Meta-analyses indicate a high prevalence of burnout among medical students. Although studies have investigated different coping strategies and health interventions to prevent burnout, professional experience's influence on burnout resilience as seldom been explored. Therefore, in our study we aimed to examine the self-efficacy's mediating role in the relationship between past vocational training and burnout resilience. In the process, we also analysed the associations between study-related variables and burnout resilience. METHODS: In our cross-sectional study, we analysed the data of 2217 medical students at different stages of their university education (i.e. 1st, 3rd, 6th, 10th semester, and final year) at five medical faculties in Germany. The questionnaire included items addressing variables related to medical school, previous professional and academic qualifications, and validated instruments for measuring burnout and self-efficacy. RESULTS: The overall prevalence of burnout was 19.7%, as defined by high scores for emotional exhaustion and notable values in at least one of the other two dimensions (cynicism or academic efficacy). Higher levels for self-efficacy (p < .001), having children (p = .004), and financing education with personal earnings (p = .03) were positively associated with burnout resilience, whereas having education financed by a partner or spouse (p = .04) had a negative association. In a mediation analysis, self-efficacy exerted a suppressor effect on the relationship between vocational training and burnout resilience (indirect effect = 0.11, 95% CI [0.04, 0.19]). CONCLUSIONS: Self-efficacy's suppressor effect suggests that the positive association between vocational training and burnout resilience identified in the mediation analysis disappears for students who have completed vocational training but do not feel efficacious. Those and other findings provide important insights into the psychological mechanisms underlying the development of burnout resilience in medical students and suggest the promotion of self-efficacy in medical education.

Cystic fibrosis in disguise - the wolf in sheep's clothing, a case report.

BACKGROUND: Childhood hypoglycemia in combination with hepatomegaly is suspicious for inborn errors of metabolism. Cystic fibrosis typically presents with failure to thrive, pulmonary and gastrointestinal symptoms. Hepatic involvement and hypoglycemia can occur in a significant number of patients, although hepatomegaly is uncommon. CASE PRESENTATION: A 28 months old boy was presented with recurrent upper airways infections, progressive lethargy and weight loss. Clinically hepatomegaly was the main presenting feature and hypoglycemia (minimum 1.4 mmol/l) was noted as were elevated transaminases. The patient did not produce enough sweat to analyze it. Infectious causes for hepatitis were excluded and a broad metabolic work-up initiated. A therapy with starch was initiated to control hypoglycemia. In further course loose stools were reported and pancreatic elastase was found to be reduced. A further sweat test yielded pathological chloride concentration and genetic testing confirmed the diagnosis of cystic fibrosis. CONCLUSIONS: Cystic fibrosis is a systemic disease and less common presentations need to be considered. Even in the age of CF-newborn screening in many countries CF needs to be ruled out in typical and atypical clinical presentations and diagnostics need to be repeated if inconclusive.

SIESTA: a quick interprofessional learning activity fostering collaboration and communication between paediatric nursing trainees and medical students.

BACKGROUND: Interprofessional education has emerged as a key concept in education of health professionals over the last 20 years. Positive effects of interprofessional education have been shown, but it has proved to be more time-consuming than traditional teaching methods. We therefore developed a 30-minute interprofessional learning activity, using peer-teaching methods. We were interested in effects on and ways of interprofessional learning, including conditions and resources that make it successful despite limited time. METHODS: Speed InterprofESsional Peer Teaching PaediAtric (SIESTA) was developed in the context of an interprofessional training ward. 20 paediatric nursing trainees and 20 medical students were enrolled in the study. Two students from each profession participated in a total of four SIESTA sessions each, supervised by registered paediatric nurses and paediatricians. We used a mixed-methods approach of quantitative and qualitative data (questionnaires, semi-guided focus group interviews) to evaluate self-perceived interprofessional competencies, interprofessional learning gains and ways of interprofessional learning. RESULTS: Questionnaires were obtained from all participants (n = 40) and n = 26 took part in the group interviews. Participants from both professions reported an increase in self-perceived understanding of interprofessional roles and tasks. Communication and cooperation emerged as important aspects. The workplace-based nature of SIESTA promoted interprofessional learning, while peer teaching fostered a safe learning environment. Regarding time constraints participants suggested thorough preparation and structuring by facilitators as a solution. CONCLUSIONS: Our short interprofessional peer teaching activity showed promising results. Participants reported enhanced interprofessional competencies and provided suggestions for successful learning in limited time. Further studies should include an objective assessment of the interprofessional learning progress. The SIESTA concept can be easily adapted to other medical fields, providing interprofessional learning opportunities for many more health care professionals to come.

A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.

IL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (ß = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.

Nursing staff's and physicians' acquisition of competences and attitudes to interprofessional education and interprofessional collaboration in pediatrics.

BACKGROUND: Interprofessional education (IPE) is deemed essential for interprofessional collaboration (IPC) in healthcare systems. IPC has positive effects for both patients and healthcare professionals. Especially in pediatrics, IPC is paramount for adequate care of patients and their families though there is a lack of data on the attitudes towards IPE and IPC and acquisition of respective competences in pediatric nursing and medical staff. METHODS: Frequencies of interactions and attitudes towards IPE and IPC, with a focus on acquisition of competences for IPE and IPC, of nurses (N = 79) and physicians (N = 70) in a large pediatric university hospital were evaluated with an online questionnaire. RESULTS: All participants worked as part of interprofessional teams, mostly consisting of nurses and physicians. The majority (94.9% (n = 75) of nurses and 100% (n = 70) of physicians) highly valued IPC. Medical doctors acquired most competences important for IPC during day-to-day work and reported a substantial lack of IPE. Nursing staff on the other hand did report significant interprofessional education during their training as well as ongoing interprofessional learning during day-to-day work. Nurses also appreciated IPE more. CONCLUSIONS: Even though IPC is commonly reported in nurses and physicians working at a large pediatric university hospital there is a lack of structured IPE. A focus should be on IPE for nurses and physicians to enable them to effectively collaborate together. Political and local initiatives for IPE are gaining momentum but still need to be established nationally and internationally.

Non-CF Bronchiectasis as a Possible Indicator of a Primary Immunodeficiency: Diagnosis, Clinical Course, and Quality of Life in a Pediatric Cohort.

BACKGROUND: Non cystic fibrosis bronchiectasis (NCBE) is an increasingly recognized chronic, progressive respiratory disorder with significant morbidity also in children and adolescents. METHODS: We longitudinally assessed a cohort of 35 pediatric patients with NCBE and investigated underlying diagnosis, symptoms, clinical course, treatment, and quality of life. RESULTS: NCBE were diagnosed at a mean age of 9.5 (±5.3) years. In half of the children NCBE were found prior to identification of the causative diagnosis. Primary immunodeficiency (PID) was identified as the underlying diagnosis in 24/35 (68%) cases, of which two-thirds showed antibody deficiency. In the 11 non-PID cases ciliopathies were most common (n=7). Clinical aspects such as manifestation age, cough or dyspnea symptoms, and exacerbation frequency did not differ significantly between PID and non-PID patients. Likewise, quality of life (QoL) was equally reduced in both groups. Lung function test parameters were stable under appropriate therapy in all children. The majority in both groups was insufficiently vaccinated against influenza and pneumococci. CONCLUSION: Our data indicates that NCBE need to be especially appreciated as a presenting sign of PID in pediatric patients. Thus, occurrence of NCBE should warrant rigorous diagnostics to identify the underlying condition. In our cohort NCBE themselves rather than the causative diagnoses seem to dictate the clinical course of disease and reduce QoL in children. More intensive efforts have to be undertaken to vaccinate patients according to recommendations.

Student-perceived exam difficulty may trump the effects of different quality improvement measures regarding the students' evaluation of a pediatric lecture series.

BACKGROUND: Lectures are still an important part of today's medical education at many medical schools. The pediatric lecture series at the Center for Pediatrics, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Germany had been evaluated poorly in recent terms. METHODS: To improve lecture quality and possibly evaluation results a combination of measures consisting of peer lecturer coaching, use of an audience response system, in depth analysis of the end of term evaluation results and changes to the exam itself were implemented. RESULTS: Peer lecturer coaching was performed successfully and both the audience response system evaluation as well as the end of term evaluation results improved significantly in the following term. Analysis of the students' comments revealed more approval of lecture content and presentation after the organization of the lecture series was changed towards less lecturers and focus on less topics. Student-perceived high exam difficulty influenced the evaluation negatively. CONCLUSION: The student-perceived exam difficulty can supersede the effects of different measures to improve lecture quality measured via evaluation. Whether better evaluation of the lecture series after different improvement measures was due to better match of the curriculum with the exam content or that an improved curriculum led to better exam performance remains to be elucidated.

Reduced PRF1 enhancer methylation in children with a history of severe RSV bronchiolitis in infancy: an association study.

BACKGROUND: Acute lower respiratory tract infection is the commonest disease affecting children under five worldwide. Respiratory syncytial virus (RSV) is among the most common causative pathogens. Epidemiological data suggest an association between severe viral respiratory infections in infancy and increased incidence of childhood wheeze and asthma. DNA methylation is involved in immune cell differentiation and identity. It provides an avenue for environmental influences on the genome and therefore has potential as a marker for sustained effects of infectious insults. In this study we investigated the association between DNA methylation patterns in the perforin gene (PRF1) in childhood and a history of hospitalisation for severe RSV disease in the first two years of life. METHODS: In this retrospective study, we explored patterns of whole blood DNA methylation at a methylation sensitive region of the proximal PRF1 enhancer in a group of children with a record of hospitalisation for severe RSV disease during infancy (n = 43) compared to healthy controls matched for age and sex with no similar hospitalisation history, no allergy and no persistent wheeze (n = 43). Univariate and bivariate conditional logistic regression analyses were conducted to test the association between PRF1 enhancer methylation and record of hospitalisation for RSV disease. RESULTS: Children with a record of hospitalisation for severe RSV bronchiolitis demonstrated markedly lower levels of DNA methylation at two cytosine-phosphate-guanine dinucleotide (CpG) loci of the PRF1 proximal enhancer, corresponding to a signal transducer and activator of transcription 5 (STAT5) responsive element, compared to controls, adjusted odds ratios of 0.82 (95% confidence interval [CI] 0.71, 0.94) and 0.73 (95% CI 0.58, 0.92) for each 1% increase in DNA methylation. Smoking in the household showed a significant influence on DNA methylation at the assayed positions. CONCLUSIONS: Our findings support an association between childhood DNA methylation patterns in PRF1 and a record of severe RSV infection in infancy. Longitudinal studies are required to establish the utility of PRF1 methylation as a marker of severe RSV disease.

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.

Modified oral food challenge used with sensitization biomarkers provides more real-life clinical thresholds for peanut allergy.

BACKGROUND: Threshold levels for peanut allergy determined by using oral challenges are important for the food industry with regard to allergen labeling. Moreover, the utility of biological markers in predicting threshold levels is uncertain. OBJECTIVE: We sought to use a modified oral food challenge regimen that might determine threshold levels for peanut allergy mimicking a more real-life exposure and to correlate the eliciting dose (ED) and severity of clinical reaction in children with peanut allergy with B-cell, T-cell, and effector cell markers. METHODS: A modified food challenge procedure with doses scheduled 2 hours apart was used in 63 children with peanut allergy. All children received a maximum of 8 semi-log increasing titration steps of roasted peanuts ranging from 3 to 4500 mg of peanut protein until objective allergic reactions occurred. Severity of symptoms was graded from I to V. Biological markers were measured before challenge. RESULTS: Forty-five of 63 patients showed objective symptoms after greater than 30 minutes, with a median latency of clinical reaction of 55 minutes. By using a log-normal dose-distribution model, the ED5 was calculated to be 1.95 mg of peanut protein. The ED was significantly and inversely correlated with peanut- and Ara h 2-specific IgE levels, skin prick test responses, basophil activation, and TH2 cytokine production by PBMCs. Symptom severity did not correlate with any of the markers or the ED. CONCLUSION: This modified food challenge procedure might better reflect threshold levels for peanut allergy than the standard procedure because most of the patients reacted at a time interval of greater than 30 minutes. By using this model, threshold levels, but not severity, could be correlated with biological markers.

How professional and academic pre-qualifications relate to success in medical education: Results of a multicentre study in Germany.

OBJECTIVE: Every year, many applicants want to study medicine. Appropriate selection procedures are needed to identify suitable candidates for the demanding curriculum. Although research on medical school admissions has shown good predictive validity for cognitive selection methods (undergraduate GPA, aptitude tests), the literature on applicants with professional and/or academic experience prior to entering medical school remains slim. In our study, we therefore aimed to examine the association between academic success in medical school and having previously completed vocational training in the medical field, voluntary service (≥11 months) or an academic degree. METHODS: Data were collected in a multicentre, cross-sectional study at five medical schools in Germany (Baden-Wuerttemberg) from students during medical school (i.e. 3rd-, 6th-, and 10th-semester and final-year students). Academic success was assessed according to scores on the first and second state examinations, the total number of examinations repeated and the number of semesters beyond the standard period of study. For the analysis we calculated ordinal logistic regression models for each outcome variable of academic success. RESULTS: A total of N = 2,370 participants (response rate: RR = 47%) participated in the study. Having completed vocational training was associated with a higher amount of repeated examinations (small effect), while having an academic degree was associated with worse scores on the second state examination (medium effect). No significant association emerged between voluntary service and academic success. CONCLUSION: The results indicate that professional and academic pre-qualifications pose no advantage for academic success. Possible associations with the financing of study and living conditions of students with pre-qualifications were analysed and discussed in an exploratory manner. However, the operationalisation of academic success from objective and cognitive data should be critically discussed, as the benefits of prior experience may be captured by personal qualities rather than examination results.

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 regulating ORMDL3 expression contribute to the risk of childhood asthma.

Asthma is caused by a combination of poorly understood genetic and environmental factors. We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P value of P < 10(-12). In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P < 10(-22)) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.

Positional cloning of a novel gene influencing asthma from chromosome 2q14.

Asthma is a common disease in children and young adults. Four separate reports have linked asthma and related phenotypes to an ill-defined interval between 2q14 and 2q32 (refs. 1-4), and two mouse genome screens have linked bronchial hyper-responsiveness to the region homologous to 2q14 (refs. 5,6). We found and replicated association between asthma and the D2S308 microsatellite, 800 kb distal to the IL1 cluster on 2q14. We sequenced the surrounding region and constructed a comprehensive, high-density, single-nucleotide polymorphism (SNP) linkage disequilibrium (LD) map. SNP association was limited to the initial exons of a solitary gene of 3.6 kb (DPP10), which extends over 1 Mb of genomic DNA. DPP10 encodes a homolog of dipeptidyl peptidases (DPPs) that cleave terminal dipeptides from cytokines and chemokines, and it presents a potential new target for asthma therapy.

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.

Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function.

BACKGROUND: The chitinase-like protein YKL-40 is involved in inflammation and tissue remodeling. We recently showed that serum YKL-40 levels were elevated in patients with asthma and were correlated with severity, thickening of the subepithelial basement membrane, and pulmonary function. We hypothesized that single-nucleotide polymorphisms (SNPs) that affect YKL-40 levels also influence asthma status and lung function. METHODS: We carried out a genomewide association study of serum YKL-40 levels in a founder population of European descent, the Hutterites, and then tested for an association between an implicated SNP and asthma and lung function. One associated variant was genotyped in a birth cohort at high risk for asthma, in which YKL-40 levels were measured from birth through 5 years of age, and in two populations of unrelated case patients of European descent with asthma and controls. RESULTS: A promoter SNP (-131C-->G) in CHI3L1, the chitinase 3-like 1 gene encoding YKL-40, was associated with elevated serum YKL-40 levels (P=1.1 x 10(-13)), asthma (P=0.047), bronchial hyperresponsiveness (P=0.002), and measures of pulmonary function (P=0.046 to 0.002) in the Hutterites. The same SNP could be used to predict the presence of asthma in the two case-control populations (combined P=1.2 x 10(-5)) and serum YKL-40 levels at birth (in cord-blood specimens) through 5 years of age in the birth cohort (P=8.9 x 10(-3) to 2.5 x 10(-4)). CONCLUSIONS: CHI3L1 is a susceptibility gene for asthma, bronchial hyperresponsiveness, and reduced lung function, and elevated circulating YKL-40 levels are a biomarker for asthma and decline in lung function.

Genomewide association analysis of respiratory syncytial virus infection in mice.

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in infants, with about half being infected in their first year of life. Yet only 2 to 3% of infants are hospitalized for RSV infection, suggesting that individual susceptibility contributes to disease severity. Previously, we determined that AKR/J (susceptible) mice developed high lung RSV titers and showed delayed weight recovery, whereas C57BL/6J (resistant) mice demonstrated low lung RSV titers and rapid weight recovery. In addition, we have reported that gene-targeted mice lacking the cystic fibrosis transmembrane conductance regulator (Cftr; ATP-binding cassette subfamily C, member 7) are susceptible to RSV infection. For this report, recombinant backcross and F2 progeny derived from C57BL/6J and AKR/J mice were infected with RSV, their lung titers were measured, and quantitative trait locus (QTL) analysis was performed. A major QTL, designated Rsvs1, was identified on proximal mouse chromosome 6 in both recombinant populations. Microarray analysis comparing lung transcripts of the parental strains during infection identified several candidate genes that mapped to the Rsvs1 interval, including Cftr. These findings add to our understanding of individual RSV susceptibility and strongly support a modifier role for CFTR in RSV infection, a significant cause of respiratory morbidity in infants with cystic fibrosis.