Analysis of C1q polymorphisms suggests association with systemic lupus erythematosus, serum C1q and CH50 levels and disease severity

Martens, Henk A.; Zuurman, Michael; Lange, Andrzej; Nolte, Ilja M.; Steege, Gerrit van der; Navis, Gerarda; Kallenberg, Cornelis; Seelen, M. A.; Bijl, Marc

doi:10.1136/ard.2007.085688

Cited by 54 publications

(51 citation statements)

References 20 publications

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“…In SLE, the level of complement C3 in the serum is inversely associated with the magnitude or extent of systemic inflammation, and polymorphisms in complement or receptors are highly linked SLE risk factors (29)(30)(31). Treatment with either 55 mg/kg or 100 mg/kg CEP-33779 significantly increased serum C3 concentration relative to vehicle (52.5% increase for 100 mg/kg and 51.4% increase for 55 mg/kg over vehicle; p , 0.05) ( Fig.…”

Section: Cep-33779 Inhibition Of Jak2 Can Protect Mrl/lpr Sle Mice Frmentioning

confidence: 99%

Depletion of Autoreactive Plasma Cells and Treatment of Lupus Nephritis in Mice Using CEP-33779, a Novel, Orally Active, Selective Inhibitor of JAK2

Lu¹,

Stump²,

Wallace³

et al. 2011

The Journal of Immunology

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Accumulating evidence suggests that autoreactive plasma cells play an important role in systemic lupus erythematosus (SLE). In addition, several proinflammatory cytokines promote autoreactive B cell maturation and autoantibody production. Hence, therapeutic targeting of such cytokine pathways using a selective JAK2 inhibitor, CEP-33779 (JAK2 enzyme IC50 = 1.3 nM; JAK3 enzyme IC50/JAK2 enzyme IC50 = 65-fold), was tested in two mouse models of SLE. Age-matched, MRL/lpr or BWF1 mice with established SLE or lupus nephritis, respectively, were treated orally with CEP-33779 at 30 mg/kg (MRL/lpr), 55 mg/kg or 100 mg/kg (MRL/lpr and BWF1). Studies included reference standard, dexamethasone (1.5 mg/kg; MRL/lpr), and cyclophosphamide (50 mg/kg; MRL/lpr and BWF1). Treatment with CEP-33779 extended survival and reduced splenomegaly/lymphomegaly. Several serum cytokines were significantly decreased upon treatment including IL-12, IL-17A, IFN-α, IL-1β, and TNF-α. Anti-nuclear Abs and frequencies of autoantigen-specific, Ab-secreting cells declined upon CEP-33779 treatment. Increased serum complement levels were associated with reduced renal JAK2 activity, histopathology, and spleen CD138+ plasma cells. The selective JAK2 inhibitor CEP-33779 was able to mitigate several immune parameters associated with SLE advancement, including the protection and treatment of mice with lupus nephritis. These data support the possibility of using potent, orally active, small-molecule inhibitors of JAK2 to treat the debilitative disease SLE.

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Section: Cep-33779 Inhibition Of Jak2 Can Protect Mrl/lpr Sle Mice Frmentioning

confidence: 99%

Depletion of Autoreactive Plasma Cells and Treatment of Lupus Nephritis in Mice Using CEP-33779, a Novel, Orally Active, Selective Inhibitor of JAK2

Lu¹,

Stump²,

Wallace³

et al. 2011

The Journal of Immunology

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“…Similarly, several studies, although small, have implicated C1q in the emergence of SLE, as several genetic variants located in the C1q region seem to associate with this disease [18][19][20][21][22]. In addition, two small studies indicated an effect of genetic variants of C1q on the progression of cancer and the efficacy of rituximab treatment for lymphoma [23,24].…”

Section: Introductionmentioning

confidence: 99%

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

Trouw

Daha

Kurreeman

et al. 2013

Clinical and Experimental Immunology

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SummaryRodent models for arthritis implicate a role for complement in disease development and progression. In humans, complement deposition has been observed in inflamed synovia of rheumatoid arthritis (RA) patients. In this study we analysed whether genetic variants of complement component C1q predispose to RA. We genotyped single nucleotide polymorphisms (SNPs) in and around the C1q genes, C1qA, C1qB and C1qC, in a Dutch set of 845 RA cases and 1046 controls. Replication was sought in a sample set from North America (868 cases/1193 controls), and a meta-analysis was performed in a combined samples set of 8000 cases and 23 262 controls of European descent. We determined C1q serum levels in relation to C1q genotypes. In the discovery phase, five of the 13 SNPs tested in the C1q genes showed a significant association with RA. Additional analysis of the genomic area around the C1q genes revealed that the strongest associating SNPs were confined to the C1q locus. Within the C1q locus we observed no additional signal independent of the strongest associating SNP, rs292001 [odds ratio (OR) = 0·72 (0·58-0·88), P = 0·0006]. The variants of this SNP were associated with different C1q serum levels in healthy controls (P = 0·006). Interestingly, this SNP was also associated significantly in genome-wide association studies (GWAS) from the North American Rheumatoid Arthritis Consortium study, confirming the association with RA [OR = 0·83 (0·69-1·00), P = 0·043]. Combined analysis, including integrated data from six GWAS studies, provides support for the genetic association. Genetic variants in C1q are correlated with C1q levels and may be a risk for the development of RA.

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“…Significant associations with the development of SLE, including LN, were established for rs292001 in studies byof 2015). They found that patients with A allele and AA genotype of rs292001 could be considered a susceptibility risk factor for SLE, juvenile SLE (jSLE) and LN in Dutch, Turkish and Egyptian cohorts (3,6,10). In these studies, the rs292001 was not associated with the disease severity or with a serum concentration of C1q or/and anti-C1q antibodies.…”

Section: Discussionmentioning

confidence: 99%

“…The rs292001 is SNP in the second intron of C1QA gene. According to several studies, the AA rs292001 genotype seems to associate with adult and juvenile SLE and LN (3,6,10).…”

Section: Introductionmentioning

confidence: 99%

“…The complement proteins C1q, C3 and C4 are deposited at the site of inflammation in the kidney and play an important role in the pathogenesis of LN. It is well known that hereditary C1q deficiency is strongly related to SLE, but there are several and inconsistent studies exploring single nucleotide poly-morphisms (SNPs) of the C1q gene cluster in relation to the pathogenesis of SLE (1)(2)(3)(4)(5)(6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

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The GG rs292001 genotype prevails in seronegative for ANA and anti-dsDNA antibodies patients with lupus nephritis

Radanova

Bratoeva

Nazifova-Tasinova

et al. 2016

SSM

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Rs292001 is single nucleotide polymorphism in non-coding regions of the C1QA gene. C1q is a subcomponent of the C1 first component of the classical pathway of complement activation. Rs292001 was investigated for an association with some conventional immunological markers of lupus nephritis (LN) activity in systemic lupus erythematosus (SLE) patients -levels of C1q, C3, C4, anti-C1q, anti-nuclear (ANA) and anti-ds-DNA autoantibodies.Genomic DNA was isolated from peripheral blood of 18 patients with biopsy-proven LN. SNP genotyping for the presence of rs292001 was performed by quantitative real-time PCR method. Presence of complement C1q, C3 and C4 and anti-C1q autoantibodies was screened by ELISA. ANA and anti-dsDNA antibodies were detected by double immunodiffusion assays and indirect immunofluorescence.We found that the GG rs292001 genotype prevailed in seronegative for ANA and anti-dsDNA antibodies LN patients (p=0.008; p<0.012). The AA rs292001 genotype showed a trend towards lower serum C1q levels.These results reaffirm a previously established probable protective role of the G allele against the clinical activity of the SLE.

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Analysis of C1q polymorphisms suggests association with systemic lupus erythematosus, serum C1q and CH50 levels and disease severity

Abstract: C1q polymorphisms are associated with SLE, serum C1q and CH50 levels in a stable founder population of patients with SLE. Although the studied population was small and allele frequencies were low, this is the first study to suggest an association of C1q polymorphisms with SLE.

Cited by 54 publications

References 20 publications

Depletion of Autoreactive Plasma Cells and Treatment of Lupus Nephritis in Mice Using CEP-33779, a Novel, Orally Active, Selective Inhibitor of JAK2

Depletion of Autoreactive Plasma Cells and Treatment of Lupus Nephritis in Mice Using CEP-33779, a Novel, Orally Active, Selective Inhibitor of JAK2

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

The GG rs292001 genotype prevails in seronegative for ANA and anti-dsDNA antibodies patients with lupus nephritis

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