Genome-wide Association Study Identifies IL1RL1 and KIAA1217 Associated With Asthma-Chronic Obstructive Pulmonary Disease Overlap in the All of Us Research Program

Purpose: Patients with asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) tend to have more severe respiratory symptoms than those with asthma or COPD only. In this study, we sought to identify genetic variants associated with ACO. Methods: ACO was defined as patients with physician-diagnosed or self-reported asthma and COPD. Meta-analysis of genome-wide association studies (GWASs) of ACO was performed in non-Hispanic White (NHW: 4,292 ACO vs. 114,816 controls) and non-Hispanic Black or African American (NHB-AA: 2,335 ACO vs. 45,949 controls). Candidate genes for asthma or COPD were further pairwise compared among ACO, asthma, COPD, and control groups. Results: The prevalence rates of ACO/asthma/COPD were 2.46/8.89/3.57 (% of 200,369), 4.06/10.00/3.89 (% of 70,329), 1.40/10.21/1.40 (% of 6,093), and 0.43/4.55/0.58 (% of 12,783) for NHW, NHB-AA, Hispanic or Latino White, and non-Hispanic Asian, respectively. Patients with ACO or COPD and asthma were predominantly smokers and non-smokers, respectively. Patients with ACO showed highest blood eosinophil counts. Meta-analysis of GWASs identified rs1420101 (odds ratio [OR], 1.11; P = 8.29 × 10⁻⁹) in interleukin 1 receptor like 1 (IL1RL1) and rs2428305 (OR, 1.16; P = 4.49 × 10⁻⁸) in KIAA1217 associated with ACO. A group of asthma candidate genes (GSDMB, IL33, IL13, TSLP, HLA-DQB1, and IL1RL1) were associated with ACO and asthma but not associated with COPD. A group of COPD candidate genes (HHIP and CHRNA5) were associated with ACO and COPD (lung function or smoking behavior) but not associated with asthma. Conclusions: Prevalence of chronic respiratory diseases differs in racial/ethnic groups. On the basis of our phenotypic and genetic findings, we speculate that patients who carry asthma and COPD risk alleles, further influenced by smoking, may develop into ACO. IL1RL1 is a biomarker for ACO, and anti-IL1RL1 biologics may be investigated in patients with ACO stratified by single nucleotide polymorphisms and IL1RL1 expression levels.