Genetic association and epistatic interaction of the interleukin-10 signaling pathway in pediatric inflammatory bowel disease

Figure 1 Epistatic interaction between IL-10 single nucleotide polymorphisms rs3024496 and rs1800872. Graphic depiction of epistatic interaction between the IL-10 SNPs, rs3024496 and rs1800872. Four interaction models for rs3024496 and rs1800872 are shown. The additive-additive model is significant (Bp = 0.003), the additive-dominant model is weak (Bp = 0. 216), and the other two models are not observed (Bp = 1, no color). Bp: Bonferroni P value; SNPs: Single nucleotide polymorphisms.

Figure 2 Gene-gene interaction between IL-10 and IL10RA, IL10RB and HO1 in pediatric inflammatory bowel disease. A: Graphic depiction of epistatic interaction between the IL-10 SNP rs3024496 and the IL10RA rs3135932. Four interaction models for rs3024496 and rs3135932 are shown. The additive-additive and additive-dominant models are both weak (Bp = 0.433 and 0.426 respectively), and the other two models are not observed (Bp = 1, no color); B: Graphical depiction of epistatic interaction between the HO1 rs2071746 and the IL10RB rs2834167. Four interaction models for rs3024496 and rs3135932 are shown. Only the additive-dominant model is significant (Bp = 0.039), and the other three models are not observed (Bp = 1, no color). The levels of Bp values are shown in the bar as shades of blue color from none (Bp = 1) to high (Bp = 0.001). Bp: Bonferroni P value; SNPs: Single nucleotide polymorphisms.

Figure 3 Epistatic interaction of two IL-10 single nucleotide polymorphisms, rs1800872 and rs3024496, with IL10RA, IL10RB, STAT3 and HO1 in pediatric inflammatory bowel disease. Graphic depiction of epistatic interaction of the IL-10 SNPs rs3024496 and rs1800872 with the IL10RA rs3135932. All the interaction models analyzed for the IL-10 SNPs rs3024496 and rs1800872 with the IL10RA rs3135932 are shown. However, only one significant interaction model additive-additive-additive (a1a2a3) was observed (P = 0.003, Bp = 0.099). Levels of Bp values are shown in the bar as shades of blue color from none (Bp = 1) to high (Bp = 0.001). a1, d1, a2, d2, a3, d3: Letters, a and d, are for interaction model additive and dominant respectively; Numbers 1, 2, and 3 depict the IL-10 rs3024496, IL-10 rs1800872, and IL10RA rs3135932 respectively. The contribution of a single SNP in an interaction model could be either a or d (a1 and d1 for SNP #1, a2 and d2 for SNP #2, and a3 and d3 for SNP #3). The interaction models for two and three SNPs are the combination of the two and three SNPs; such as, a1a2 for SNPs 1 and 2, and a1a2a3 for SNPs 1, 2, and 3. Bp: Bonferroni P value; SNPs: Single nucleotide polymorphisms.

Figure 4 Epistatic interaction of IL10RB and HO1 with IL-10 (three single nucleotide polymorphisms), IL10RA and STAT3 in pediatric inflammatory bowel disease. Graphic depiction of epistatic interaction of the IL-10 rs1800872, IL10RB rs2834167 and HO1 rs2071746. Of all the interaction models analyzed, a three SNP interaction (a1d2a3) for IL-10 rs1800872, IL10RB rs2834167 and HO1 rs2071746 is significant (Bp = 0.005). The levels of Bp values are shown in the bar as shades of blue color from none (Bp = 1) to high (Bp = 0.001). a1, d1, a2, d2, a3, d3: Letters, a and d, denote interaction models, additive and dominant respectively; Numbers 1, 2, and 3 are for IL-10 rs1800872, IL10RB rs2834167, and HO1 rs2071746, respectively. The contribution of a single SNP in an interaction model could be either a or d: a1 and d1 for SNP #1, a2 and d2 for SNP #2, and a3 and d3 for SNP #3. The interaction models for two and three SNPs are the combination of two and three SNPs (e.g., a1a2 for SNPs 1 and 2, and a1a2a3 for SNPs 1, 2, and 3). Bp: Bonferroni P value; SNP: Single nucleotide polymorphism.

Figure 5 Summary of gene function and epistatic interaction of the IL-10/STAT3 signaling pathway in pediatric inflammatory bowel disease. In the IL-10 pathway genes, genetic variations in IL-10 and STAT3 are associated with adult IBD, and genetic mutations identified from IL10RA and IL10RB are associated with pediatric/very early onset inflammatory bowel disease (published data). In this study, we found SNP-SNP epistatic interaction within the IL-10 gene, between IL10 and IL10RA genes, and between IL10RB and HO1 genes. We also found epistatic interaction among three SNPs between the two genes IL-10 (two SNPs) and IL10RA, and among the three genes IL-10, IL10RB and HO1. Bp: Bonferroni P value.