Identification and functional characterization of gastrointestinal disease genes

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