Prenatal and postnatal genetic influence on lung function development.

Abstract

It is unknown to what extent adult lung function genes affect lung function development from birth to childhood. Our aim was to study the association of candidate genetic variants with neonatal lung function and lung function development until age 7 years. Lung function measurement by means of spirometry with the raised-volume thoracoabdominal compression technique and bronchial responsiveness to methacholine challenge were assessed in 411 high-risk newborns from the Copenhagen Prospective Study on Asthma in Childhood 2000 (COPSAC2000) cohort. Measures were repeated at age 7 years. Genetic risk scores were calculated based on reported single nucleotide polymorphisms for adult lung function (FEV1/forced expiratory vital capacity [FVC] ratio and FEV1) as the number of risk alleles weighted on known effect size. These genetic risk scores were analyzed against lung function measures as z scores at birth (forced expiratory volume in 0.5 seconds [FEV0.5], forced expiratory flow at 50% of functional vital capacity [FEF50], and provocative dose of methacholine causing a 15% decrease in lung function [PD15]) and at age 7 years (FEV1, FEF50, and provocative dose of methacholine causing a 20% decrease in lung function [PD20]) and with development from birth to age 7 years (FEV0.5/1, FEF50, and PD15/20). The genetic risk scores were not associated with lung function measures at age 1 month, but the FEV1/FVC genetic risk score was associated with reduced FEF50 values at age 7 years (P = .01) and similarly with reduced growth in FEF50 from birth to age 7 years (P = .02). This score was also associated with increased bronchial responsiveness (reduced PD20) at age 7 years (P = .02) and change in responsiveness from birth to age 7 years (P = .05). Lung function genetic variants identified in adults were not associated with neonatal lung function or bronchial responsiveness but with the development of these lung function measures during early childhood, suggesting a window of opportunity for interventions targeting these genetic mechanisms.