Genetic Variants in Surfactant, Pulmonary-associated Protein D (SFTPD) and Japanese Susceptibility to Ulcerative Colitis

Background: 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. Methods: 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. Results: 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. Conclusions: 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.