Tanaka Michihiro, Arimura Yoshiaki, Goto Akira, Hosokawa Masayo, Nagaishi Kanna, Yamashita Kentaro, Yamamoto Hiroyuki, Sonoda Tomoko, Nomura Masafumi, Motoya Satoshi, Imai Kohzoh, Shinomura Yasuhisa
First Department of Internal Medicine, Sapporo Medical University, Chuo-ku, Sapporo, Japan.
Inflamm Bowel Dis. 2009 Jun;15(6):918-25. doi: 10.1002/ibd.20936.
Identifying culprit genes for a complex trait in a homogeneous population such as the Japanese remains challenging. We aimed to use previous achievements of genome-wide association studies to identify precise susceptibility loci for inflammatory bowel disease in Japanese people and to simultaneously investigate the replication of recently identified susceptibility loci.
An unrelated Japanese population of 174 Crohn's disease patients, 296 ulcerative colitis (UC) patients, and 394 healthy controls was consecutively enrolled in this study. Genotype and haplotype analyses focusing on susceptibility to inflammatory bowel disease were performed using 7 single nucleotide polymorphisms (SNPs) including 5 HapMap tag SNPs within surfactant, pulmonary-associated protein D (SFTPD) along with the 2 Caucasian susceptibility loci. We performed fine-scale mapping of trait-associated loci with the extension of a shattered coalescent process in a Bayesian framework. Epistasis on disease phenotypes was statistically explored with the interaction dendrogram.
A minor allele G of rs911887 reached statistical significance for susceptibility to UC. The 2-allele haplotype GG comprising rs911887 and rs2243639 (Ala160Thr) within SFTPD was significantly associated with susceptibility to UC. A posterior density plot shows that trait-associated variants in the vicinity of rs911887 are likely to exist. An association between NKX2-3 and UC susceptibility was replicated and diverse evidence of epistasis in Japan was suggested.
This preliminary study suggests that SFTPD is both a susceptibility gene and a disease-modifying gene for UC in Japanese. Replication of the causality and functional analyses of SFTPD is urgently warranted.
在像日本人群这样的同质群体中，识别复杂性状的致病基因仍然具有挑战性。我们旨在利用全基因组关联研究的先前成果，确定日本人群中炎症性肠病的确切易感位点，并同时研究最近确定的易感位点的重复性。
本研究连续纳入了174例克罗恩病患者、296例溃疡性结肠炎（UC）患者和394例健康对照组成的无亲缘关系的日本人群。使用7个单核苷酸多态性（SNP）进行了聚焦于炎症性肠病易感性的基因型和单倍型分析，其中包括表面活性物质、肺相关蛋白D（SFTPD）内的5个HapMap标签SNP以及2个白种人的易感位点。我们在贝叶斯框架下通过扩展破碎合并过程对性状相关位点进行了精细定位。用相互作用树状图对疾病表型的上位性进行了统计学探索。
rs911887的次要等位基因G在UC易感性方面达到统计学显著性。包含rs911887和SFTPD内的rs2243639（Ala160Thr）的双等位基因单倍型GG与UC易感性显著相关。后验密度图显示在rs911887附近可能存在性状相关变异。NKX2 - 3与UC易感性之间的关联得到了重复验证，并提示了日本存在多种上位性证据。
这项初步研究表明，SFTPD是日本人UC的一个易感基因和疾病修饰基因。迫切需要对SFTPD的因果关系进行重复验证和功能分析。
