Convergent Evidence Supports TH2LCRR as a Novel Asthma Susceptibility Gene

Asthma is a common, complex disease with apparent genetic predispositions, and previous genome-wide association studies suggest that rs1295686 within the IL13 (IL-13) gene is significantly associated with asthma. Analysis of the data provided by the 1,000 Genomes Project indicated an additional four SNPs in nearly complete linkage disequilibrium with rs1295686 in White people. However, the causal SNPs and the associated mechanism remain unclear. To investigate this issue, functional genomics approaches were utilized to analyze the functions of these SNPs. Dual-luciferase assays indicated that the functional SNP is not rs1295686 but a haplotype consisting of three other SNPs: rs1295685, rs848, and rs847. Through chromosome conformation capture, it was found that the enhancer containing the three functional SNPs interacts with the promoter of TH2LCRR (T helper type 2 locus control region associated RNA), a recently identified long noncoding RNA. RNA-seq data analysis indicated that TH2LCRR expression is significantly increased in patients with asthma and is dependent on the genotype at this locus, indicating that TH2LCRR is a novel susceptibility gene for asthma and that these SNPs confer asthma risk by regulating TH2LCRR expression. By chromatin immunoprecipitation, the related transcription factors that bind in the region surrounding these three SNPs were identified, and their interactions were investigated by functional genomics approaches. Our effort identified a novel mechanism through which genetic variations at this locus could influence asthma susceptibility.