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

Abstract

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 [ppFEV1], 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 ppFEV1 (P < 10(-4)) belong to the TH1 or IL-12 cytokine family pathway. By using a linear additive model, these 4 TH1 pathway SNPs cumulatively explained 2.9% to 7.8% of the variance in ppFEV1 values in 4 populations (P = 3 × 10(-11)). Genetic scores of these 4 SNPs were associated with ppFEV1 values (P = 2 × 10(-7)) and the American Thoracic Society severe asthma classification (P = .005) in the Severe Asthma Research Program population. TH2 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. TH1 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.

Keywords: ACRN; ATS; American Thoracic Society; Asthma Clinical Research Network; BASALT; Best Adjustment Strategy for Asthma in Long Term; CSGA; Collaborative Studies on the Genetics of Asthma; FEV(1); FVC; Forced vital capacity; GWAS; Genome-wide association study; IL12A; IL12RB1; IRF2; LD; Linkage disequilibrium; Lung function; NHLBI; National Heart, Lung, and Blood Institute; Percent predicted FEV(1); Percent predicted forced vital capacity; SARP; SNP; STAT4; Severe Asthma Research Program; Single nucleotide polymorphism; T(H)1; TALC; TENOR; The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens; Tiotropium Bromide as an Alternative to Increased Inhaled Corticosteroid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroids; asthma; ppFEV(1); ppFVC.