| 1. |
- Mellander, Marie-Rose
(författare)
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Microscopic colitis
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Microscopic colitis (MC) is an inflammatory bowel disease (IBD) and a common cause of chronic non-bloody diarrhoea, especially in elderly women. There are two main subtypes, lymphocytic colitis (LC) and collagenous colitis (CC) which are clinically indistinguishable and can be separated only by their characteristic histopathological features. The colonoscopy is usually macroscopically normal although subtle mucosal changes have been reported. The aetiology of MC is unknown and the genetic factors are poorly investigated. This thesis aims to describe MC in a large urban cohort and compare LC and CC regarding clinical and endoscopic features, both at diagnosis and at follow-up (F-U), and to observe the occurrence of coeliac disease, ulcerative colitis (UC) and Crohn’s disease (CD). We also reported the histological change of the MC phenotype over time and patients’ MC medication at last F-U. Further, we tested immune-related genes, known to impact several autoimmune diseases, for their potential CC-predisposing role. Finally, this thesis aims to report on chromoendoscopic findings in MC. A retrospective study of 795 patients showed that the clinical features of LC (n=451) and CC (n=344) were similar, though watery diarrhoea occurred at a lower frequency in LC (43%) than CC (55%) as did nocturnal diarrhoea, LC (18%) and CC (28%). The mean age at diagnosis was lower in LC, at 59 years compared 63 years in CC. Subtle endoscopic mucosal findings were frequently reported at a higher rate in CC (37%) than LC (25%). Our study confirms MC’s strong association with coeliac disease, which occurred in 6% of the patients. UC and CD occurred in 2.1% of the patients. In the MC cohort, 687 patients had a clinical F-U after a mean time of 2.89 years at which 64% were in clinical remission. The cumulative clinical remission was higher in LC. About half of the patients had received medical treatment for MC at last F-U and about a quarter of them were on steroids; both these parameters were lower in patients with LC. The mean time for the first F-U colonoscopy (n=187) was 3.33 years and the histological remission was 44% and the cumulative histologic remission was higher in LC. Histological change of phenotype over time was not uncommon and was observed in 12 % of the patients (10 CC to LC, 13 LC to CC). Three independent CC and control cohorts were genotyped with Immunochip and 42 markers gave rise to significant genome-wide associations signals, all within the HLA region of chromosome 6. The most pronounced risk effects were observed for 8.1 haplotype alleles including DQ2.5. The HLA genotype is associated with CC and indicates immune-driven pathogenesis. Previously, two case reports described that chromoendoscopy in CC patients showed uneven surface. We reported additional chromoendoscopic findings in 13 MC patients that showed continuous mucosal changes. Our study supports the fact that chromoendoscopy can reveal mucosal changes in MC and therefore might be diagnostically useful. LC and CC are similar but not identical, since LC has a milder clinical presentation and a better prognosis than CC. Conversions between subtypes and between MC and UC or CD exist. It is not uncommon with macroscopic changes of the colonic mucosa in patients with MC which are more manifest with chromoendoscopy. Specific HLA alleles are associated with CC, indicating an autoimmune role.
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| 2. |
- Noren, Elisabeth, et al.
(författare)
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Genetic Variation and Gene Expression Levels of Tight Junction Genes Indicates Relationships Between PTEN as well as MAGI1 and Microscopic Colitis
- 2018
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Ingår i: Digestive Diseases and Sciences. - : SPRINGER. - 0163-2116 .- 1573-2568. ; 63:1, s. 105-112
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Tidskriftsartikel (refereegranskat)abstract
- Microscopic colitis (MC) has been associated with increased paracellular permeability. Therefore, we aimed to investigate potential associations between MC and several genes encoding tight junction (TJ) proteins reported to interact with each other. The association between MC and single nucleotide polymorphisms (SNP; n = 63) within TJ genes (F11R, MAGI1, MAGI2, MAGI3, PARD3, PTEN, and TJP1) were investigated in a case-control study (n (MC patients) = 104 and n (controls) = 423). The genes that exhibited an association with MC were further investigated for gene expression related to genotype, MC phenotype, and gender using colonic biopsies from MC patients (n = 25) and controls (n = 58). Based on the number of investigated genes and after correction for multiple testing, an association was detected between a SNP marker in PTEN (rs1234224) and both MC overall (OR = 1.70, 95% CI 1.23-2.34, p = 0.001) and collagenous colitis (CC; OR = 1.79, 95% CI 1.22-2.62, p = 0.003). Further, SNP markers in MAGI1 (rs17417230) and F11R (rs790055) were associated with MC overall (OR = 1.58, 95% CI 1.14-2.19, p = 0.006) and with CC (OR = 2.58, 95% CI 1.27-5.25, p = 0.007), respectively. However, none of the associated SNPs contributed markedly to the expression of the respective genes. Nonetheless, decreased MAGI1 (p = 3.47 x 10(-4)) and PTEN (p = 0.004) expression was associated with lymphocytic colitis (LC) and CC, respectively, compared to controls. Decreased expression of PTEN and MAGI1 in the colonic mucosa might contribute to the pathogenesis of MC and its sub-phenotypes. Furthermore, our study indicates that genetic variants of TJ components are predisposing factors in the etiology of MC. Finally, F11R, MAGI1, and PTEN are new candidate genes that exhibit an association with MC.
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| 3. |
- Westerlind, Helga, et al.
(författare)
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Dense genotyping of immune-related loci identifies HLA variants associated with increased risk of collagenous colitis.
- 2017
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Ingår i: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 66:3, s. 421-428
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Collagenous colitis (CC) is a major cause of chronic non-bloody diarrhoea, particularly in the elderly female population. The aetiology of CC is unknown, and still poor is the understanding of its pathogenesis. This possibly involves dysregulated inflammation and immune-mediated reactions in genetically predisposed individuals, but the contribution of genetic factors to CC is underinvestigated. We systematically tested immune-related genes known to impact the risk of several autoimmune diseases for their potential CC-predisposing role.DESIGN: Three independent cohorts of histologically confirmed CC cases (N=314) and controls (N=4299) from Sweden and Germany were included in a 2-step association analysis. Immunochip and targeted single nucleotide polymorphism (SNP) genotype data were produced, respectively, for discovery and replication purposes. Classical human leucocyte antigen (HLA) variants at 2-digit and 4-digit resolution were obtained via imputation from single marker genotypes. SNPs and HLA variants passing quality control filters were tested for association with CC with logistic regression adjusting for age, sex and country of origin.RESULTS: Forty-two markers gave rise to genome-wide significant association signals, all contained within the HLA region on chromosome 6 (best p=4.2×10(-10) for SNP rs4143332). Among the HLA variants, most pronounced risk effects were observed for 8.1 haplotype alleles including DQ2.5, which was targeted and confirmed in the replication data set (p=2.3×10(-11); OR=2.06; 95% CI (1.67 to 2.55) in the combined analysis).CONCLUSIONS: HLA genotype associates with CC, thus implicating HLA-related immune mechanisms in its pathogenesis.
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| 4. |
- Zheng, Tenghao, et al.
(författare)
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Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes
- 2024
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Ingår i: Journal of Crohn's and Colitis. - : OXFORD UNIV PRESS. - 1873-9946 .- 1876-4479. ; 18:3, s. 349-359
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies. Methods: We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied. Results: We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC. Conclusion: Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.
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