A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in ulcerative colitis

Abstract

We describe a precision medicine workflow, the integrated single nucleotide polymorphism network platform (iSNP), designed to determine the mechanisms by which SNPs affect cellular regulatory networks, and how SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC). Using SNP profiles of 378 UC patients we map the regulatory effects of the SNPs to a human signalling network containing protein-protein, miRNA-mRNA and transcription factor binding interactions. With unsupervised clustering algorithms we group these patient-specific networks into four distinct clusters driven by PRKCB, HLA, SNAI1/CEBPB/PTPN1 and VEGFA/XPO5/POLH hubs. The pathway analysis identifies calcium homeostasis, wound healing and cell motility as key processes in UC pathogenesis. Using transcriptomic data from an independent patient cohort, with three complementary validation approaches focusing on the SNP-affected genes, the patient specific modules and affected functions, we confirm the regulatory impact of non-coding SNPs. iSNP identified regulatory effects for disease-associated non-coding SNPs, and by predicting the patient-specific pathogenic processes, we propose a systems-level way to stratify patients.

Functional Genomics Analysis to Disentangle the Role of Genetic Variants in Major Depression

“…The regulatory variation analysis pipelines we have implemented involve fine-mapping, cis-eQTL colocalization, transcription factor binding analysis, and chromatin accessibility data, specially designed to perform well when full-genome summary statistics are not available [59]. These pipelines are in line with other approaches that leverage available omics data, and as such, they could be applied to other complex disorders with a similar genetic architecture and similar data access issues [53,60,61].…”

Updated immunomodulatory roles of gut flora and microRNAs in inflammatory bowel diseases

“…An autophagy process requires synergistic action of a variety of proteins, such as NOD2, IRGM, vimentin and multiprotein complexes (ATG16L1 and ATG5-ATG12) [ 78 ]. Many miRNAs can regulate these proteins, thereby controlling intestinal mucosal immunity and epithelial functions [ 68 , 79 , 80 ]. During the endoplasmic reticulum stress response, a group of miRNAs can utilize autophagy to regulate the unfolded protein response (UPR), a process that contributes to intestinal fibrosis in IBD [ 81 ].…”

“…Incremental documents uncover the implications of innate and adaptive immune cells, including epithelial cells [ 71 – 77 , 79 , 80 , 91 – 93 ], macrophage [ 68 , 86 , 94 – 109 ], neutrophil [ 110 – 113 ], NK cells [ 114 ], DCs [ 67 , 115 – 122 ], Th17 cells [ 65 , 123 – 129 ], Tregs [ 66 , 130 , 131 ] in IBD amelioration and exacerbation upon altered miRNA profiling (Table 2 ).…”

Holistic healthcare in inflammatory bowel disease: time for patient-centric approaches?

“…Inflammatory bowel disease (IBD) is a chronic disorder characterised by inflammation of the gastrointestinal tract with complex aetiologies,1 intestinal symptoms (such as abdominal pain, diarrhoea, loss of appetite, bloody stools),2 heterogeneity3–7 and complex interactions with the microbiota 8–10. The aetiology of IBD has been expanded from being solely linked to gut physiology to other aspects such as the gut–brain,11 gut–liver12 and gut–joint13 14 axis as well as psychological/emotional well-being 15.…”