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Clinical and epidemiologic studies have shown that obesity is associated with asthma and that these associations differ by asthma subtype. Little is known about the shared genetic components between obesity and asthma. We sought to identify shared genetic associations between obesity-related traits and asthma subtypes in adults. A cross-trait genome-wide association study (GWAS) was performed using 457,822 subjects of European ancestry from the UK Biobank. Experimental evidence to support the role of genes significantly associated with both obesity-related traits and asthma through a GWAS was sought by using results from obese versus lean mouse RNA sequencing and RT-PCR experiments. We found a substantial positive genetic correlation between body mass index and later-onset asthma defined by asthma age of onset at 16 years or greater (Rg = 0.25, P = 9.56 × 10−22). Mendelian randomization analysis provided strong evidence in support of body mass index causally increasing asthma risk. Cross-trait meta-analysis identified 34 shared loci among 3 obesity-related traits and 2 asthma subtypes. GWAS functional analyses identified potential causal relationships between the shared loci and Genotype-Tissue Expression (GTEx) quantitative trait loci and shared immune- and cell differentiation–related pathways between obesity and asthma. Finally, RNA sequencing data from lungs of obese versus control mice found that 2 genes (acyl-coenzyme A oxidase-like [ACOXL] and myosin light chain 6 [MYL6]) from the cross-trait meta-analysis were differentially expressed, and these findings were validated by using RT-PCR in an independent set of mice. Our work identified shared genetic components between obesity-related traits and specific asthma subtypes, reinforcing the hypothesis that obesity causally increases the risk of asthma and identifying molecular pathways that might underlie both obesity and asthma. [ABSTRACT FROM AUTHOR]

Background Asthma is a heterogeneous disease in which age of onset plays an important role. Objective We sought to identify the genetic variants associated with time to asthma onset (TAO). Methods We conducted a large-scale meta-analysis of 9 genome-wide association studies of TAO (total of 5462 asthmatic patients with a broad range of age of asthma onset and 8424 control subjects of European ancestry) performed by using survival analysis techniques. Results We detected 5 regions associated with TAO at the genome-wide significant level ( P < 5 × 10 −8 ). We evidenced a new locus in the 16q12 region (near cylindromatosis turban tumor syndrome gene [CYLD] ) and confirmed 4 asthma risk regions: 2q12 (IL-1 receptor–like 1 [IL1RL1] ), 6p21 (HLA-DQA1) , 9p24 (IL33) , and 17q12-q21 (zona pellucida binding protein 2 [ZPBP2] –gasdermin A [GSDMA] ). Conditional analyses identified 2 distinct signals at 9p24 (both upstream of IL33 ) and 17q12-q21 (near ZPBP2 and within GSDMA ). Together, these 7 distinct loci explained 6.0% of the variance in TAO. In addition, we showed that genetic variants at 9p24 and 17q12-q21 were strongly associated with an earlier onset of childhood asthma ( P ≤ .002), whereas the 16q12 single nucleotide polymorphism was associated with later asthma onset ( P = .04). A high burden of disease risk alleles at these loci was associated with earlier age of asthma onset (4 vs 9-12 years, P = 10 −4 ). Conclusion The new susceptibility region for TAO at 16q12 harbors variants that correlate with the expression of CYLD and nucleotide-binding oligomerization domain 2 (NOD2) , 2 strong candidates for asthma. This study demonstrates that incorporating the variability of age of asthma onset in asthma modeling is a helpful approach in the search for disease susceptibility genes. [ABSTRACT FROM AUTHOR]

Background: The association between allergic sensitization and eczema has been debated for years. Objective: We sought to determine and compare the strength of the association between allergen skin sensitization and eczema in both developing and industrialized countries. Methods: Twenty-eight thousand five hundred ninety-one randomly selected 8- to 12-year-old schoolchildren in 20 countries were physically examined for flexural eczema and received skin prick testing to Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat hair, Alternaria tenuis, mixed tree and grass pollen, and allergens of local relevance. Results: The age- and sex-adjusted odds ratios (ORs) for a positive association between flexural eczema and atopy ranged between 0.74 (95% CI, 0.31-1.81) and 4.53 (95% CI, 1.72-11.93), with a significantly stronger association in affluent compared with nonaffluent countries (combined age- and sex-adjusted ORaffluent = 2.69 [95% CI, 2.31-3.13] and ORnonaffluent = 1.17 [95% CI, 0.81-1.70]). The combined population attributable fraction for atopy in flexural eczema was 27.9% for affluent and 1.2% for nonaffluent-country centers. Correlating gross national per-capita income with either ORs or population attributable fractions for atopy in flexural eczema confirmed a highly significant positive association (P = .006 and P < .001, respectively). Conclusions: The association between atopy and flexural eczema is weak and more variable than previously suggested, and the strength of this association is positively linked to gross national income. [Copyright &y& Elsevier]

Background Genome-wide association studies have identified the ORM (yeast)-like protein isoform 3 ( ORMDL3 ) gene locus on human chromosome 17q to be a highly significant risk factor for childhood-onset asthma. Objective We sought to investigate in vivo the functional role of ORMDL3 in disease inception. Methods An Ormdl3 -deficient mouse was generated and the role of ORMDL3 in the generation of allergic airways disease to the fungal aeroallergen Alternaria alternata was determined. An adeno-associated viral vector was also used to reconstitute ORMDL3 expression in airway epithelial cells of Ormdl3 knockout mice. Results Ormdl3 knockout mice were found to be protected from developing allergic airways disease and showed a marked decrease in pathophysiology, including lung function and airway eosinophilia induced by Alternaria. Alternaria is a potent inducer of cellular stress and the unfolded protein response, and ORMDL3 was found to play a critical role in driving the activating transcription factor 6–mediated arm of this response through Xbp1 and downstream activation of the endoplasmic reticulum–associated degradation pathway. In addition, ORMDL3 mediated uric acid release, another marker of cellular stress. In the knockout mice, reconstitution of Ormdl3 transcript levels specifically in the bronchial epithelium resulted in reinstatement of susceptibility to fungal allergen–induced allergic airways disease. Conclusions This study demonstrates that ORMDL3 , an asthma susceptibility gene identified by genome-wide association studies, contributes to key pathways that promote changes in airway physiology during allergic immune responses. [ABSTRACT FROM AUTHOR]