DOP58 Human Leukocyte Antigen drives methylation signatures in primary sclerosing cholangitis but not in IgG4-related sclerosing cholangitis

Abstract

Abstract Background Primary sclerosing cholangitis (PSC) and IgG4-related sclerosing cholangitis (IgG4-SC) are fibro-inflammatory hepatobiliary conditions, with genetic, environmental, and immunologic risk factors, in which epigenetic alterations may provide insights into pathophysiology and novel biomarkers. Methods Whole blood DNA methylation profiling and genotyping was performed in 70 PSC (57 with PSC and ulcerative colitis (PSC-UC)), 56 IgG4-SC, 66 UC, and 88 healthy controls (HC), with MethylationEPIC and Global Screening arrays (Illumina). UC patients were selected to match the clinical characteristics of UC in the PSC-UC cohort. Methylation data was processed with Minfi and limma, genotyping analysed with Plink, and meQTLs with linear models. Results There were 31, 13 and 8 Holm-significant methylation differences between PSC and controls, IgG4-SC and controls, and UC and controls respectively (8 probes shared). Inflammatory genes (including CEP97, IFNAR1, TXK, and SMAD2) and methylation loci associated with mitochondrial DNA copy number (C5orf36, PYY, and MTRNR2L1) were predominant. Sub-analyses of PSC-UC and PSC without IBD detected 25 and 4 differences with HC respectively (p<0.05). DNA methylation age acceleration was observed in IgG4-SC, but not on PSC, PSC-IBD or UC. MeQTL analyses to identify genetic determinants of methylation revealed a strong HLA signal in PSC but not IgG4-SC, with 19/40 significant findings in 5 clusters (HLA-DRB1, HLA-DPB1, BTNL2, CSNK2B, and SFTA2). There was no overlap with the 36 meQTLs found in IgG4-SC. Using multivariate adaptive shrinkage for meQTLs in PSC, IgG4-SC, and UC yielded 5505 meQTLs with local false discovery rate <0.05 in at least one condition, with 1230 unique to PSC, and 1043 to IgG4-SC. Conclusion We identify characteristic epigenetic alterations in PSC and IgG4-related disease, providing insights into disease pathogenesis; and highlight the potential interaction with germ-line variation.