abstract
- Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease (COPD).To determine the genetic underpinnings of lung function patterns in childhood asthmatics.We performed a genome-wide association study of 581 non-Hispanic white asthmatics that were previously classified by patterns of lung function growth and decline, (Normal Growth, Normal Growth with Early Decline, Reduced Growth, and Reduced Growth with Early Decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large COPD meta-analysis cohort. Interaction between the genomic region encompassing the most strongly associated single nucleotide polymorphism (SNP) and nearby genes was assessed by two chromosomal conformation capture assays.An intergenic SNP (rs4445257) on chromosome 8 was strongly associated with the Normal Growth with Early Decline pattern compared to all other pattern groups (p=6.7×10-9, OR=2.8, 95% CI=2.4-3.4); replication analysis suggested this variant had opposite effects in Normal Growth with Early Decline and Reduced Growth with Early Decline pattern groups. Chromosomal conformation capture experiments indicated a chromatin interaction between rs4445257 and the promoter of the distal CSMD3 gene.Early decline in lung function after normal growth is associated with a genetic polymorphism that may also be protective of early decline in reduced growth groups.