Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2

Abstract

Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC.

Acetylcholinesterase Inhibitor Pyridostigmine Bromide Attenuates Gut Pathology and Bacterial Dysbiosis in a Murine Model of Ulcerative Colitis

“…Mucus is made by goblet cells, and the major gel-forming mucin in the gut is MUC2 [46]. MUC2 synthesis is defective in UC patients, and variants of MUC2 gene are associated with increased incidence of UC [47]. In UC patients and experimental animals, bacteria penetrate the normally impenetrable colonic mucus layer and MUC2 expression is strongly downregulated in UC [48].…”

Dutch Parelsnoer Institute-Cerebrovascular Accident (CVA) Study: A Large Multicenter Clinical Biobank with Standardized Collection and Storage

“…PSI is a cooperation of all eight Dutch University Medical Centers (UMCs) and aims at building large prospectively collected datasets with uniform and standardized storage of biomaterials for complex diseases. Currently, PSI covers 18 disease-specific cohorts called 'Pearls', and this number is still growing [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. PSI is centrally organized and has an executive board for operational management to ensure collective standardization strategies.…”

“…Regarding all disease cohorts, the research projects based on PSI data and samples have led to several scientific publications [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]18].…”

The Parelsnoer Institute: A National Network of Standardized Clinical Biobanks in the Netherlands

“…In 2007, the Netherlands Federation of University Medical Centers (NFU) launched the Parelsnoer Institute (PSI) [1], with the aim of facilitating medical research and innovation ultimately leading to better diagnosis, treatment or even prevention of complex disorders [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. PSI is a collaborative network of all eight Dutch University Medical Centers (UMCs), also known as academic teaching hospitals.…”

“…PSI releases data and samples to research projects on a regular basis. Thus far, the research projects have led to many scientific publications [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17].…”