Background: Betaine/gamma-aminobutyric acid (GABA) signaling pathway in the airway epithelium has been revealed to play a critical role in bronchial asthma. To elucidate any genetic influence of the GABAergic in aspirinexacerbated respiratory disease (AERD), we investigated the association of solute carrier family 6 (neurotransmitter transporter, betaine/GABA) member 12 (SLC6A12) gene in Japanese patients with AERD. Methods: DNA specimens were obtained from 103 AERD patients, 300 patients with aspirin-tolerant asthma (ATA) and 100 normal controls. Allelic discrimination assay for two single nucleotides polymorphisms in SLC6A12 gene (rs499368 and rs557881) was carried out. Results: The minor allele frequencies in SLC6A12 intron 2 A>T genotype (rs49936) were higher in AERD patients than in normal controls, and that in SLC6A12 exon 4 T>C genotype (rs557881) were higher in AERD patients than in ATA patients and normal controls. The frequencies of the combined TC/CC genotype group of SLC6A12 exon 4 T>C were higher than those of the TT genotype in AERD patients compared with those in ATA patients (P=0.021; odds ratio, 1.724; 95% confidence interval, 1.087-2.732). In male patients with AERD, frequencies of the TC/CC genotype group were higher than those of the TT genotype compared with male patients with ATA (P = 0.010; odds ratio, 3.177; 95% confidence interval, 1.311-7.699). Forced expiratory volume in one second (percentage predicted) in AERD patients with the TC/CC genotype group of the SLC6A12 exon 4 T>C gene was lower than that in the patients with the TT genotype (P=0.039). Conclusion: This is the first Japanese study to investigate the SLC6A12 intron 2 A>T and SLC6A12 exon 4 T>C genotype polymorphisms in patients with AERD. Our findings suggest that the association between SLC6A12 intron 2 A>T and exon 4 T>C gene sequence variations might be implicated in the development of AERD in a Japanese population.