Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients

Background: Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function. Objective: We sought to identify novel lung function loci specifically for asthma and to confirm lung function loci identified in general populations. Methods: Genome-wide association studies of lung function (percent predicted FEV1 [ppFEV(1)], percent predicted forced vital capacity, and FEV1/forced vital capacity ratio) were performed in 4 white populations of European descent (n = 1544), followed by meta-analyses. Results: Seven of 28 previously identified lung function loci (HHIP, FAM13A, THSD4, GSTCD, NOTCH4-AGER, RARB, and ZNF323) identified in general populations were confirmed at single nucleotide polymorphism (SNP) levels (P < .05). Four of 32 loci (IL12A, IL12RB1, STAT4, and IRF2) associated with ppFEV(1) (P < 10(-4)) belong to the T(H)1 or IL-12 cytokine family pathway. By using a linear additive model, these 4 T(H)1 pathway SNPs cumulatively explained 2.9% to 7.8% of the variance in ppFEV(1) values in 4 populations (P = 3 x 10(-11)). Genetic scores of these 4 SNPs were associated with ppFEV1 values (P = 2 x 10(-7)) and the American Thoracic Society severe asthma classification (P = .005) in the Severe Asthma Research Program population. T(H)2 pathway genes (IL13, TSLP, IL33, and IL1RL1) conferring asthma susceptibility were not associated with lung function. Conclusion: Genes involved in airway structure/remodeling are associated with lung function in both general populations and asthmatic subjects. T(H)1 pathway genes involved in anti-virus/ bacterial infection and inflammation modify lung function in asthmatic subjects. Genes associated with lung function that might affect asthma severity are distinct from those genes associated with asthma susceptibility.