Genetic variants in the region of the C1q genes are associated with rheumatoid arthritis

Trouw, Leendert A.; Daha, Nina A.; Kurreeman, Fina; Böhringer, Stefan; Goulielmos, George N.; Westra, Harm Jan; Zhernakova, Alexandra; Franke, Lude; Stahl, Erich; Levarht, E. W. Nivine; Stoeken-Rijsbergen, Gerrie; Verduijn, Willem; Roos, Anja; Li, Y; Houwing-Duistermaat, Jeanine J.; Huizinga, T.W.J.; Toes, René E. M.

doi:10.1111/cei.12097

Cited by 42 publications

(29 citation statements)

References 50 publications

(84 reference statements)

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“…Clinical evidence shows that homozygous deficiency in any of the classical pathway proteins—C1q, C1r, C1s, C4 and C2—can lead to the development of SLE and other autoimmune diseases such as rheumatoid arthritis (RA) (Pickering et al, 2000; Walport et al, 1998; Liu et al, 2004; Martens et al, 2009, Trouw et al, 2013). Among these proteins, C1q is the most significant because homozygous deficiency or hereditary deficiency due to mutation in the C1q gene (predominantly the A-chain) is a strong susceptibility factor for the development of SLE.…”

Section: Role Of C1/c1q In Autoimmune Diseases: a C1-centric Hypotmentioning

confidence: 99%

C1q as an autocrine and paracrine regulator of cellular functions

Ghebrehiwet

Hosszu

Peerschke

2017

Molecular Immunology

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Most of the complement proteins in circulation are, by and large, synthesized in the liver. However data accumulated over the past several decades provide incontrovertible evidence that some if not most of the individual complement proteins are also synthesized extrahepatically by activated as well as non-activated cells. The question that is finally being addressed by various investigators is: are the locally synthesized proteins solely responsible for the myriad of biological functions in situ without the contribution of systemic complement? The answer is probably “yes”. Among the proteins that are synthesized locally, C1q takes center stage for several reasons. First, it is synthesized predominantly by potent antigen presenting cells such as monocytes, macrophages and dendritic cells (DCs), which by itself is a clue that it plays an important role in antigen presentation and/or DC maturation. Second, it is transiently anchored on the cell surface via a transmembrane domain located in its A chain before it is cleaved off and released into the pericellular milieu. The membrane-associated C1q in turn, is able to sense danger patterns via its versatile antigen-capturing globular head domains. More importantly, locally synthesized C1q has been shown to induce a plethora of biological functions through the induction of immunomodulatory molecules by an autocrine- or paracrine-mediated signaling in a manner that mimics those of TNFα. These include recognition of pathogen- and danger-associated molecular patterns, phagocytosis, angiogenesis, apoptosis and induction of cytokines or chemokines that are important in modulating the inflammatory response. The functional convergence between C1q and TNFα in turn is attributed to their shared genetic ancestry. In this paper, we will infer to the aforementioned “local-synthesis-for-local function” paradigm using as an example, the role played by locally synthesized C1q in autoimmunity in general and in systemic lupus erythematosus in particular.

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Section: Role Of C1/c1q In Autoimmune Diseases: a C1-centric Hypotmentioning

confidence: 99%

C1q as an autocrine and paracrine regulator of cellular functions

Ghebrehiwet

Hosszu

Peerschke

2017

Molecular Immunology

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“…Accordingly, mutations in C1q and C1q deficiency are linked to systemic lupus erythematosus autoimmune disease. In addition, genetic variants of C1q are associated with the development of rheumatoid arthritis [9,13,14]. The binding of C1q to the apoptotic cell surface is a multimolecular event which has not yet been completely deciphered.…”

Section: Introductionmentioning

confidence: 99%

Relative Contribution of C1q and Apoptotic Cell-Surface Calreticulin to Macrophage Phagocytosis

Verneret¹,

Tacnet-Delorme²,

Osman³

et al. 2014

J Innate Immun

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C1q has been shown to recognize apoptotic cells, to enhance their uptake and to modulate cytokine release by phagocytes and thus promote immune tolerance. Surface-exposed calreticulin (CRT), known as a C1q receptor, is also considered to be an early eat-me signal that enhances the phagocytosis of apoptotic cells and is capable of eliciting an immunogenic response. However, the molecular mechanisms that trigger these functions are not clear. We hypothesized that CRT and C1q might act together in these processes. We first showed, by means of fluorescence resonance energy transfer (FRET), that CRT interacts with the C1q globular region at the surface of early apoptotic cells. Next, we pointed out that knockdown of CRT on early apoptotic HeLa cells impairs the enhancement effect of C1q on their uptake by THP-1 monocyte-derived macrophages. Furthermore, a deficiency of CRT induces contrasting effects on cytokine release by THP-1 macrophages, increasing interleukin (IL)-6 and monocyte chemotactic protein 1/CCL2 and decreasing IL-8. Remarkably, these effects were greatly reduced when apoptotic cells were opsonized by C1q, which counterbalanced the effect of the CRT deficiency. These results demonstrate that CRT-C1q interaction is involved in the C1q bridging function and they highlight the particular ability of C1q to control the phagocyte inflammatory status, i.e. by integrating the molecular changes that could occur at the surface of dying cells.

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“…reported that C1q rs292001 is associated with type 2 diabetes mellitus (22). Other genetic polymorphisms of C1q have been also associated with susceptibility to autoimmune diseases, such as rheumatoid arthritis (23). Since C1q deficiency can result in increased susceptibility to lupus-like autoimmune disease, the genetic polymorphisms of C1q may also have important roles in SLE (24).…”

Section: Discussionmentioning

confidence: 99%

Association between C1q gene polymorphisms and autoimmune thyroid diseases

Yao

et al. 2017

Arch. Endocrinol. Metab.

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Objective: In the present study, we aimed to assess the associations of C1q gene polymorphisms with autoimmune thyroid diseases (AITD) susceptibility. Subjects and methods: A set of 1,003 AITD patients (661 with Graves' disease and 342 with Hashimoto's thyroiditis) and 880 ethnicallyand geographically-matched controls from Chinese Han population were included. Five common single nucleotide polymorphisms (SNPs) (rs294185, rs292001, rs682658, rs665691 and rs294179) in C1q gene locus were genotyped. Frequencies of genotypes and alleles were compared between patients and controls, and haplotype analysis was also performed. Results: There was no statistically significant difference between AITD patients and controls in the frequencies of alleles of rs294185 (P = 0.41), rs292001 (P = 0.71), rs682658 (P = 0.68), rs665691 (P = 0.68) and rs294179 (P = 0.69). There was also no statistically significant difference between AITD patients and controls in the frequencies of genotypes of rs294185 (P = 0.72), rs292001 (P = 0.89), rs682658 (P = 0.83), rs665691 (P = 0.90) and rs294179 (P = 0.43). Stratified analyses showed that none of those five SNPs in C1q gene were associated with Graves' disease or Hashimoto's thyroiditis (all P values > 0.05). Haplotype analysis revealed that there were no obvious genetic associations of C1q gene polymorphisms with AITD susceptibility. Conclusions: We, for the first time, identified the associations between C1q gene SNPs and AITD, and our findings suggested that five common SNPs in C1q gene were not associated with AITD susceptibility in Chinese Han population. Arch Endocrinol Metab. 2017;61(3):337-42.

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Genetic variants in the region of the C1q genes are associated with rheumatoid arthritis

Cited by 42 publications

References 50 publications

C1q as an autocrine and paracrine regulator of cellular functions

C1q as an autocrine and paracrine regulator of cellular functions

Relative Contribution of C1q and Apoptotic Cell-Surface Calreticulin to Macrophage Phagocytosis

Association between C1q gene polymorphisms and autoimmune thyroid diseases

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