Association of the T allele of an intronic single nucleotide polymorphism in the colony stimulating factor 1 receptor with Crohn's disease: a case-control study

Zapata-Velandia, Adriana M.; Ng, S.K.; Brennan, R.; Simonsen, Neal; Gastañaduy, Mariella; Zabaleta, Jovanny; Lentz, Jennifer J; Craver, Randall; Correa, Hernán; Delgado, Alberto; Pitts, Angela L; Himel, Jane R; Udall, John N.; Schmidt-Sommerfeld, Eberhard; Brown, Raynorda F.; Athas, Grace; Keats, Bronya B; Mannick, Elizabeth E.

doi:10.1186/1476-8518-2-6

Cited by 7 publications

(3 citation statements)

References 33 publications

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“…Previous studies con rmed that CSF1R was highly expressed in in ammatory bowel disease, which is consistent with our research results (29,30). Zapata-Velandia et al speculated that CSF1R may be a susceptibility gene for Crohn's disease (31). The latest research shows that patients with in ammatory bowel disease may bene t from CSF1R inhibitors (32).…”

Section: Discussionsupporting

confidence: 91%

Uncovering potential novel biomarkers in Crohn's disease using integrated bioinformatics analysis

Feng¹

2022

Preprint

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Background: Crohn's disease is a chronic nonspecific intestinal inflammatory disease with unknown etiology. This study aimed to predict potential novel biomarkers of Crohn's disease.Methods: Gene expression datasets of Crohn's disease and normal samples were downloaded from the Gene Expression Omnibus (GEO) database. First, differential gene expression analysis and weighted gene coexpression network analysis (WGCNA) were performed. Common genes (CGs) were obtained by the intersection of differentially expressed genes (DEGs) and optimal modal genes of WGCNA. Subsequently, a protein-protein interaction (PPI) network was established to screen hub genes and then establish a Crohn's disease risk prediction model based on hub genes. A receiver operating characteristic (ROC) curve, and area under the curve (AUC) were used to evaluate the prediction ability of the model. Finally, the mirTarBase database, starBase database, and TargetScan database were used to predict microRNAs (miRNAs) and transcription factors (TFs) that cause Crohn's disease.Results: A total of 74 DEGs were identified. WGCNA showed that the signature gene in the blue module was significantly associated with Crohn's disease (p=4e-6) and obtained 32 CGs. Five hub genes (CDH17, CSF1R, CXCL10, CXCL9, COL3A1) were identified and well predicted Crohn's disease risk (AUC=0.853). Meanwhile, in the miRNA-mRNA regulatory network and TF-mRNA regulatory network, we found that 3 miRNAs (hsa-miR-29a-3p, hsa-miR-29b-3p, hsa-miR-29c-3p) and 2 TFs (TCF4, HINFP) regulate multiple CGs.Conclusions: Five genes (CDH17, CSF1R, CXCL10, CXCL9 and COL3A1), three miRNAs (hsa-miR-29a-3p, hsa-miR-29b-3p, hsa-miR-29c-3p) and two TFs (TCF4, HINFP) may be involved in the pathogenesis of Crohn's disease.

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Section: Discussionsupporting

confidence: 91%

Uncovering potential novel biomarkers in Crohn's disease using integrated bioinformatics analysis

Feng¹

2022

Preprint

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“…Heterozygous mutation in Csf1r has been shown to protect against pathology in a colitis model in mice [ 133 ]. There is no evidence of association with IBD in the more immediate vicinity of CSF1R in the GWA data, but one report based upon direct sequencing in a Acadian American population indicated linkage to an intron 11 SNP [ 134 ]. Whole genome sequence data from 1000 genomes and other sources ( http://www.ensembl.org ), and the recent human exome paper [ 135 ] also reveal the existence of numerous likely loss-of-function alleles, with allele frequencies of 1/1000 or more, within the intracellular tyrosine kinase domain of CSF1R .…”

Section: Discussionmentioning

confidence: 99%

Analysis of the human monocyte-derived macrophage transcriptome and response to lipopolysaccharide provides new insights into genetic aetiology of inflammatory bowel disease

et al. 2017

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The FANTOM5 consortium utilised cap analysis of gene expression (CAGE) to provide an unprecedented insight into transcriptional regulation in human cells and tissues. In the current study, we have used CAGE-based transcriptional profiling on an extended dense time course of the response of human monocyte-derived macrophages grown in macrophage colony-stimulating factor (CSF1) to bacterial lipopolysaccharide (LPS). We propose that this system provides a model for the differentiation and adaptation of monocytes entering the intestinal lamina propria. The response to LPS is shown to be a cascade of successive waves of transient gene expression extending over at least 48 hours, with hundreds of positive and negative regulatory loops. Promoter analysis using motif activity response analysis (MARA) identified some of the transcription factors likely to be responsible for the temporal profile of transcriptional activation. Each LPS-inducible locus was associated with multiple inducible enhancers, and in each case, transient eRNA transcription at multiple sites detected by CAGE preceded the appearance of promoter-associated transcripts. LPS-inducible long non-coding RNAs were commonly associated with clusters of inducible enhancers. We used these data to re-examine the hundreds of loci associated with susceptibility to inflammatory bowel disease (IBD) in genome-wide association studies. Loci associated with IBD were strongly and specifically (relative to rheumatoid arthritis and unrelated traits) enriched for promoters that were regulated in monocyte differentiation or activation. Amongst previously-identified IBD susceptibility loci, the vast majority contained at least one promoter that was regulated in CSF1-dependent monocyte-macrophage transitions and/or in response to LPS. On this basis, we concluded that IBD loci are strongly-enriched for monocyte-specific genes, and identified at least 134 additional candidate genes associated with IBD susceptibility from reanalysis of published GWA studies. We propose that dysregulation of monocyte adaptation to the environment of the gastrointestinal mucosa is the key process leading to inflammatory bowel disease.

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“…50 It maps in an intron of the colony stimulating factor 1 receptor (CSF1R [MIM 164770]) that is involved in monocyte to macrophage differentiation and innate immunity. 51 For CSF1R, some weak association has also been reported with Crohn's disease, 52 another inflammatory gastrointestinal disorder for which molecular mechanisms, comparable to celiac disease, have been implicated. 46 It is relevant to note that if the null allele itself is not associated with disease, but the A or B alleles are, biallelic assumptions will result in either an overestimation or underestimation of the effect, depending on whether the effect is dominant or recessive, respectively (see details and Figure 3).…”

Section: Association Analysismentioning

confidence: 99%

Detection, Imputation, and Association Analysis of Small Deletions and Null Alleles on Oligonucleotide Arrays

Franke

Kovel

Aulchenko

et al. 2008

The American Journal of Human Genetics

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Copy-number variation (CNV) is a major contributor to human genetic variation. Recently, CNV associations with human disease have been reported. Many genome-wide association (GWA) studies in complex diseases have been performed with sets of biallelic single-nucleotide polymorphisms (SNPs), but the available CNV methods are still limited. We present a new method (TriTyper) that can infer genotypes in case-control data sets for deletion CNVs, or SNPs with an extra, untyped allele at a high-resolution single SNP level. By accounting for linkage disequilibrium (LD), as well as intensity data, calling accuracy is improved. Analysis of 3102 unrelated individuals with European descent, genotyped with Illumina Infinium BeadChips, resulted in the identification of 1880 SNPs with a common untyped allele, and these SNPs are in strong LD with neighboring biallelic SNPs. Simulations indicate our method has superior power to detect associations compared to biallelic SNPs that are in LD with these SNPs, yet without increasing type I errors, as shown in a GWA analysis in celiac disease. Genotypes for 1204 triallelic SNPs could be fully imputed, with only biallelic-genotype calls, permitting association analysis of these SNPs in many published data sets. We estimate that 682 of the 1655 unique loci reflect deletions; this is on average 99 deletions per individual, four times greater than those detected by other methods. Whereas the identified loci are strongly enriched for known deletions, 61% have not been reported before. Genes overlapping with these loci more often have paralogs (p = 0.006) and biologically interact with fewer genes than expected (p = 0.004).

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Association of the T allele of an intronic single nucleotide polymorphism in the colony stimulating factor 1 receptor with Crohn's disease: a case-control study

Cited by 7 publications

References 33 publications

Uncovering potential novel biomarkers in Crohn's disease using integrated bioinformatics analysis

Uncovering potential novel biomarkers in Crohn's disease using integrated bioinformatics analysis

Analysis of the human monocyte-derived macrophage transcriptome and response to lipopolysaccharide provides new insights into genetic aetiology of inflammatory bowel disease

Detection, Imputation, and Association Analysis of Small Deletions and Null Alleles on Oligonucleotide Arrays

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