Replication Study of Ulcerative Colitis Risk Loci in a Lithuanian–Latvian Case–Control Sample

Skiecevičienė, Jurgita; Kiudelis, Gediminas; Ellinghaus, Eva; Balschun, Tobias; Jonaitis, Laimas Virginijus; Žvirblienė, Aida; Denapiene, Goda; Leja, Mārcis; Pranculienė, Gitana; Kalibatas, Vytenis; Saadati, Hamidreza; Ellinghaus, David; Andersen, Vibeke; Valantinas, Jonas; Irnius, Algimantas; Derovs, Aleksejs; Tamelis, Algimantas; Schreiber, Stefan; Kupčinskas, Limas; Franke, André

doi:10.1097/mib.0b013e3182a3eaeb

Cited by 12 publications

(5 citation statements)

References 51 publications

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“…Similarly, we have recently shown that macrophages and neutrophils from individuals carrying the hypomorphic LACC1 variant Ile254Val (rs3764147) produce less ROS [16]. Interestingly, a SNP-SNP interaction for PTPN22 (rs2476601) and LACC1 (rs3764147) was shown to confer increased risk of UC in a study of Lithuanian and Latvian IBD patients [24], indicating that these two genes may act across overlapping pathogenetic mechanisms of disease predisposition, through neutrophils or macrophage-specific functions.…”

Section: Discussionmentioning

confidence: 96%

Functional Analyses of the Crohn’s Disease Risk Gene LACC1

et al. 2016

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BackgroundGenetic variation in the Laccase (multicopper oxidoreductase) domain-containing 1 (LACC1) gene has been shown to affect the risk of Crohn’s disease, leprosy and, more recently, ulcerative colitis and juvenile idiopathic arthritis. LACC1 function appears to promote fatty-acid oxidation, with concomitant inflammasome activation, reactive oxygen species production, and anti-bacterial responses in macrophages. We sought to contribute to elucidating LACC1 biological function by extensive characterization of its expression in human tissues and cells, and through preliminary analyses of the regulatory mechanisms driving such expression.MethodsWe implemented Western blot, quantitative real-time PCR, immunofluorescence microscopy, and flow cytometry analyses to investigate fatty acid metabolism-immune nexus (FAMIN; the LACC1 encoded protein) expression in subcellular compartments, cell lines and relevant human tissues. Gene-set enrichment analyses were performed to initially investigate modulatory mechanisms of LACC1 expression. A small-interference RNA knockdown in vitro model system was used to study the effect of FAMIN depletion on peroxisome function.ResultsFAMIN expression was detected in macrophage-differentiated THP-1 cells and several human tissues, being highest in neutrophils, monocytes/macrophages, myeloid and plasmacytoid dendritic cells among peripheral blood cells. Subcellular co-localization was exclusively confined to peroxisomes, with some additional positivity for organelle endomembrane structures. LACC1 co-expression signatures were enriched for genes involved in peroxisome proliferator-activated receptors (PPAR) signaling pathways, and PPAR ligands downregulated FAMIN expression in in vitro model systems.ConclusionFAMIN is a peroxisome-associated protein with primary role(s) in macrophages and other immune cells, where its metabolic functions may be modulated by PPAR signaling events. However, the precise molecular mechanisms through which FAMIN exerts its biological effects in immune cells remain to be elucidated.

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Section: Discussionmentioning

confidence: 96%

Functional Analyses of the Crohn’s Disease Risk Gene LACC1

et al. 2016

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“…For rs10883365 polymorphism, the pooled ORs were estimated for G versus A, GG versus AA, GA versus AA, dominant model (GG + GA versus AA), and recessive model (GG versus GA + AA). Because of only three studies194950 available for the association between rs11190140 variant and UC risk, we have performed meta-analysis of correlation between rs11190140 polymorphism and CD risk. Subgroup analysis was performed according to ethnicity.…”

Section: Methodsmentioning

confidence: 99%

Contribution of NKX2-3 Polymorphisms to Inflammatory Bowel Diseases: A Meta-Analysis of 35358 subjects

Tang

et al. 2014

Sci Rep

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Polymorphisms in NKX2-3 gene have been inconsistently associated with Crohn's disease (CD) and ulcerative colitis (UC). To generate large-scale evidence on whether NKX2-3 polymorphisms are associated with CD or UC susceptibility we have conducted a meta-analysis of 17 studies involving 17329 patients and 18029 controls. A significantly increased CD or UC risk was observed in persons carrying a G allele at rs10883365 polymorphism (A/G) compared with those with a A allele. (OR = 1.226, 95%CI: 1.177–1.277 and OR = 1.274, 95%CI: 1.175–1.382 respectively). In the subgroup analysis, a significantly increased CD risk was found in both Europeans and Asians. For rs11190140 polymorphism (C/T) and CD risk, the risk estimate for the allele contrast was OR = 1.201 (1.136–1.269). This meta-analysis provided a robust result that persons with a G or T allele may have a moderately increased risk of CD, and suggested that rs10883365 polymorphism was also a candidate gene polymorphism for UC susceptibility.

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“…The elevated intestinal expression of some genes involved in sphingolipid metabolism was recently reported, prompting exploration of S1P in signaling and subsequent targeting in IBD [77,78]. The authors have studied 13 gene loci that are linked to ulcerative colitis; they found that polymorphism of orosomucoid (ORM) 1-like 3, which is a homologue of the SL regulatory protein ORM1, was associated with UC.…”

Section: Inflammation In Ibd and S1pmentioning

confidence: 99%

Sphingosine-1-Phosphate Metabolism and Its Role in the Development of Inflammatory Bowel Disease

Wollny

Wątek

Durnaś

et al. 2017

IJMS

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Beyond their role as structural molecules, sphingolipids are involved in many important cellular processes including cell proliferation, apoptosis, inflammation, and migration. Altered sphingolipid metabolism is observed in many pathological conditions including gastrointestinal diseases. Inflammatory bowel disease (IBD) represents a state of complex, unpredictable, and destructive inflammation of unknown origin within the gastrointestinal tract. The mechanisms explaining the pathophysiology of IBD involve signal transduction pathways regulating gastro-intestinal system’s immunity. Progressive intestinal tissue destruction observed in chronic inflammation may be associated with an increased risk of colon cancer. Sphingosine-1-phosphate (S1P), a sphingolipid metabolite, functions as a cofactor in inflammatory signaling and becomes a target in the treatment of IBD, which might prevent its conversion to cancer. This paper summarizes new findings indicating the impact of (S1P) on IBD development and IBD-associated carcinogenesis.

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Replication Study of Ulcerative Colitis Risk Loci in a Lithuanian–Latvian Case–Control Sample

Cited by 12 publications

References 51 publications

Functional Analyses of the Crohn’s Disease Risk Gene LACC1

Functional Analyses of the Crohn’s Disease Risk Gene LACC1

Contribution of NKX2-3 Polymorphisms to Inflammatory Bowel Diseases: A Meta-Analysis of 35358 subjects

Sphingosine-1-Phosphate Metabolism and Its Role in the Development of Inflammatory Bowel Disease

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