We propose a model in which up-regulation of STAT4 expression and subsequent STAT4-driven production of inflammatory cytokines, such as IL-17, constitute a potential pathway leading to BD.
Six SNPs (in decreasing order of significance, rs7616215 located 38 kb downstream of CCR1, rs2617170 [rs2617170;rs281860419" genes_norm="3107;8302">p.Asn104Ser] in KLRC4, rs17810546 in IL12A-AS1, rs7574070 in STAT4, and rs10050860 [rs10050860" genes_norm="51752">p.Asp575Asn] and rs13154629 in ERAP1) were nominally associated with BD in both allelic association tests (5.05 × 10(-9) ≤ Pallele ≤ 7.55 × 10(-3) ) and sex-adjusted genotypic association tests (6.01 × 10(-9) ≤ adjusted P value ≤ 1.30 × 10(-2) ).
Our results indicate that the interaction of specific IL17A, IL23R, and STAT4 SNPs modulate susceptibility to intestinal BD in the Korean population, suggesting that the IL-17/23 axis plays a significant role in disease pathogenesis.
Along with human leukocyte antigen gene encoding B*51 (HLA-B*51) and areas including the major histocompatibility complex class I, genome-wide association studies have recognized numerous other BD susceptibility genes including those encoding interleukin (IL)-10, IL-12 receptor β 2 (IL-12RB2), IL-23 receptor (IL-23R), C-C chemokine receptor 1 gene, signal transducer and activator of transcription 4 (STAT4), endoplasmic reticulum aminopeptidase (ERAP1), and genes encoding killer cell lectin-like receptor family members (KLRC4-KLRK1).
Behçet's disease (BD) susceptibility had been associated with single-nucleotide polymorphisms (SNPs) in IL23R-IL12RB2, IL10, STAT4, or ERAP1 locus in Japanese, Turkish, Chinese, and other populations, but not in a Korean genome-wide association study (GWAS).