Genetic Variation at the Chromosome 16 Chemokine Gene Cluster: Development of a Strategy for Association Studies in Complex Disease

Fisher, Sheila; Moody, Anne Marie; Mirza, Muddassar M.; Cuthbert, Andrew; Hampe, Jochen; Sanderson, Jeremy; Forbes, Alastair; Mansfield, John C.; Schreiber, S; Lewis, Cathryn M.; Mathew, Christopher G.

doi:10.1046/j.1469-1809.2003.00040.x

Cited by 5 publications

(12 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ethnicity of both cases and controls was approximately 94% white Caucasian and 6% non-Caucasian; there was no evidence of population stratification in these cohorts in previous case-control studies. [28][29][30][31] Mutation screening We designed primers to amplify the exons and flanking introns of the 10 genes shown in Figure 1 in 24 unrelated CD cases (primers and PCR conditions available on request). Conserved sequences of the hypothetical gene LOC441108 most likely to represent exons were identified by comparing seven different orthologues.…”

Section: Patient Ascertainmentmentioning

confidence: 99%

Sequence variation, linkage disequilibrium and association with Crohn's disease on chromosome 5q31

et al. 2006

View full text Add to dashboard Cite

Chromosome 5q31 contains a cluster of genes involved in immune response, including a 250 kb risk haplotype associated with Crohn's disease (CD) susceptibility. Recently, two functional variants in , encoding the cation transporters OCTN1 and OCTN2, were proposed as causal variants for CD, but with conflicting genetic evidence regarding their contribution. We investigated this locus by resequencing the coding regions of 10 genes in 24 CD cases and deriving a linkage disequilibrium (LD) map of the 27 single nucleotide polymorphisms (SNPs) detected. Ten SNPs representative of the LD groups observed, were tested for CD association. L503F in SLC22A4 was the only nonsynonymous SNP significantly associated with CD (P ¼ 0.003), but was not associated with disease in the absence of other markers of the 250 kb risk haplotype. Two other SNPs, rs11242115 in IRF1 and rs17166050 in RAD50, lying outside the 250 kb risk haplotype, also showed CD association (P ¼ 0.019 and P ¼ 0.0080, respectively). The RAD50 gene contains a locus control region regulating expression of the Th2 cytokine genes at this locus. Other as yet undiscovered SNPs in this region may therefore modulate gene expression and contribute to the risk of CD, and perhaps of other inflammatory phenotypes.

show abstract

Section: Patient Ascertainmentmentioning

confidence: 99%

Sequence variation, linkage disequilibrium and association with Crohn's disease on chromosome 5q31

et al. 2006

View full text Add to dashboard Cite

show abstract

“…(27), and the CCL17 gene variant -431C>T was previously described as having a functional consequence on serum levels (28,29). We therefore investigated the prevalence of these gene polymorphisms in CRC patients and control subjects.…”

Section: Alleles) (N=512 Alleles) -----------------------------------mentioning

confidence: 99%

“…This SNP has been shown to enhance the promoter activity of the CCL17 (28,29). The SNPs of the CCL22 gene have been identified and one of them, -961G>A (rs223888), is located in the 5'-flanking region (27). However, its functional significance is as yet unknown.…”

Section: Introductionmentioning

confidence: 99%

“…A single nucleotide polymorphism (SNP) of the CCL17 gene, located in the promoter region as a C'T change at position -431 (rs223828), has been reported (27). This SNP has been shown to enhance the promoter activity of the CCL17 (28,29).…”

Section: Introductionmentioning

confidence: 99%

“…However, its functional significance is as yet unknown. Both CCL17 and CCL22 are members of the chemokine gene cluster (CCL22, CX3CL1, CCL17) located on chromosome 16 (27). Based on the documented importance of chemokines as important actors in cancer biology and the maintenance of normal local immunity, we performed an investigation of CCL17 and CCL22 protein expression in CRC patients.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Quantification of the chemokines CCL17 and CCL22 in human colorectal adenocarcinomas

Wågsäter

Dienus²,

Löfgren³

et al. 2008

Mol Med Report

View full text Add to dashboard Cite

Abstract. Chemokines are believed to play a crucial role in local immunoresponse by regulating leukocyte movement in various tissues, including the intestinal mucosa. It has been suggested that they are key players in cancer biology, and several studies have identified leukocyte infiltration as a hallmark of most cancers. The chemokines CCL17 and CCL22 attract CCR4-bearing cells, which are especially polarised to Th2-type cells and regulatory T cells (Treg). Recent studies have revealed the participation of the CCL17 and CCL22 proteins in diseases such as atopic dermatitis and lymphoma. The purpose of this study was to assess the role of CCL17 and CCL22 protein expression in colorectal cancer (CRC) and to ascertain whether an association exists between promoter -431C>T CCL17 and -961G>A CCL22 gene polymorphisms in CRC versus non-CRC subjects. Using the ELISA assay, we noted a significantly higher expression of CCL22 in tumour tissue with a 2.3-fold up-regulation (tumour vs. paired normal tissue, n=78) but no significant difference in CCL17 protein expression. Immunohistochemistry revealed protein expression of CCL22 and CCL17 in the epithelial compartment of cancer tissue, in epithelial cells at the resection border that reflects normal tissue, and in some stromal cells such as lymphocytes, macrophages, and fibroblasts. Using a TaqMan system we screened for -431C>T CCL17 and -961G>A CCL22 gene variants in 245 CRC patients and 256 controls, but could not find any significant difference in genotype distribution or in allelic frequencies between the two groups. The genotype and allelic distributions of CRC patients were not related to tissue levels of CCL17 and CCL22 protein, and none of the variables were associated with plasma levels or clinical characteristics. To ascertain whether the tissue expression of CCL17 and CCL22 exerts an influence on the pathogenesis of CRC, a forthcoming study on the 5-year survival rate of CRC patients will be conducted. IntroductionChemokines are chemotactic cytokines that participate in the migration of various types of inflammatory cells and play an important role in the local immunoregulation of various tissues, including the intestinal mucosa (1-3). In general, chemokines are thought to be key players in cancer biology (4). Studies have demonstrated that leukocyte infiltration is a hallmark of most cancers (5-7) and promotes and regulates tumour growth, including metastasis and angiogenesis (8,9). T cell infiltration has been shown to be associated with a favourable prognosis in colorectal cancer (CRC) (10,11).The chemokines CCL17 and CCL22 have been the subject of immunogene therapy studies in murine models of colon carcinoma (12). The chemokine CCL17, also referred to as TARC (thymus-and activation-regulated chemokine), is a member of the CC chemokine group that is expressed in the thymus, dendritic cells, endothelial cells, colon tissue, keratinocytes and fibroblasts (13-17). Moreover, CCL17 is a ligand for CC chemokine receptor 4 (CCR4) and attracts CCR4 + cells (18,19). It...

show abstract

CCL17 exerts a neuroimmune modulatory function and is expressed in hippocampal neurons

Fülle

Offermann

Hansen

et al. 2018

Glia

View full text Add to dashboard Cite

Chemokines are important signaling molecules in the immune and nervous system. Using a fluorescence reporter mouse model, we demonstrate that the chemokine CCL17, a ligand of the chemokine receptor CCR4, is produced in the murine brain, particularly in a subset of hippocampal CA1 neurons. We found that basal expression of Ccl17 in hippocampal neurons was strongly enhanced by peripheral challenge with lipopolysaccharide (LPS). LPS‐mediated induction of Ccl17 in the hippocampus was dependent on local tumor necrosis factor (TNF) signaling, whereas upregulation of Ccl22 required granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). CCL17 deficiency resulted in a diminished microglia density under homeostatic and inflammatory conditions. Further, microglia from naïve Ccl17‐deficient mice possessed a reduced cellular volume and a more polarized process tree as assessed by computer‐assisted imaging analysis. Regarding the overall branching, cell surface area, and total tree length, the morphology of microglia from naïve Ccl17‐deficient mice resembled that of microglia from wild‐type mice after LPS stimulation. In line, electrophysiological recordings indicated that CCL17 downmodulates basal synaptic transmission at CA3–CA1 Schaffer collaterals in acute slices from naïve but not LPS‐treated animals. Taken together, our data identify CCL17 as a homeostatic and inducible neuromodulatory chemokine affecting the presence and morphology of microglia and synaptic transmission in the hippocampus.

show abstract

Genetic Variation at the Chromosome 16 Chemokine Gene Cluster: Development of a Strategy for Association Studies in Complex Disease

Cited by 5 publications

References 31 publications

Sequence variation, linkage disequilibrium and association with Crohn's disease on chromosome 5q31

Sequence variation, linkage disequilibrium and association with Crohn's disease on chromosome 5q31

Quantification of the chemokines CCL17 and CCL22 in human colorectal adenocarcinomas

CCL17 exerts a neuroimmune modulatory function and is expressed in hippocampal neurons

Contact Info

Product

Resources

About