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Identification and functional characterization of gastrointestinal disease genes

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posted on 2024-09-03, 03:56 authored by Ghazaleh AssadiGhazaleh Assadi

The inflammatory bowel diseases (IBD) Crohn’s disease (CD) and ulcerative colitis (UC) are conditions characterized by chronic and relapsing inflammation of the gastrointestinal tract. IBD affects around 2.5 million people of European ancestry and the incidence is increasing worldwide (currently, 1% of the population suffers from IBD in Sweden). IBD patients require life-long medication, hospitalizations, recurring sick-leaves, surgical intervention and may acquire serious complications, such as colorectal cancer. There is as yet no definitive cure, and new treatment modalities are effective, but far from being optimal. A much greater understanding of IBD pathophysiology is therefore needed, in order to delineate improved therapeutic strategies, and to predict disease course and response to treatment.

Although the etiology of IBDs is unknown, current consensus is that they occur in genetically predisposed individuals, primarily due to a dysregulated immune response to gut microbiota. IBD genetic research has highlighted the importance of innate immune interactions with the gut microbiota, the regulation of immune functions, the maintenance of gut epithelial barrier, and autophagy in order to maintain gut homeostasis. However, these discoveries have not yet led to the identification of novel pathogenetic pathways that may be amenable to exploitation for renewed therapeutic intervention. Eventually, this may come from the study of risk genes of unknown function. The overall aim of this thesis is the functional characterization of novel gastrointestinal disease genes, and in particular the Laccase (multicopper oxidoreductase) domain-containing 1 (LACC1) gene, in order to elucidate the mechanism(s) by which its genetic variation(s) contributes to IBD, and ultimately provide novel opportunities for therapeutic exploitation.

In paper I, we tested a series of LACC1 common variants for association with disease in two Swedish cohorts of IBD and non-systemic juvenile idiopathic arthritis (nsJIA). Significant findings were detected for multiple LACC1 markers in the studied cohorts, thereby expanding previous results for CD to both UC and nsJIA. In paper II, we identified FAMIN (the LACC1 encoded protein) as a core metabolic regulator of macrophage function. By forming a complex with fatty acid synthase at peroxisomes, FAMIN promotes carbon flux through de novo lipogenesis (DNL) and drives high levels of fatty-acid oxidation (FAO) alongside high levels of glycolysis. As a consequence, FAMIN deficiency causes defects in DNL, FAO, reactive oxygen species production, inflammasome activation, endotoxin-response and bacterial clearance, thereby providing a plausible explanation to the observed disease phenotype in patients with the variants Ile254Val and Cys284Arg. In paper III, we found higher LACC1 expression in human immune-tissues and cells such as spleen, lymph nodes, monocytes/macrophages, DCs and neutrophils. In addition, FAMIN expression was shown to be regulated by peroxisome proliferator-activated receptor ligands. In paper IV, we identified a number of potential candidate biomarkers that may be followed up in validation experiments in independent IBD case-control cohorts. Of particular interest, FAMIN serum levels were found to differ between IBD patients and healthy controls, with lowest expression in CD patients. This parallels mouse and human data suggesting reduced FAMIN activity predisposes to disease.

In summary, this thesis characterizes LACC1/FAMIN as a new major player in IBD pathophysiology, identifying novel biological pathways that may be amenable to modulation for therapeutic purposes, while at the same time providing preliminary data of potential exploitation for biomarkers delineation.

List of scientific papers

I. Assadi G, Saleh R, Hadizadeh F, Vesterlund L, Bonfiglio F, Halfvarson J, Törkvist L, Eriksson AS, Harris HE, Sundberg E, D’Amato M. LACC1 polymorphisms in inflammatory bowel disease and juvenile idiopathic arthritis. Genes and Immunity. 2016 Jun;17(4):261-4.
https://doi.org/10.1038/gene.2016.17

II. Cader ZM, Boroviak K, Zhang Q, Assadi G, Kempster SL, Sewell G, Saveljeva S, Ashcroft JW, Clare S, Mukhopadhyay S, Brown KP, Tschurtschenthaler M, Raine T, Doe B, Chilvers ER, Griffin JL, Kaneider NC, Floto RA, D’Amato M, Bradley A, Wakelam MJO, Dougan G, Kaser A. C13orf31 (FAMIN) is a central regulator of immunometabolic function. Nature Immunology. 2016 Sep;17(9):1046-56.
https://doi.org/10.1038/ni.3532

III. Assadi G, Vesterlund L, Bonfiglio F, Mazzurana L, Cordeddu L, Schepis D, Mjösberg J, Ruhrmann S, Fabbri A, Vukojevic V, Percipalle P, Salomons FA, Laurencikiene J, Törkvist L, Halfvarson J, D’Amato M. Functional analyses of the Crohn’s disease risk gene LACC1. [Manuscript]

IV. Drobin K, Assadi G, Hong MG, Reznichenko A, Akhter T, Ek W, Bonfiglio F, Hansen MB, Sandberg K, Greco D, Repsilber D, Schwenk JM, D’Amato M, Halfvarson J. Exploration of the IBD risk proteome through affinity-based profiling of patient sera. [Manuscript]

History

Defence date

2016-10-20

Department

  • Department of Medicine, Huddinge

Publisher/Institution

Karolinska Institutet

Main supervisor

D'Amato, Mauro

Publication year

2016

Thesis type

  • Doctoral thesis

ISBN

978-91-7676-350-6

Number of supporting papers

4

Language

  • eng

Original publication date

2016-09-21

Author name in thesis

Assadi, Ghazaleh

Original department name

Department of Biosciences and Nutrition

Place of publication

Stockholm

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