Functional Genetic Polymorphisms in the IL1RL1–IL18R1 Region Confer Risk for Ocular Behçet’s Disease in a Chinese Han Population

Single nucleotide polymorphisms (SNPs) in the IL1RL1–IL18R1 region are associated with various immune-mediated diseases. This study was carried out to investigate the causal variant for ocular Behçet’s disease (BD) and elucidate its target genes in the IL1RL1–IL18R1 region. Nine candidate functional SNPs were prioritized with bioinformatics analysis, followed by a two-stage association study in 694 ocular BD patients and 1,458 unaffected controls. Functional studies were performed in the peripheral blood mononuclear cells (PBMCs) of 45 healthy men and 16 active male BD patients. Genotyping was performed using the MassARRAY System. The mRNA expressions of IL1RL1, IL18R1, IL18RAP, and SLC9A4 were assayed by real-time PCR and secretion of cytokines was examined by ELISA. Significantly lower frequencies of the rs12987977 GG genotype/G allele (P(c) = 8.93 × 10(–7), OR = 0.39; P(c) = 2.60 × 10(–3), OR = 0.77, respectively), rs12999364 TT genotype/T allele (P(c) = 3.15 × 10(–4), OR = 0.51; P(c) = 1.13 × 10(–2), OR = 0.80, respectively), and rs4851569 AA genotype/A allele (P(c) = 3.29 × 10(–4), OR = 0.52; P(c) = 9.72 × 10(–3), OR = 0.80, respectively) were observed in BD patients compared with the controls. Functional experiments revealed a downregulation of IL1RL1, IL18R1, and SLC9A4 and a decreased secretion of IFN-γ in the anti-CD3/CD28 antibody-treated PBMCs as well as a decreased production of TNF-α in the lipopolysaccharide (LPS)-stimulated PBMCs in carriers of the protective homozygous rs12987977/GG genotype compared with the TT genotype. Our findings show that functional SNPs—rs12987977, rs12999364, and rs4851569—in the IL1RL1–IL18R1 region confer susceptibility to ocular BD in a Chinese Han population. And IL1RL1, IL18R1, and SLC9A4 may be the target genes of rs12987977.