Variants of gene for microsomal prostaglandin E2 synthase show association with disease and severe inflammation in rheumatoid arthritis

Korotkova, Marina; Daha, Nina A.; Seddighzadeh, Maria; Ding, Bo; Catrina, Anca I.; Lindblad, Staffan; Huizinga, Tom W J; Toes, René E. M.; Alfredsson, Lars; Klareskog, Lars; Jakobsson, Per‐Johan; Padyukov, Leonid

doi:10.1038/ejhg.2011.50

Cited by 14 publications

(6 citation statements)

References 32 publications

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“…To our knowledge, this variant has not been implicated in lung cancer risk to date; however, other epoxide hydrolase genes have been associated with lung cancer risk in candidate studies (Lee et al 2002). Epoxide hydrolases play an important role in the lung by metabolizing inhaled irritants and carcinogens (Petruzzelli et al 1992), and variants in the genes have been shown to be related to other inflammatory disease risk (Korotkova et al 2011). We examined the effects of the variant across smoking, gender, age at onset and histology groups to determine whether the variant was acting as a marker of exposure or subgroup risk.…”

Section: Discussionmentioning

confidence: 99%

Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls

et al. 2013

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Recent evidence suggests that inflammation plays a pivotal role in the development of lung cancer. In this study, we used a two-stage approach to investigate associations between genetic variants in inflammation pathways and lung cancer risk based on genome-wide association study (GWAS) data. A total of 7,650 sequence variants from 720 genes relevant to inflammation pathways were identified using keyword and pathway searches from Gene Cards and Gene Ontology databases. In Stage 1, six GWAS datasets from the International Lung Cancer Consortium were pooled (4,441 cases and 5,094 controls of European ancestry), and a hierarchical modeling (HM) approach was used to incorporate prior information for each of the variants into the analysis. The prior matrix was constructed using (1) role of genes in the inflammation and immune pathways; (2) physical properties of the variants including the location of the variants, their conservation scores and amino acid coding; (3) LD with other functional variants and (4) measures of heterogeneity across the studies. HM affected the priority ranking of variants particularly among those having low prior weights, imprecise estimates and/or heterogeneity across studies. In Stage 2, we used an independent NCI lung cancer GWAS study (5,699 cases and 5,818 controls) for in silico replication. We identified one novel variant at the level corrected for multiple comparisons (rs2741354 in EPHX2 at 8q21.1 with p value = 7.4 × 10−6), and confirmed the associations between TERT (rs2736100) and the HLA region and lung cancer risk. HM allows for prior knowledge such as from bioinformatic sources to be incorporated into the analysis systematically, and it represents a complementary analytical approach to the conventional GWAS analysis.

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Section: Discussionmentioning

confidence: 99%

Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls

et al. 2013

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“…Both schizophrenia and RA are associated with membrane phospholipid abnormalities involving the production of prostaglandins from arachidonic acid. RA is associated with overall increase in membrane phospholipids, such as prostaglandin E2 (PGE2) levels (McCoy et al, 2002; Westman et al, 2004; Korotkova et al, 2011). Prostaglandin levels are also abnormally regulated in schizophrenia, and PGE2 levels also elevated (Elaborated in section 6.4).…”

Section: Adulthood Biomarkers and Comorbiditymentioning

confidence: 99%

Inflammation and the two-hit hypothesis of schizophrenia

Feigenson

Kusnecov

Silverstein

2014

Neuroscience & Biobehavioral Reviews

234

174

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The high societal and individual cost of schizophrenia necessitates finding better, more effective treatment, diagnosis, and prevention strategies. One of the obstacles in this endeavor is the diverse set of etiologies that comprises schizophrenia. A substantial body of evidence has grown over the last few decades to suggest that schizophrenia is a heterogeneous syndrome with overlapping symptoms and etiologies. At the same time, an increasing number of clinical, epidemiological, and experimental studies have shown links between schizophrenia and inflammatory conditions. In this review, we analyze the literature on inflammation and schizophrenia, with a particular focus on comorbidity, biomarkers, and environmental insults. We then identify several mechanisms by which inflammation could influence the development of schizophrenia via the two-hit hypothesis. Lastly, we note the relevance of these findings to clinical applications in the diagnosis, prevention, and treatment of schizophrenia.

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“…PTGES encodes a glutathione-dependent synthase catalyzing the oxidoreduction to prostaglandin E2. By playing a role in inflammatory responses, fever and pain, PTGES protein has been reported to be involved in inflammatory diseases such as collagen-induced arthritis and gastritis (Gudis et al 2005 ; Korotkova et al 2011 ). Similarly, the gene product encoded by SLC15A4 regulates innate immune responses.…”

Section: Resultsmentioning

confidence: 99%

Whole exome sequencing identifies novel germline variants of SLC15A4 gene as potentially cancer predisposing in familial colorectal cancer

et al. 2022

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About 15% of colorectal cancer (CRC) patients have first-degree relatives affected by the same malignancy. However, for most families the cause of familial aggregation of CRC is unknown. To identify novel high-to-moderate-penetrance germline variants underlying CRC susceptibility, we performed whole exome sequencing (WES) on four CRC cases and two unaffected members of a Polish family without any mutation in known CRC predisposition genes. After WES, we used our in-house developed Familial Cancer Variant Prioritization Pipeline and identified two novel variants in the solute carrier family 15 member 4 (SLC15A4) gene. The heterozygous missense variant, p. Y444C, was predicted to affect the phylogenetically conserved PTR2/POT domain and to have a deleterious effect on the function of the encoded peptide/histidine transporter. The other variant was located in the upstream region of the same gene (GRCh37.p13, 12_129308531_C_T; 43 bp upstream of transcription start site, ENST00000266771.5) and it was annotated to affect the promoter region of SLC15A4 as well as binding sites of 17 different transcription factors. Our findings of two distinct variants in the same gene may indicate a synergistic up-regulation of SLC15A4 as the underlying genetic cause and implicate this gene for the first time in genetic inheritance of familial CRC.

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Variants of gene for microsomal prostaglandin E2 synthase show association with disease and severe inflammation in rheumatoid arthritis

Cited by 14 publications

References 32 publications

Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls

Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls

Inflammation and the two-hit hypothesis of schizophrenia

Whole exome sequencing identifies novel germline variants of SLC15A4 gene as potentially cancer predisposing in familial colorectal cancer

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