Gene-Environment Interaction in the Onset of Eczema in Infancy: Filaggrin Loss-of-Function Mutations Enhanced by Neonatal Cat Exposure

Background Loss-of-function variants in the gene encoding filaggrin (FLG) are major determinants of eczema. We hypothesized that weakening of the physical barrier in FLG-deficient individuals may potentiate the effect of environmental exposures. Therefore, we investigated whether there is an interaction between FLG loss-of-function mutations with environmental exposures (pets and dust mites) in relation to the development of eczema. Methods and Findings We used data obtained in early life in a high-risk birth cohort in Denmark and replicated the findings in an unselected birth cohort in the United Kingdom. Primary outcome was age of onset of eczema; environmental exposures included pet ownership and mite and pet allergen levels. In Copenhagen(n = 379), FLG mutation increased the risk of eczema during the first year of life (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.27–4.00, p = 0.005), with a further increase in risk related to cat exposure at birth amongst children with FLG mutation (HR 11.11, 95% CI 3.79–32.60, p < 0.0001); dog exposure was moderately protective (HR 0.49, 95% CI 0.24–1.01, p = 0.05), but not related to FLG genotype. In Manchester (n = 503) an independent and significant association of the development of eczema by age 12 mo with FLG genotype was confirmed (HR 1.95, 95% CI 1.13–3.36, p = 0.02). In addition, the risk increased because of the interaction of cat ownership at birth and FLG genotype (HR 3.82, 95% CI 1.35–10.81, p = 0.01), with no significant effect of the interaction with dog ownership (HR 0.59, 95% CI 0.16–2.20, p = 0.43). Mite-allergen had no effects in either cohort. The observed effects were independent of sensitisation. Conclusions We have demonstrated a significant interaction between FLG loss-of-function main mutations (501x and 2282del4) and cat ownership at birth on the development of early-life eczema in two independent birth cohorts. Our data suggest that cat but not dog ownership substantially increases the risk of eczema within the first year of life in children with FLG loss-of-function variants, but not amongst those without. FLG-deficient individuals may need to avoid cats but not dogs in early life

Instrumenting gait with an accelerometer: A system and algorithm examination

Gait is an important clinical assessment tool since changes in gait may reflect changes in general health. Measurement of gait is a complex process which has been restricted to the laboratory until relatively recently. The application of an inexpensive body worn sensor with appropriate gait algorithms (BWM) is an attractive alternative and offers the potential to assess gait in any setting. In this study we investigated the use of a low-cost BWM, compared to laboratory reference using a robust testing protocol in both younger and older adults. We observed that the BWM is a valid tool for estimating total step count and mean spatio-temporal gait characteristics however agreement for variability and asymmetry results was poor. We conducted a detailed investigation to explain the poor agreement between systems and determined it was due to inherent differences between the systems rather than inability of the sensor to measure the gait characteristics. The results highlight caution in the choice of reference system for validation studies. The BWM used in this study has the potential to gather longitudinal (real-world) spatio-temporal gait data that could be readily used in large lifestyle-based intervention studies, but further refinement of the algorithm(s) is required

Neonatal Urine Metabolic Profiling and Development of Childhood Asthma

none9Urine metabolomics case-control studies of childhood asthma have demonstrated a discriminative ability. Here, we investigated whether urine metabolic profiles from healthy neonates were associated with the development of asthma in childhood. Untargeted metabolomics by liquid chromatography-mass spectrometry was applied to urine samples collected at age 4 weeks in 171 and 161 healthy neonates born from mothers with asthma from the COPSAC2000 and COPSAC2010 cohorts, respectively, where persistent wheeze/asthma was prospectively diagnosed using a symptom-based algorithm. Univariate and multivariate analyses were applied to investigate differences in metabolic profiles between children who developed asthma and healthy children. Univariate analysis showed 63 and 87 metabolites (q-value 0.60. Database search enabled annotation of three discriminative features: a glucoronidated compound (steroid), 3-hydroxytetradecanedioic acid (fatty acid), and taurochenodeoxycholate-3-sulfate (bile acid). The urine metabolomics profiles from healthy neonates were associated with the development of childhood asthma, but further research is needed to understand underlying metabolic pathways.noneChawes, Bo L; Giordano, Giuseppe; Pirillo, Paola; Rago, Daniela; Rasmussen, Morten A; Stokholm, Jakob; Bønnelykke, Klaus; Bisgaard, Hans; Baraldi, EugenioChawes, Bo L; Giordano, Giuseppe; Pirillo, Paola; Rago, Daniela; Rasmussen, Morten A; Stokholm, Jakob; Bønnelykke, Klaus; Bisgaard, Hans; Baraldi, Eugeni