Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan.
Inflamm Bowel Dis. 2020 Jul 17;26(8):1177-1187. doi: 10.1093/ibd/izaa033.
To clarify the genetic background of ulcerative colitis (UC) in the Japanese population, we conducted a genome-wide association study (GWAS) using a population-specific single nucleotide polymorphism (SNP) array.
We performed a GWAS and replication study including 1676 UC patients and 2381 healthy controls. The probability of colectomy was compared between genotypes of rs117506082, the top hit SNP at HLA loci, by the Kaplan-Meier method. We studied serum expression of miR-622, a newly identified candidate gene, from 32 UC patients and 8 healthy controls by quantitative reverse-transcription polymerase chain reaction.
In the GWAS, only the HLA loci showed genome-wide significant associations with UC (rs117506082, P = 6.69E-28). Seven nominally significant regions included 2 known loci, IL23R (rs76418789, P = 6.29E-7) and IRF8 (rs16940202, P = 1.03E-6), and 5 novel loci: MIR622 (rs9560575, P = 8.23E-7), 14q31 (rs117618617, P = 1.53E-6), KAT6B (rs12260609, P = 1.81E-6), PAX3-CCDC140-SGPP2 (rs7589797, P = 2.87E-6), and KCNA2 (rs118020656, P = 4.01E-6). Combined analysis revealed that IL23R p.G149R (rs76418789, P = 9.03E-11; odds ratio [OR], 0.51) had genome-wide significant association with UC. Patients with GG genotype of rs117506082 had a significantly lower probability of total colectomy than those with the GA+AA genotype (P = 1.72E-2). Serum expression of miR-622 in patients with inactive UC tended to be higher than in healthy controls and patients with active UC (inactive UC vs healthy controls, P = 3.03E-02; inactive UC vs active UC, P = 6.44E-02).
IL23R p.G149R is a susceptibility locus for UC in Japanese individuals. The GG genotype of rs117506082 at HLA loci may predict a better clinical course.
为了阐明溃疡性结肠炎（UC）在日本人群中的遗传背景，我们使用人群特异性单核苷酸多态性（SNP）阵列进行了全基因组关联研究（GWAS）。
我们进行了 GWAS 和包含 1676 例 UC 患者和 2381 例健康对照的复制研究。通过 Kaplan-Meier 法比较 HLA 基因座中 rs117506082 （HLA 基因座中的顶级命中 SNP）基因型之间的全结肠切除术概率。我们通过定量逆转录聚合酶链反应（qRT-PCR）从 32 例 UC 患者和 8 例健康对照中研究了新鉴定的候选基因 miR-622 的血清表达。
在 GWAS 中，仅 HLA 基因座与 UC 具有全基因组显著关联（rs117506082，P = 6.69E-28）。七个名义上显著的区域包括 2 个已知的基因座，IL23R（rs76418789，P = 6.29E-7）和 IRF8（rs16940202，P = 1.03E-6），以及 5 个新的基因座：MIR622（rs9560575，P = 8.23E-7），14q31（rs117618617，P = 1.53E-6），KAT6B（rs12260609，P = 1.81E-6），PAX3-CCDC140-SGPP2（rs7589797，P = 2.87E-6）和 KCNA2（rs118020656，P = 4.01E-6）。联合分析表明，IL23R p.G149R（rs76418789，P = 9.03E-11；优势比[OR]，0.51）与 UC 具有全基因组显著关联。与 GA+AA 基因型相比，rs117506082 的 GG 基因型患者全结肠切除术的概率显著降低（P = 1.72E-2）。在不活跃 UC 患者中，miR-622 的血清表达水平趋于高于健康对照和活跃 UC 患者（不活跃 UC 与健康对照相比，P = 3.03E-02；不活跃 UC 与活跃 UC 相比，P = 6.44E-02）。
IL23R p.G149R 是日本人群中 UC 的易感基因座。HLA 基因座中 rs117506082 的 GG 基因型可能预测更好的临床病程。
