RESUMEN
BACKGROUND: Although the genetics of asthma has been extensively studied using both quantitative and molecular genetic analysis methods, both approaches lack studies specific to the childhood phenotype and including other allergic diseases. This study aimed to give specific estimates for the heritability of childhood asthma and other allergic diseases, to attempt to replicate findings from genomewide association studies (GWAS) for childhood asthma and to test the same variants against other allergic diseases. METHODS: In a cohort of 25 306 Swedish twins aged 9 or 12 years, data on asthma were available from parental interviews and population-based registers. The interviews also inquired about wheeze, hay fever, eczema, and food allergy. Through structural equation modeling, the heritability of all phenotypes was calculated. A subset of 10 075 twins was genotyped for 16 single nucleotide polymorphisms (SNPs) selected from previous GWAS; these were first tested for association with asthma and significant findings also against the other allergic diseases. RESULTS: The heritability of any childhood asthma was 0.82 (95% CI 0.79-0.85). For the other allergic diseases, the range was approximately 0.60-0.80. Associations for six SNPs with asthma were replicated, including rs2305480 in the GSDMB gene (OR 0.80, 95% CI 0.74-0.86, P = 1.5*10(-8) ; other significant associations all below P = 3.5*10(-4) ). Of these, only rs3771180 in IL1RL1 was associated with any other allergic disease (for hay fever, OR 0.64, 95% CI 0.53-0.77, P = 2.5*10(-6) ). CONCLUSION: Asthma and allergic diseases of childhood are highly heritable, and these high-risk genetic variants associated specifically with childhood asthma, except for one SNP shared with hay fever.
Asunto(s)
Asma/epidemiología , Asma/etiología , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Patrón de Herencia , Gemelos , Alelos , Asma/diagnóstico , Niño , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Oportunidad Relativa , Fenotipo , Polimorfismo de Nucleótido Simple , Suecia/epidemiologíaRESUMEN
BACKGROUND: Children born with low gestational age (GA) or low birthweight (BW) are at increased risk of asthma. Twins as compared to singletons are on average more likely to be born with lower GA and BW and have been hypothesized to comprise a high-risk population for asthma. Many previous studies have not accounted for potential confounders or mediators. OBJECTIVE: To investigate the association between twinship and childhood asthma or early life wheeze and identify potential mediators, such as GA/BW. METHODS: The study population consisted of two cohorts including all children born in Sweden from 1 January 1993 to 1 June 2001 (n = 756,363 singletons, n = 22,478 twins) and 1 July 2005 to 31 December 2009 (n = 456,239 singletons, n = 12,872 twins). Asthma was defined using validated register-based outcomes of diagnosis or medication. The data were analysed using logistic (older cohort) and Cox regression (younger cohort). Adjusted models incorporated potential confounding or mediating factors including gestational age and birthweight. RESULTS: In the younger cohort, the crude hazard ratio (HR) of asthma medication after 1.5 years of age was 1.12 (95% CI 1.01-1.23), and fully adjusted HR was 0.80, 95% CI 0.72-0.89. Crude HR of asthma diagnosis in the same age group was 1.14 (95% CI 0.99-1.30), fully adjusted 0.78 (0.68-0.98). Adjusted analyses in the older group yielded similar results. CONCLUSIONS: Twins were at significantly higher unadjusted risk of asthma or early life wheeze compared to singletons in the younger, but not in the older cohort. Associations attenuated following adjustment for GA/BW, suggesting that GA/BW mediates the effect of twinship on asthma risk. After adjustments, twins were at lower risk of asthma outcomes, possibly due to unmeasured confounding.