An investigation of polymorphisms in the 17q11.2-12 CC chemokine gene cluster for association with multiple sclerosis in Australians

Bugeja, Matthew J; Booth, David R.; Bennetts, Bruce; Heard, Robert; Rubio, Justin P.; Stewart, Graeme J.

doi:10.1186/1471-2350-7-64

Cited by 10 publications

(8 citation statements)

References 68 publications

(61 reference statements)

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“…CXCL10/IP-10, CCL2/MCP-1, CCL3/MIP-1a, CCL4/MIP-1b, CCL5/Rantes, CCL7/MCP-3 and CXCL9/Mig [ 11 – 25 ] are among the described proinflammatory chemokines produced by immune cells and CNS glia in MS and in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). Most of the β-chemokines or CC chemokine ligands (CCL) genes are clustered in chromosome 17q11.2–12, a location that has been associated with MS in different studies [ 26 – 28 ]. In a model of EAE, increased levels of Eotaxin/CCL11 were associated with milder disease phenotype, tighter blood brain barrier, reduced antigenic specific response and an anti-inflammatory Th2 phenotype [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Plasma Biomarkers Discriminate Clinical Forms of Multiple Sclerosis

et al. 2015

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Multiple sclerosis, the most common cause of neurological disability in young population after trauma, represents a significant public health burden. Current challenges associated with management of multiple sclerosis (MS) patients stem from the lack of biomarkers that might enable stratification of the different clinical forms of MS and thus prompt treatment for those patients with progressive MS, for whom there is currently no therapy available. In the present work we analyzed a set of thirty different plasma cytokines, chemokines and growth factors present in circulation of 129 MS patients with different clinical forms (relapsing remitting, secondary progressive and primary progressive MS) and 53 healthy controls, across two independent cohorts. The set of plasma analytes was quantified with Luminex xMAP technology and their predictive power regarding clinical outcome was evaluated both individually using ROC curves and in combination using logistic regression analysis. Our results from two independent cohorts of MS patients demonstrate that the divergent clinical and histology-based MS forms are associated with distinct profiles of circulating plasma protein biomarkers, with distinct signatures being composed of chemokines and growth/angiogenic factors. With this work, we propose that an evaluation of a set of 4 circulating biomarkers (HGF, Eotaxin/CCL11, EGF and MIP-1β/CCL4) in MS patients might serve as an effective tool in the diagnosis and more personalized therapeutic targeting of MS patients.

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Section: Discussionmentioning

confidence: 99%

Plasma Biomarkers Discriminate Clinical Forms of Multiple Sclerosis

et al. 2015

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“…Genetic polymorphisms in the homologous region on human chromosome 17 have been studied for involvement in MS susceptibility, [29][30][31][32] as well as other autoimmune or chronic inflammatory diseases including RA, 60 myocardial infarction 66,67 and allergy. 68 A second cluster including chemokine genes (CCL5, CCL16, CCL14, CCL15, CCL23, CCL18, CCL3 and CCL4) located further upstream has also been studied in relation to MS, but in this study we have focused on the centromeric cluster, as this was identified in the rat linkage study.…”

Section: Discussionmentioning

confidence: 99%

“…24,25 There is evidence for a role of specific chemokines in regulation of disease and cell migration in both MS 26 and EAE. 27 The chemokine genes have also been included in linkage and association studies, [28][29][30][31] but despite substantial evidence for linkage and association to this chemokine cluster, data lack conclusive replication. 32 In this study, we refine the Eae18b locus to a 0.88 Mb region containing the chemokine gene cluster and show that the expression of chemokines Ccl2, Ccl11 and Ccl1 is regulated by the locus.…”

Section: Il7rmentioning

confidence: 99%

Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multiple sclerosis and rheumatoid arthritis

et al. 2009

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Multiple sclerosis (MS) is a complex disorder of the central nervous system, causing inflammation, demyelination and axonal damage. A limited number of genetic risk factors for MS have been identified, but the etiology of the disease remains largely unknown. For the identification of genes regulating neuroinflammation we used a rat model of MS, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), and carried out a linkage analysis in an advanced intercross line (AIL). We thereby redefine the Eae18b locus to a 0.88 Mb region, including a cluster of chemokine genes. Further, we show differential expression of Ccl2, Ccl11 and Ccl11 during EAE in rat strains with opposite susceptibility to EAE, regulated by genotype in Eae18b. The human homologous genes were tested for association to MS in 3841 cases and 4046 controls from four Nordic countries. A haplotype in CCL2 and rs3136682 in CCL1 show a protective association to MS, whereas a haplotype in CCL13 is disease predisposing. In the HLA-DRB1*15 positive subgroup, we also identified an association to a risk haplotype in CCL2, suggesting an influence from the human leukocyte antigen (HLA) locus. We further identified association to rheumatoid arthritis in CCL2, CCL8 and CCL13, indicating common regulatory mechanisms for complex diseases.

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“…Most chemokine genes are encoded in a cluster on chromosome 17q11.2-12, which has been identified in a number of genome-wide screens as being potentially associated with MS (15). Polymorphism of CCR2, IL-10 receptor α, and Fas-L may confer protective effects for MS; and polymorphism of CCR5, IL-10, IL-4 receptor α, IL-2 receptor ß, IFN-γ, vitamin D, and estrogen receptor confer risk to MS (1).…”

Section: Ccr5-δ32 Genetic Polymorphism Associated With Benign Clinicamentioning

confidence: 99%

CCR5-Δ32 genetic polymorphism associated with benign clinical course and magnetic resonance imaging findings in Brazilian patients with multiple sclerosis

Kaimen-Maciel

Reiche²,

Souza³

et al. 2007

Int J Mol Med

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Abstract. The CCR5 chemokine receptor has been implicated in the pathogenesis of multiple sclerosis (MS). This research was carried out to investigate the association between the CCR5-Δ32 deletion in 124 patients with MS from Southern Brazil. Ninety-eight (79.0%) patients presented with relapsingremitting MS (RR-MS), 17 (13.7%) secondary progressive MS (SP-MS), 8 (6.5%) primary progressive MS (PP-MS) and one (0.8%) clinically isolated syndrome (CIS). The control group consisted of 127 healthy blood donors from the same geographic region. The disease severity was assessed clinically using the Expanded Disability Status Scale (EDSS). Genomic DNA was extracted from peripheral blood cells and the genetic polymorphism was evaluated by polymerase chain reaction. Of the MS patients, 85 (68.5%) were females (p=0.0093). The CCR5-Δ32 frequency among the controls was 5.5%, and did not differ from that observed among the MS patients (4.8%) (p=0.7337). The mean (±SD) age at disease onset among the carriers and non-carriers of the CCR5-Δ32 allele was 31.7 (±11.1) and 36.6 (±12.0) years, respectively (p=0.1312). The duration (±SD) of the disease was 11.2 (±12.9) and 7.7 (± 5.6) years among the CCR5-Δ32 heterozygous, and CCR5 wild type, respectively (p=0.396). The mean (±SD) EDSS among the MS patients carriers and non-carriers of the CCR5-Δ32 allele was 2.4±1.2 and 2.67±2.2, respectively (p=0.9796). The MRI findings in MS patients with the CCR5-Δ32 genotype exhibited lower positive gadolinium enhancing-imaging (p=0.0013) and lower brain atrophy (p=0.1333) than MS patients with the CCR5 wild-type genotype. Despite that the differences were not significant, the results suggested that the disease onset and progression to disability may be prolonged in MS carriers of CCR5-Δ32, and CCR5-Δ32 could be considered a favorable prognostic biomarker of MS. Further studies comprising larger numbers of individuals carrying non-wild-type haplotypes are needed to determine CCR5-Δ32 involvement in the specific process of MS pathology and pathogenesis.

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An investigation of polymorphisms in the 17q11.2-12 CC chemokine gene cluster for association with multiple sclerosis in Australians

Cited by 10 publications

References 68 publications

Plasma Biomarkers Discriminate Clinical Forms of Multiple Sclerosis

Plasma Biomarkers Discriminate Clinical Forms of Multiple Sclerosis

Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multiple sclerosis and rheumatoid arthritis

CCR5-Δ32 genetic polymorphism associated with benign clinical course and magnetic resonance imaging findings in Brazilian patients with multiple sclerosis

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