RESUMO
Early allergic sensitisation (atopy) is the first step in the development of allergic diseases such as atopic asthma later in life. Genes and pathways associated with atopy and atopic asthma in children and adolescents have not been well characterised.A transcriptome-wide association study (TWAS) of atopy and atopic asthma in white blood cells (WBCs) or whole blood was conducted in a cohort of 460 Puerto Ricans aged 9-20â years (EVA-PR study) and in a cohort of 250 Swedish adolescents (BAMSE study). Pathway enrichment and network analyses were conducted to further assess top findings, and classification models of atopy and atopic asthma were built using expression levels for the top differentially expressed genes (DEGs).In a meta-analysis of the study cohorts, both previously implicated genes (e.g. IL5RA and IL1RL1) and genes not previously reported in TWASs (novel) were significantly associated with atopy and/or atopic asthma. Top novel genes for atopy included SIGLEC8 (p=8.07×10-13), SLC29A1 (p=7.07×10-12) and SMPD3 (p=1.48×10-11). Expression quantitative trait locus analyses identified multiple asthma-relevant genotype-expression pairs, such as rs2255888/ALOX15 Pathway enrichment analysis uncovered 16 significantly enriched pathways at adjusted p<0.01, including those relevant to T-helper cell type 1 (Th1) and Th2 immune responses. Classification models built using the top DEGs and a few demographic/parental history variables accurately differentiated subjects with atopic asthma from nonatopic control subjects (area under the curve 0.84).We have identified genes and pathways for atopy and atopic asthma in children and adolescents, using transcriptome-wide data from WBCs and whole blood samples.
Assuntos
Asma/genética , Hipersensibilidade/genética , Leucócitos , Transcriptoma , Adolescente , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos B/genética , Araquidonato 15-Lipoxigenase/genética , Asma/etiologia , Estudos de Casos e Controles , Criança , Transportador Equilibrativo 1 de Nucleosídeo/genética , Feminino , Humanos , Hipersensibilidade/complicações , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Lectinas/genética , Modelos Logísticos , Masculino , Porto Rico , Esfingomielina Fosfodiesterase/genética , Adulto JovemRESUMO
BACKGROUND: Little is known about synergistic effects of several risk factors on asthma. We developed a risk score in Puerto Rican children, and then used this score to estimate the combined effects of multiple risk factors on asthma at school age in Puerto Rican and Swedish children. METHODS: Case-control study in 609 Puerto Rican children (aged 6-14 years) and longitudinal birth cohort study of 2290 Swedish children followed up to age 12 years (The Children, Allergy, Milieu, Stockholm, Epidemiological Survey [BAMSE] Study). In both cohorts, there was data on parental asthma, sex, obesity, allergic rhinitis, and early-life second-hand smoke (SHS); data on diet and (in children ≥9 years) lifetime exposure to gun violence were also available in the Puerto Rico study. Asthma was defined as physician-diagnosed asthma and ≥1 episode of wheeze in the previous year. RESULTS: In a multivariable analysis in Puerto Rican children, male sex, parental asthma, allergic rhinitis, early-life SHS, an unhealthy diet and (in children ≥9 years) gun violence were each significantly associated with asthma. We next created a risk score using these variables (range, 0 to 5-6 in Puerto Rico and 0 to 4 in BAMSE). Compared with Puerto Rican children without any risk factors (i.e. a score of 0), Puerto Rican children with 2, 3, and at least 4 risk factors had 3.6 times (95% CI = 1.4-9.2), 10.4 times (95% CI = 4.0-27.0), and 21.6 times (95% CI = 7.2-64.9) significantly higher odds of asthma, respectively. In BAMSE, the presence of 2, 3, and at least 4 risk factors was significantly associated with 4.1 times (95% CI = 2.3-7.4), 6.3 times (95% CI = 3.0-13.3), and 17.2 times (95% CI = 4.1-73.2) increased odds of asthma at age 12 years. CONCLUSIONS: Our findings emphasize the multifactorial etiology of asthma, and suggest that concurrent eradication or reduction of several modifiable risk factors may better prevent or reduce the burden of childhood asthma.