Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
Arthritis Res Ther. 2017 Oct 10;19(1):227. doi: 10.1186/s13075-017-1435-5.
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). We aimed to fine-map BD risk association of these four loci using extensive imputation and additional genotyping for replication.
In 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).
An IL23R-IL12RB2 intergenic SNP rs1495965 was significantly associated with BD risk (OR (95% CI) = 1.5 (1.3, 1.7), P = 2.5 × 10) in the pooled meta-analysis of the discovery (1.4 (1.2, 1.7), P = 4.9 × 10) and replication (1.9 (1.3, 2.6), P = 6.0 × 10) 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 = 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.
BD susceptibility association was fine-mapped on the intergenic region between IL23R and IL12RB2 as marked by three correlated SNPs, rs1495965, rs1495966, and rs4655535.
在日本、土耳其、中国和其他人群中，白塞病（BD）易感性与 IL23R-IL12RB2、IL10、STAT4 或 ERAP1 基因座中的单核苷酸多态性（SNP）有关，但在韩国全基因组关联研究（GWAS）中没有发现。我们旨在通过广泛的基因分型和复制来精细定位这四个基因座与 BD 风险的关联。
在发现阶段，我们对之前韩国 GWAS 中招募的 369 名 BD 患者和从韩国基于人群的健康队列中检索的 2000 名对照进行基因分型，使用亚洲 1000 基因组计划的数据作为参考对四个基因座中的所有 SNP 进行基因型推断。对于 ERAP1 SNP 的基因分型，还覆盖了相邻的 ERAP2 SNP。对于 10 个最显著相关的 SNP（8 个推断和 2 个 GWAS 基因分型），我们对另外 84 名 BD 患者和 283 名健康对照进行了基因分型以进行复制。使用 Mantel-Haenszel 检验对发现和复制阶段的结果进行汇总，以估计比值比（OR）和 95%置信区间（CI）。
在发现和复制阶段的汇总分析中，IL23R-IL12RB2 基因间 SNP rs1495965 与 BD 风险显著相关（OR（95%CI）=1.5（1.3, 1.7），P=2.5×10）。BD 风险关联在基因间区域而不是两个侧翼基因上进行了精细定位，因为 rs1495966 和 rs4655535 与 rs1495965 几乎完全相关（r=0.99），它们也位于相同的基因间区域。与之前的报道一致，在 IL23R 内的 P 值往往低于 IL12RB2。另一方面，在发现阶段提示了几个 IL10 SNP 与关联，但在复制阶段均未成功。甚至在发现阶段，在 ERAP1-ERAP2 和 STAT4 中也没有提示 SNP。
BD 易感性关联在 IL23R 和 IL12RB2 之间的基因间区域进行了精细定位，由三个相关的 SNP，rs1495965、rs1495966 和 rs4655535 标记。
