Functional sequence variants of intergenic long non-coding RNA on Chromosome 17q21 are associated with asthma.

Background: The genetic and molecular basis of asthma remains unclear and its gene-environment interaction is still enigmatic. In the present study, we aimed to identify asthma-causing genetic variants and their interactions with the environment.

Methods: We performed case-control genome-wide association studies on individuals of Han Chinese descent from the Taiwan biobank (case=4877 and control=(98 218) to identify asthma susceptibility loci, validated in a hospital-based population of subjects (N=2595). The 10- to 15-year exposure of cumulative ambient particulate matter with a diameter of less than 2.5 μm (PM_2.5) and polycyclic aromatic hydrocarbons (PAHs) were assessed for gene-environment relationships. The function of the newly identified long non-coding RNA, lncZPBP2-3, and its interaction with PM_2.5 and PAH exposure were analyzed using RNA immunoprecipitation, RNA pull-down, RT-qPCR, and western blotting.

Findings: Chromosome 17q12-21 was found to be a significant risk region, encompassing variants of lncZPBP2-3 and its neighboring genes, which interacted with increasing exposure to PM_2.5 and its adsorbed PAHs. The expression of lncZPBP2-3 was elevated, correlating with the expression of its neighboring genes, in the peripheral blood of asthmatic individuals compared to that in controls. Unlike non-risk lncZPBP2-3, the risk variant of lncZPBP2-3 disrupted the transcriptional suppression of the risk locus via its interaction with the transcription insulator, CCCTC-binding factor (CTCF), concomitant with the higher expression levels of neighboring genes in individuals with the risk genotype.

Interpretation: An functional variant of lncRNA, lncZPBP2-3, was significantly associated with asthma and inducible by environmental PAH, suggesting a potentially novel genetic and molecular mechanism of asthma.