Genetic variants of SMAD2/3/4/7 are associated with susceptibility to ulcerative colitis in a Japanese genetic background

Purpose: Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is attributed to inappropriate inflammatory response in intestinal mucosa. Transforming growth factor beta (TGF-beta)/SMAD signaling plays key role in differentiation of naive CD4(+) T cells to T helper 17 (Th17) cells or regulatory T (T-reg) cells. This study aimed to investigate associations between single nucleotide polymorphisms (SNPs) of SMAD family genes and susceptibility to IBD in a Japanese cohort to elucidate genetic determinants of IBD. Methods: This study included 81 patients with CD, 108 patients with UC, and 199 healthy subjects as controls. A total of 21 SNPs in four genes (SMAD2, SMAD3, SMAD4, and SMAD7) involved in the TGF-beta/SMAD signaling pathway were genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism, PCR-direct DNA sequencing, or PCR-high resolution melting curve analysis. Results: Four SNPs (rs13381619, rs9955626, rs1792658, and rs1792671) within SMAD2, one SNP within SMAD3 (rs41473580), two SNPs within SMAD4 (rs7229678 and rs9304407), and one SNP within SMAD7 (rs12956924) were significantly associated with susceptibility only to UC. rs13381619 within SMAD2, rs4147358 within SMAD3, rs9304407 within SMAD4, and rs12956924 within SMAD7 exhibited the strongest association (p < 0.001, p = 0.021, p = 0.005, and p = 0.001, respectively). Furthermore, rs4147358 of SMAD3 altered the expression of a luciferase reporter gene in Jurkat T cell line in vitro. Conclusions: Genetic variants of several SMAD family of genes might alter the balance of differentiation between Th17 and T-reg, resulting in the development of IBD, especially UC.