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P694 A functional variant of SLC26A3 in association with Ulcerative Colitis down regulates SLC26A3 expression

A. Hirano*1, 2, J. Umeno1, K. Asano1, M. Esaki1, T. Matsumoto3

1Kyushu University, Department of Medicine and Clinical Science, Fukuoka, Japan, 2Yamaguchi Red Cross Hospital, Department of internal medicine, Yamaguchi, Japan, 3Iwate Medical University, Division of Gastroenterology, Department of Internal Medicine, Morioka, Japan


Our recent genome-wide association study has identified that rs2108225, located at 9 kb upstream of SLC26A3 gene, is associated with the susceptibility to ulcerative colitis (UC) in a Japanese population. The present study aimed to identify a functional variant in this locus.


We first carried out a re-sequencing of this locus using 94 UC cases to determine other misidentified causal variants. After fine-mapping, we investigated possible association of the identified single nucleotide polymorphisms (SNPs) and UC by single-marker and haplotype analyses using 752 UC cases and 2068 controls. Allelic difference in binding affinity to nuclear proteins of each SNP was evaluated by electrophoretic mobility shift assay (EMSA) and luciferase reporter assay. We also performed a chromatin immunoprecipitation (ChIP) assay to analyze the difference in binding affinity to the specific transcription factor.


We identified 24 newly identified SNPs by re-sequencing and genotyped a total of 99 SNPs in this locus. The strongest signal was observed at rs6466189 (P = 7.51 × 10-6), which was absolutely linked with rs2108225 and other seven SNPs (r2>0.95, respectively), in single-marker analysis. Haplotype analysis failed to identify any haplotype showing stronger association with UC than the nine SNPs. EMSA and reporter assay showed different binding affinity to nuclear proteins in rs7785790, causing the difference in transcriptional activity. In ChIP assay, such a difference in transcription relative to rs7785790 was caused by the negative transcription factor YY1, which suppressed the transcriptional activity by binding to the susceptible A allele.


The present study suggests that the functional variant rs7785790 affects the transcription of SLC26A3 by altering the binding affinity to YY1. Lower expression of SLC26A3 in the colonic mucosa might be associated with the susceptibility to UC.