Interplay of genetic and environmental triggers in intestinal inflammation: Genetics and transcriptomics in celiac disease and inflammatory bowel disease
Year: 2013
Type: dissertation
Abstract: Celiac disease (CelD) and inflammatory bowel disease (IBD) are chronic inflammatory diseases of the gastrointestinal (GI) tract. Both genetic and environmental factors contribute to disease etiology. Gliadin is the alcohol-soluble fraction of gluten protein which is found in food grains such as wheat, rye and barley. In CelD, gliadin-derived peptides constitute the environmental trigger and genes within the human leukocyte antigen (HLA) region on chromosome six encoding HLA-DQ2 and DQ8 heterodimers form the genetic basis for disease susceptibility. The two major forms of IBD are Crohn s disease (CD) and ulcerative colitis (UC). The environmental triggers in IBD are unknown, but an inappropriate immune response to gut microbiota is thought to precede disease onset. The fucosyltransferase 2 (FUT2) gene controls the expression of A-, B- and H- blood group antigens in mucus and other body secretions. Absence of these antigens affects the composition of gut microbiota. Genetic studies in CelD and IBD have identified several non-HLA risk loci harboring genes involved in the regulation of immune responses. Both CelD and IBD being immunological diseases, share many susceptibility genes. Nevertheless, the etiology of CelD and IBD is not completely understood. In this thesis work we investigated the interplay between genes and environment in disease progression and explored shared genetics between CelD and IBD. In study I, we investigated how gliadin peptides affect epithelial cell gene transcription. Using DNA microarray chips, we obtained a gene expression profile of enterocytes which were exposed to pepsin and trypsin (PT)-digested gliadin (PT-G) and a synthetic gliadin peptide p31-43. The expression of 1705 and 211 probes was affected by respective treatments. The validation of microarray results by qRT-PCR for selected genes showed that PT-G affected genes were also affected by negative controls that were digested with PT. The expression of p31-43 affected genes in qRT-PCR was comparable to that of untreated and negative control. It was concluded that gliadin effects on enterocyte gene expression may be marginal and PT may affect enterocyte gene expression in non-enzymatic manner. In study II, association of a FUT2 genetic variant (rs601338G>A) with CelD and IBD was investigated. Homozygosity for this mutation leads to the absence of ABH blood group antigens in body fluids and such individuals are called non-secretors. The FUT2 non-secretor genotype (rs601338-AA) was associated with increased risk for CelD. The rs601338 SNP did not associate with CD, but rs601338-A showed significant association with UC under the dominant association model suggesting a protective effect of the rs601338-A allele. We concluded that the FUT2 non-secretor status (rs601338-AA) is associated with increased risk for CelD but not IBD in the Finnish population. In Study III, we investigated the association of novel CelD risk markers with IBD (and its subphenotypes) in the Finnish and Swedish populations. Meta-analyses on Finnish and Swedish UC datasets were also performed. Six SNPs each were associated (P less than 0.05) with CD and UC and two SNPs (rs1893217-PTPN2 and rs4819388-ICOSLG) were associated with both forms of IBD. Of the associated SNPs one CelD risk allele was protective and nine alleles conferred higher risk for CD or UC. In the UC and UC subphenotype meta-analyses, the SNP rs6974491-A-ELMO1 was associated with early-onset UC (less than or egual to 18 years) whereas rs2298428-T-UBE2L3 associated with early-onset CD (less than or equal to 18 years) and also with non-stricturing non-penetrating phenotype of CD. The SNP rs1738074-A-TAGAP showed an association with familial UC whereas rs4819388-G-ICOSLG associated with sporadic UC. Based on these results, it was thus concluded that several CelD risk SNPs are associated with CD and/or UC or their associated subphenotypes in the Finnish and Swedish populations.
Source: Työväentutkimus Vuosikirja
Author: Amarjit Parmar
Language: English
Subfield: Gastroenterology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: Helsingin Yliopisto
OpenAlex ID: W1587294223