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A novel locus for exertional dyspnoea in childhood asthma.

ABSTRACT: Most children diagnosed with asthma have respiratory symptoms such as cough, dyspnoea and wheezing, which are also important markers of overall respiratory function. A decade of genome-wide association studies (GWAS) have investigated genetic susceptibility to asthma 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 dyspnoea and exertional chest tightness. We tested whether genome-wide significant associations were replicated in two additional studies: 1) 286 asthmatic trios from the Childhood Asthma Management Program (CAMP), and 2) 2691 African American current or former smokers from the COPDGene study.In the 894 Costa Rican trios, we identified a genome-wide significant association (p=2.16×10-9) between exertional dyspnoea and the single nucleotide polymorphism (SNP) rs10165869, located on chromosome 2q37.3, that was replicated in the CAMP cohort (p=0.023) with the same direction of association (combined p=3.28×10-10). This association was not found in the African American participants from COPDGene. We also found suggestive evidence for an association between SNP rs10165869 and the atypical chemokine receptor 3 (ACKR3).Our finding encourages the secondary association analysis of a wider range of phenotypes that characterise respiratory symptoms in other airway diseases/studies.

SUBMITTER: Lee S

PROVIDER: S-EPMC8185954 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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A novel locus for exertional dyspnoea in childhood asthma.

Lee Sanghun S Lasky-Su Jessica Ann JA Lange Christoph C Kim Wonji W Kumar Preeti Lakshman PL McDonald Merry-Lynn N MN Vaz Fragoso Carlos A CA Laurie Cecelia C Raby Benjamin A BA Celedón Juan C JC Cho Michael H MH Won Sungho S Weiss Scott T ST Hecker Julian J

The European respiratory journal 20210204 2

Most children diagnosed with asthma have respiratory symptoms such as cough, dyspnoea and wheezing, which are also important markers of overall respiratory function. A decade of genome-wide association studies (GWAS) have investigated genetic susceptibility to asthma 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 test ...[more]

PMID: 32855217

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Project description:BackgroundThe order and extent of interactions across the factors affecting exertional dyspnoea (ED) and exercise intolerance (EI) in patients with chronic obstructive pulmonary disease (COPD) are not clear. We hypothesized that lung and non-lung variables were the primary variables, ED was the secondary variable and EI was the tertiary variable.MethodsData on demographics, blood tests, cardiac imaging, lung function tests and invasive dead space fractions (VD/VT) during incremental exercise test of 46 male COPD subjects were obtained. These variables were categorized by factor analysis and pair-wise correlation analysis was conducted. The best factor of each category was selected and then multivariate regression was conducted.ResultsPeak tidal inspiratory flow (VT/TIpeak), VD/VTpeak and tidal lung expansion capability, and resting diffusing capacity of the lungs (DLCO)% predicted were the primary pulmonary factors most related to ED, whereas body mass index (BMI), haemoglobin and cholesterol levels were the primary non-pulmonary factors. In multivariate regression analysis, VT/TIpeak, VD/VTpeak and DLCO% were the primary factors most related to ED (r2 = 0.69); ED was most related to EI (r = -0.74 to -0.83).ConclusionUsing hierarchical stratification and statistical methods may improve understanding of the pathophysiology of ED and EI in patients with COPD. KEY MESSAGESThe pathophysiology of exertional dyspnoea (ED) and exercise intolerance (EI) in chronic obstructive pulmonary disease (COPD) is complex. The order and extent of interactions across factors are not clear. In multivariate regression analysis, we found that tidal inspiratory flow, dead space fraction and resting diffusing capacity of the lungs % but not the non-pulmonary factors affected ED.Using correlation coefficients, we further found that ED was the secondary variable and EI was the tertiary variable.Hierarchical stratification of the important factors associated with ED and EI in patients with COPD clarifies their relationships and could be incorporated into management programmes and outcome studies for these patients.

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A novel locus for exertional dyspnoea in childhood asthma.

Publications

A novel locus for exertional dyspnoea in childhood asthma.

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