Behçet’s disease risk association fine-mapped on the IL23R–IL12RB2 intergenic region in Koreans

Abstract

BackgroundBehçet’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). We aimed to fine-map BD risk association of these four loci using extensive imputation and additional genotyping for replication.MethodsIn the discovery phase, 369 patients with BD enrolled in the previous Korean GWAS and 2000 controls retrieved from a population-based cohort of healthy Koreans were imputed for their genotypes of all SNPs in the four loci using the Asian data of the 1000 Genomes Project as reference. For genotype imputation of ERAP1 SNPs, the adjacent ERAP2 SNPs were also covered. For the 10 most significantly associated SNPs (8 imputed and 2 GWAS-genotyped), an additional 84 patients with BD and 283 healthy controls were genotyped for replication. The results from the discovery and replication phases were pooled for meta-analysis using the Mantel-Haenszel test to estimate the odds ratio (OR) and 95% confidence interval (CI).ResultsAn IL23R–IL12RB2 intergenic SNP rs1495965 was significantly associated with BD risk (OR (95% CI) = 1.5 (1.3, 1.7), P = 2.5 × 10−7) in the pooled meta-analysis of the discovery (1.4 (1.2, 1.7), P = 4.9 × 10−7) and replication (1.9 (1.3, 2.6), P = 6.0 × 10−4) phases. BD risk association was fine-mapped on the intergenic region rather than the two flanking genes, as rs1495966 and rs4655535, almost perfectly correlated with rs1495965 (r 2 = 0.99), were also located in the same intergenic region. Consistent with previous reports, the P values tended to be lower within IL23R than IL12RB2. On the other hand, several IL10 SNPs were suggested for association in the discovery phase but all failed in the replication phase. No SNP in ERAP1–ERAP2 and STAT4 was suggested even in the discovery phase.ConclusionsBD susceptibility association was fine-mapped on the intergenic region between IL23R and IL12RB2 as marked by three correlated SNPs, rs1495965, rs1495966, and rs4655535.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1435-5) contains supplementary material, which is available to authorized users.

Genetics of Behçet’s Disease

“…A significant association (reaching a GWAS p value) of the IL-23R gene with BD was found at the SNP rs11209026 (Gly149Arg) in Japanese, and at the SNP rs76418789 (Arg381Gln) in Turkish cohort [61]. The association between BD and the IL-23R/IL-12RB2 genes appeared to be consistent in multiple reports with different populations including Turkey [52], Japanese [53], Han Chinese [62,63], Iranian [64], Western Algeria [65], and Korean [66].…”

“…The associations of the TLR4 gene with BD are conflict in different reports. It was found in Japanese [91], Korea [92] and Turkish cohorts [66], but not in Italian [93], Tunisian [94], and Chinese cohorts [95]. Of note, two BD protective TLR4 variants identified in the Turkish cohort, p.Asp299Gly (rs4986790) and p.Thr399Ile (rs4986791) were associated with hyporesponsiveness to endotoxin [96].…”

Behçet’s syndrome: focus on pathogenetic background, clinical phenotypes and specific treatments

“…Recently, several different genetic studies have also identified non-HLA variants with biological meaning (e.g., IL10, IL23RIL12RB2) [10,11]. A GWAS has recently shown that the Endoplasmic Reticulum Aminopeptidase Protein 1 (ERAP1) gene is associated with BS, and that ERAP1 is epistatic with HLA-B*51 allele [11].…”

“…Recently, several different genetic studies have also identified non-HLA variants with biological meaning (e.g., IL10, IL23RIL12RB2) [10,11]. A GWAS has recently shown that the Endoplasmic Reticulum Aminopeptidase Protein 1 (ERAP1) gene is associated with BS, and that ERAP1 is epistatic with HLA-B*51 allele [11]. Interestingly, ERAP1 encodes for a molecule in the endoplasmic reticulum that cuts the N-terminal amino acids from epitope precursors for HLA class I presentation [10,12,13].…”

Immune Regulatory Genes Are Major Genetic Factors to Behcet Disease: Systematic Review

“…The GWAS identified the IL-23R SNP rs11209026 (Gly149Arg) in association with the Japanese cohort, and SNP rs76418789 (Arg381Gln) with the Turkish population [ 65 ]. In addition, the IL-23R/IL-12RB2 genes with multiple SNPs (rs1495965, rs924080 rs11209032, rs17375018, rs7517847, 10489629 and rs1966176) were associated with BD in the cohorts of Turkey [ 56 ], Japanese [ 57 ], Han Chinese [ 66 , 67 ], Iranian [ 68 ], Western Algeria [ 69 ] and Korean [ 70 ].…”