A Novel Locus for Exertional Dyspnea in Childhood Asthma.

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Most children diagnosed with asthma suffer from respiratory symptoms such as cough, dyspnea, and wheezing which are also important markers of overall respiratory function. A decade of genome-wide association studies (GWAS) have investigated the genetic susceptibility of asthma diagnosis itself, but few have focused on important respiratory symptoms that characterise childhood asthma.Using whole-genome sequencing (WGS) data for 894 asthmatic trios from a Costa Rican cohort, we performed family-based association tests (FBATs) to assess the association between genetic variants and multiple asthma-relevant respiratory phenotypes: cough, phlegm, wheezing, exertional dyspnea, and exertional chest tightness. We tested whether genome-wide significant associations replicated in two additional studies: 1) 286 WGS trios from the Childhood Asthma Management Program (CAMP), and 2) 2691 African American (AA) current or former smokers from the COPDGene study.In the 894 Costa Rican trios, we identified a genome-wide significant association between exertional dyspnea and single nucleotide polymorphism (SNP) rs10165869, located on chromosome 2q37.3 with a p value of 3.49×10-9 that was replicated in the CAMP cohort (p=0.0222) with the same direction of association (combined p=5.54×10-10), but was not associated in the AA subjects from COPDGene. We also found suggestive evidence of a link between SNP rs10165869 and the atypical chemokine receptor 3 (ACKR3) for the biological interpretation.We identified and replicated a novel association between exertional dyspnea and SNP rs10165869 in childhood asthma which encourages to discover respiratory symptom associated variants in various airway diseases.


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