Melbourne School of Population and Global Health - Research Publications
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ItemNo Preview AvailableMeta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis(NATURE PUBLISHING GROUP, 2012-02)Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.
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ItemGenome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA(PUBLIC LIBRARY SCIENCE, 2012-09-28)RATIONALE: Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. OBJECTIVES: To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations. METHODS: The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5 x 10(-8)) and three variants reported as suggestive (P<5× 10(-7)). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever. MAIN RESULTS: We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4 × 10(-9)). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (P(Stage1+Stage2) = 1.1x10(-9)), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (P(Stage1+Stage2) = 1.1x10(-8)), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status. CONCLUSIONS: Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.
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ItemNo Preview AvailableEnvironmental and demographic risk factors for egg allergy in a population-based study of infants(WILEY, 2012-11)BACKGROUND: Although egg allergy is the most common food allergy in infants and young children, risk factors for egg allergy remain largely unknown. This study examined the relationship between environmental and demographic factors and egg allergy in a population-based infant cohort. METHODS: In a study of 5276 infants (HealthNuts), infants underwent skin prick testing (SPT) to egg white at 12 months of age. Questionnaire data on relevant exposures were obtained. 699/873 (80%) infants eligible for oral food challenge (detectable wheal on SPT) attended for formal assessment of egg allergy status; 453 had confirmed egg allergy (positive challenge and SPT ≥ 2 mm). Associations between environmental and demographic factors and egg allergy were investigated using multivariable logistic regression. RESULTS: Children with older siblings and those with a pet dog at home were less likely to develop egg allergy by 1 year of age (adjusted OR [aOR], 0.72; 95% CI, 0.62, 0.83 per sibling; and aOR, 0.72; 95% CI, 0.52, 0.99, respectively). Caesarean section delivery, antibiotic use in infancy, childcare attendance and maternal age were not associated with egg allergy. History of allergic disease in an immediate family member and having parents born in East Asia were strong risk factors for infantile egg allergy (aOR, 1.82; 95% CI, 1.40, 2.36; and aOR, 3.30; 95% CI, 2.45, 4.45, respectively). CONCLUSIONS: Exposure in the first year of life to siblings and dogs may decrease the risk of subsequent egg allergy. Infants with a family history of allergy and those with parents born in East Asia are at increased risk of egg allergy.
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ItemNo Preview AvailableChildhood Infections and the Risk of Asthma A Longitudinal Study Over 37 Years(ELSEVIER, 2012-09)BACKGROUND: Few studies have examined common childhood infections and adult asthma. We examined associations between childhood infectious diseases, childhood pneumonia, and current, persisting, and incident asthma to middle age. METHODS: We analyzed data from the Tasmanian Longitudinal Health Study (TAHS). A history of pneumonia was ascertained from their parents when the TAHS participants were 7 years old. Measles, rubella, mumps, chickenpox, diphtheria, and pertussis were identified from school medical records. Associations with current, persisting, or incident asthma were examined using regression techniques. RESULTS: Greater infectious diseases load was negatively associated with persisting asthma at all ages. Individually, pertussis (adjusted OR [aOR], 0.53; 95% CI, 0.28-1.00) was negatively associated with asthma persisting to age 13 years, chickenpox (aOR, 0.58; 95% CI, 0.38-0.88) was negatively associated with asthma persisting to age 32 years, and rubella was negatively associated with asthma persisting to ages 32 (aOR, 0.61; 95% CI, 0.31-0.96) and 44 years (aOR 0.53; 95% CI, 0.35-0.82). Pertussis was associated with preadolescent incident asthma (adjusted hazard ratio [aHR], 1.80; 95% CI, 1.10-2.96), whereas measles was associated with adolescent incident asthma (aHR, 1.66; 1.06-2.56). Childhood pneumonia was associated with current asthma at ages 7 (aOR, 3.12; 95% CI, 2.61-3.75) and 13 years (aOR, 1.32; 95% CI, 1.00-1.75), an association stronger in those without than those with eczema (aOR, 3.46; 95% CI, 2.83-4.24 vs aOR, 2.08; 95% CI, 1.38-3.12). CONCLUSIONS: Overall, childhood infectious diseases protected against asthma persisting in later life, but pertussis and measles were associated with new-onset asthma after childhood. Measles and pertussis immunization might lead to a reduction in incident asthma in later life.