Extended Data Fig. 6: Cytokine-induced islet regulatory elements are enriched in T1D associated variants.
a, EndoC-βH1 cytokine-induced regulatory elements (IREs) overlap more often than expected T1D associated variants while the opposite is true for T2D. EndoC-βH1 cytokine-invariant regulatory elements (SREs) are instead enriched for T2D, but not T1D associated variants. Each dot denotes the Varian Set Enrichment (VSE) score in IREs or SREs regions. Boxplot shows the enrichment distribution of the matched null permutated data sets. Red dots indicate that the difference is statistically significant as determined by VSE (Bonferroni adjusted P < 0.05). Box plot limits show upper and lower quartiles, whiskers extend to 1.5 times the interquartile range and the notch represents the confidence interval around the median. b-f, Representative regional plots of different T1D risk loci containing T1D variants overlapping IREs and up-regulated genes. R2 values are based on 1KG phase 3 EUR and the leading SNPs in the locus is represented by a diamond. If different leading variants are present in the same locus, their proxies are depicted in different colors. Yellow squares highlight those variants that overlap a human islet IRE. IREs are depicted as boxes, with the filling color corresponding to the H3K27ac log2 fold change. g, The IRE bearing the T1D associated variant rs78037977 is marked by the ENCODE ChromHMM classification as a ‘strong enhancer’ (orange) in other non β-cell lines (left). ENCODE ChromHMM classification in non β-cell lines for the IRE bearing the T1D associated variant rs193778. h, i, Allele-specific luciferase experiments for rs78037977 (h) and rs193778 (i) in untreated EndoC-βH1. ANOVA followed by Bonferroni correction * P < 0.05; ** P < 0.01. Bars represent mean ± sd.
