Increased expression of NKX2.3 mRNA transcribed from the risk haplotype for ulcerative colitis in the involved colonic mucosa.

NKX2.3 is a promising candidate for susceptibility genes to inflammatory bowel disease (IBD). The aim of this study was to perform a candidate gene analysis of NKX2.3 in Japanese IBD and to examine how the risk allele (haplotype) affects susceptibility to IBD using allelic expression ratios of NKX2.3 mRNA in the involved colonic mucosa. A total of 344 patients with Crohn's disease (CD), 253 patients with ulcerative colitis (UC), and 243 healthy controls (HCs) were genotyped for 3 tag-single nucleotide polymorphisms (SNPs; rs10883365, rs888208, and rs11596008) around NKX2.3. The allelic expression ratio of NKX2.3-mRNA was examined by TaqMan assay using rs888208 as an allelic (haplotypic) marker. Two SNPs (rs10883365 and rs888208) were significantly associated with UC (p = 7.79 × 10(-4), odds ratio [OR] = 1.54 [95% confidence interval (95% CI) 1.20-1.99], p = 7.70 × 10(-3), OR = 1.41 [95% CI 1.10-1.81], respectively) and 1 SNP (rs10883365) was associated with CD (p = 0.0366, OR = 1.29 [95% CI 1.02-1.63]). Haplotype B formed by the 3 SNPs demonstrated a significant association with UC (p = 6.11 × 10(-4), OR = 1.56 [95% CI 1.21-2.00]). Subgroup analyses indicated that rs10883365 was significantly associated mainly with colonic CD (p = 1.99 × 10(-3), OR = 1.91 [95% CI 1.27-2.88], vs HCs). The allelic expression ratios of NKX2.3 mRNA transcribed from haplotype B (risk haplotype) to haplotype A (the nonrisk haplotype) in the involved mucosa from 10 IBD patients were significantly higher than the allelic ratio of respective genomic DNA (p = 0.00195). We confirmed the association of SNP rs10883365 located in the 5' flanking region of NKX2-3 with Japanese UC and colonic CD and determined the risk haplotype (haplotype B) for UC. The demonstrated allelic expression imbalance supports the idea that the risk haplotype of NKX2.3 confers susceptibility to UC through increasing expression of NKX2.3 mRNA in the colonic mucosa.