Genetic influences modulating the radiological severity of rheumatoid arthritis

Marinou, Ioanna; Maxwell, James R.; Wilson, Anthony G.

doi:10.1136/ard.2009.117721

Cited by 22 publications

(19 citation statements)

References 91 publications

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“…sIL-6R concentrations have been shown to be higher in A358 IL6R carriers compared to those with the D358 IL6R variant in both serum[2,11,48,49] and the CSF[4]. We confirmed the previous observations that the minor allele (A358) is associated with increased circulating levels of sIL-6R in cerebrospinal fluid (CSF, Fig.…”

Section: Resultssupporting

confidence: 90%

A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer’s Disease Brains

Haddick¹,

Larson²,

Rathore³

et al. 2017

JAD

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The common p.D358A variant (rs2228145) in IL-6R is associated with risk for multiple diseases and with increased levels of soluble IL-6R in the periphery and central nervous system (CNS). Here, we show that the p.D358A allele leads to increased proteolysis of membrane bound IL-6R and demonstrate that IL-6R peptides with A358 are more susceptible to cleavage by ADAM10 and ADAM17. IL-6 responsive genes were identified in primary astrocytes and microglia and an IL-6 gene signature was increased in the CNS of late onset Alzheimer’s disease subjects in an IL6R allele dependent manner. We conducted a screen to identify variants associated with the age of AD onset in APOE ε4 carriers. Across 5 datasets, p.D358A had a meta P=3×10−4 and an odds ratio (OR) = 1.3, 95% confidence interval (CI) 1.12 – 1.48. Our study suggests that a common coding region variant of the IL-6 receptor results in neuroinflammatory changes that may influence the age of onset in AD in APOE ε4 carriers.

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Section: Resultssupporting

confidence: 90%

A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer’s Disease Brains

Haddick¹,

Larson²,

Rathore³

et al. 2017

JAD

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“…Genetic variants of candidate genes encoding for several cytokines (for example, IL-1, IL-6, IL-10 and TGF-β), proteases (for example, protein tyrosine phosphatase nonreceptor type 22) and other immune/inflammatory genes (for example, macrophage protein 1) have been investigated with contrasting results. When the candidate gene approach was used previously, the study limitations were a lack of statistical power, small cohort dimensions and lack of replication studies [26]. …”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor β 869C/T and interleukin 6 -174G/C polymorphisms relate to the severity and progression of bone-erosive damage detected by ultrasound in rheumatoid arthritis

et al. 2011

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IntroductionSingle nucleotide polymorphisms (SNPs) of transforming growth factor β (TGF-β) and IL-6 genes (respectively, 869C/T and -174G/C) have been associated with radiographic severity of bone-erosive damage in patients with rheumatoid arthritis (RA). Musculoskeletal ultrasound (US) is more sensitive than radiography in detecting bone erosion. We analyzed the association between TGF-β 869C/T and IL-6 -174G/C SNPs and bone-erosive damage, evaluated by US, in a cohort of patients with severely active RA.MethodsSeventy-seven patients were enrolled before beginning anti-TNF treatment. Disease activity was measured using the disease activity score in 28 joints, and the clinical response was evaluated according to the European League Against Rheumatism response criteria. Rheumatoid factor (RF) and anticitrullinated protein/peptide antibodies (ACPAs) were detected. The 869C/T TGF-β and -174G/C IL-6 SNPs were analyzed by PCR amplification. US was performed to assess the bone surfaces of metacarpophalengeal (MCP), proximal interphalangeal (PIP) and metatarsophalangeal (MTP) joints by obtaining multiplanar scans. According to the number of erosions per joint, a semiquantitative score ranging from 0 to 3 was calculated in each anatomical site to obtain a MCP total erosion score (TES), a PIP TES and a MTP TES, all ranging from 0 to 30, and a global patient TES calculated as the sum of these scores (range, 0 to 90).ResultsPatients carrying the TGF-β 869TT genotype showed a statistically significant lower MTP TES than those with the CC or CT genotype (mean MTP TES ± standard deviation for 869TT 6.3 ± 5.7 vs. 869CC/CT 11.7 ± 7.8; P = 0.011). Interestingly, patients with the TT genotype showed dichotomous behavior that was dependent on autoantibody status. In the presence of ACPAs and/or RF, the TT genotype was associated with lower erosion scores at all anatomical sites compared with the CC and CT genotypes. Conversely, the same 869TT patients showed higher erosion scores in the absence of ACPAs or RF.ConclusionsIn RA patients, TGF-β 869C/T SNPs could influence the bone-erosive damage as evaluated by US. The serological autoantibody status (ACPAs and RF) can modulate this interaction.

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“…The severity of RA varies from a mild condition with little joint damage to an unremitting condition that leads to extensive bone and cartilage damage. The radiological severity of damage to the hands and feet is widely used to measure outcome of RA and has been shown to have a significant genetic component (3,4). Loci genetically associated with radiological damage include DRB1 (5), CD40 (6) and TRAF1/C5 (7), IL-4 (8), and IL-15 (9).…”

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confidence: 99%

C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis

Muthana

Hawtree

Wilshaw

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The variant rs26232, in the first intron of the chromosome 5 open reading frame 30 (C5orf30) locus, has recently been associated with both risk of developing rheumatoid arthritis (RA) and severity of tissue damage. The biological activities of human C5orf30 are unknown, and neither the gene nor protein show significant homology to any other characterized human sequences. The C5orf30 gene is present only in vertebrate genomes with a high degree of conservation, implying a central function in these organisms. Here, we report that C5orf30 is highly expressed in the synovium of RA patients compared with control synovial tissue, and that it is predominately expressed by synovial fibroblast (RASF) and macrophages in the lining and sublining layer of the tissue. These cells play a central role in the initiation and perpetuation of RA and are implicated in cartilage destruction. RASFs lacking C5orf30 exhibit increased cell migration and invasion in vitro, and gene profiling following C5orf30 inhibition confirmed up-regulation of genes involved in cell migration, adhesion, angiogenesis, and immune and inflammatory pathways. Importantly, loss of C5orf30 contributes to the pathology of inflammatory arthritis in vivo, because inhibition of C5orf30 in the collagen-induced arthritis model markedly accentuated joint inflammation and tissue damage. Our study reveal C5orf30 to be a previously unidentified negative regulator of tissue damage in RA, and this protein may act by modulating the autoaggressive phenotype that is characteristic of RASFs.

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Genetic influences modulating the radiological severity of rheumatoid arthritis

Cited by 22 publications

References 91 publications

A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer’s Disease Brains

A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer’s Disease Brains

Transforming growth factor β 869C/T and interleukin 6 -174G/C polymorphisms relate to the severity and progression of bone-erosive damage detected by ultrasound in rheumatoid arthritis

C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis

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