Genetics and Genomics of Longitudinal Lung Function Patterns in Individuals with Asthma

Abstract

Rationale: 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.

Objectives: To determine the genetic underpinnings of lung function patterns in subjects with childhood asthma.

Methods: We performed a genome-wide association study of 581 non-Hispanic white individuals with asthma 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 chronic obstructive pulmonary disease metaanalysis cohort. Interaction between the genomic region encompassing the most strongly associated single-nucleotide polymorphism and nearby genes was assessed by two chromosome conformation capture assays.

Measurements and main results: An intergenic single-nucleotide polymorphism (rs4445257) on chromosome 8 was strongly associated with the normal growth with early decline pattern compared with all other pattern groups (P = 6.7 × 10^-9; odds ratio, 2.8; 95% confidence interval, 2.0-4.0); replication analysis suggested this variant had opposite effects in normal growth with early decline and reduced growth with early decline pattern groups. Chromosome conformation capture experiments indicated a chromatin interaction between rs4445257 and the promoter of the distal CSMD3 gene.

Conclusions: Early decline in lung function after normal growth is associated with a genetic polymorphism that may also protect against early decline in reduced growth groups. Clinical trial registered with www.clinicaltrials.gov (NCT00000575).

Keywords: CSMD3; asthma; chronic obstructive pulmonary disease; genome-wide association studies; longitudinal lung function patterns.

Figure 1.

Longitudinal lung function trajectories. Possible lung function trajectories over a person’s lifetime are shown; the lung function is plotted for each age as the percentage of the maximum FEV₁ obtained for a normal individual (maximum usually attained in the 18- to 30-yr range). Normal lung function growth and decline (Normal growth) is characterized by a steep increase in adolescence, a plateau in early adulthood, and a gradual decline into old age. Abnormal trajectories (Reduced Growth, Early Decline, and Reduced Growth with Early Decline) are also shown. The red dotted line and red brace indicate levels of FEV₁ that meet spirometric criteria for chronic obstructive pulmonary disease (COPD) Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 2 and 3.

Figure 2.

Diagram of included populations. CAMP (Childhood Asthma Management Program) is the primary discovery population; the Dutch cohort and chronic obstructive pulmonary disease metaanalysis cohort were used for generalization of the association to related lung-function cohorts. COPD = chronic obstructive pulmonary disease; ECLIPSE = Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points; ED = early decline; GenKOLS = Genetics of Chronic Obstructive Lung Disease study; GWAS = genome-wide association study; NAS = Normative Aging Study; NETT = National Emphysema Treatment Trial; NG = normal growth pattern (without early decline); NG/ED = normal growth with early decline pattern; RG = reduced growth pattern (without early decline); RG/ED = reduced growth with early decline pattern.

Figure 3.

Locus plot of single-nucleotide polymorphism associations with normal growth and early decline on chromosome 8. The peak at rs4445257 is approximately 633 kbp upstream from CSMD3 and approximately 1.4 Mbp downstream from TRPS1. Color indicates linkage disequilibrium from rs4445257 (r²).

Figure 4.

Hi-C interaction data (40 kb bins) in NCI-H460 lung epithelium cells on chromosome 8 from 110 to 118 Mbp. Clear domains of increased chromatin interaction are observed as triangles that correspond to topologically associating domains (TADs), separated by boundaries. The dark line through the heatmap represents the TAD insulation score calculated from the Hi-C data. Dips in the plot represent domain boundaries that are also indicated as green blocks at the bottom of the heatmap. Single-nucleotide polymorphism (SNP) rs4445257 is shown with a blue highlighted arrow in the genome snapshot under the heatmap and is located in a large domain. The promoter of CSMD3 is at the boundary of this domain, indicating possible interaction with the SNP; the promoter of TRPS1 is located in a different domain.