Deletion Variants of <i>RABGAP1L</i>, 10q21.3, and <i>C4</i> Are Associated With the Risk of Systemic Lupus Erythematosus in Korean Women

Kim, Ji Eun; Jung, Seung‐Hyun; Bae, Joon Seol; Lee, Hye‐Soon; Yim, Seon‐Hee; Park, So‐Yeon; Bang, So-Young; Hu, Hae‐Jin; Shin, Hyoung Doo; Bae, Sang‐Cheol; Chung, Yeun‐Jun

doi:10.1002/art.37854

Cited by 35 publications

(39 citation statements)

References 26 publications

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“…As a physician, this is important to keep in mind when using C4 levels to monitor disease activity 24. Low gene copy numbers of the C4A gene increase the risk of SLE in a Korean population, whereas increased gene copy numbers are protective 27. On the other hand, copy numbers of the C4B gene are not associated with SLE 28.…”

Section: Genetic Associationsmentioning

confidence: 99%

The complement system in systemic lupus erythematosus: an update

2014

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The complement system plays a major role in the autoimmune disease, systemic lupus erythematosus (SLE). However, the role of complement in SLE is complex since it may both prevent and exacerbate the disease. In this review, we explore the latest findings in complement-focused research in SLE. C1q deficiency is the strongest genetic risk factor for SLE, although such deficiency is very rare. Various recently discovered genetic associations include mutations in the complement receptors 2 and 3 as well as complement inhibitors, the latter related to earlier onset of nephritis. Further, autoantibodies are a distinct feature of SLE that are produced as the result of an adaptive immune response and how complement can affect that response is also being reviewed. SLE generates numerous disease manifestations involving contributions from complement such as glomerulonephritis and the increased risk of thrombosis. Furthermore, since most of the complement system is present in plasma, complement is very accessible and may be suitable as biomarker for diagnosis or monitoring of disease activity. This review highlights the many roles of complement for SLE pathogenesis and how research has progressed during recent years.

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Section: Genetic Associationsmentioning

confidence: 99%

The complement system in systemic lupus erythematosus: an update

2014

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“…15 28 29 Low gene copy number (GCN) for total C4 or C4A deficiency has been observed as a risk factor of human systemic lupus erythematosus. [30][31][32][33] Many earlier epidemiological studies of complement C4A and C4B in rheumatic diseases, including JDM, were based on an incomplete or inaccurate model with two-locus (C4A-C4B) on a haplotype for data interpretation, and thus the conclusions drawn became uncertain. [34][35][36][37] Here we perform an investigation of C4 genetic diversity and examine the effects on the risk and pathogenesis of JDM, with further considerations to the presence and absence of HLA-DRB1 risk and protective alleles.…”

Section: Introductionmentioning

confidence: 99%

Gene copy-number variations (CNVs) of complementC4andC4Adeficiency in genetic risk and pathogenesis of juvenile dermatomyositis

et al. 2015

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Objective Complement-mediated vasculopathy of muscle and skin are clinical features of juvenile dermatomyositis (JDM). We assess gene copy-number variations (CNVs) for complement C4 and its isotypes, C4A and C4B, in genetic risks and pathogenesis of JDM. Methods The study population included 105 JDM patients and 500 healthy European Americans. Gene copy-numbers (GCNs) for total C4, C4A, C4B and HLA-DRB1 genotypes were determined by Southern blots and PCRs. Processed activation product C4d bound to erythrocytes (E-C4d) was measured by flow cytometry. Global gene-expression microarrays were performed in 19 JDM and 7 controls using PAXgene-blood RNA. Differential expression levels for selected genes were validated by qPCR. Results Significantly lower GCNs and differences in distribution of GCN groups for total C4 and C4A were observed between JDM and controls. Lower GCN of C4A in JDM remained among HLA DR3-positive subjects (p=0.015). Homozygous or heterozygous C4A-deficiency was present in 40.0% of JDM compared to 18.2% of controls [odds ratio (OR)=3.00 (1.87–4.79), p=8.2x10−6]. JDM had higher levels of E-C4d than controls (p=0.004). In JDM, C4A-deficient subjects had higher levels of E-C4d (p=0.0003) and higher frequency of elevated levels of multiple serum muscle enzymes at diagnosis (p=0.004). Microarray profiling of blood RNA revealed upregulation of type I Interferon-stimulated genes and lower abundance of transcripts for T-cell and chemokine function genes in JDM, but this was less prominent among C4A-deficient or DR3-positive patients. Conclusions Complement C4A-deficiency appears to be an important factor for the genetic risk and pathogenesis of JDM, particularly in patients with a DR3-positive background.

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“…CNVs account for a major proportion of human genetic variation, and several reports have suggested that CNVs play a role in susceptibility to diseases, especially autoimmune diseases (19)(20)(21)(22)(23). However, no GWAS exploring ASassociated CNVs have been reported.…”

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confidence: 99%

Genome‐Wide Copy Number Variation Analysis Identifies Deletion Variants Associated With Ankylosing Spondylitis

Jung

Yim

et al. 2014

Arthritis & Rheumatology

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Objective. To identify ankylosing spondylitis (AS)-associated copy number variations (CNVs) in Korean subjects and their synergistic roles in the development of AS.Methods. A genome-wide association study (GWAS) was performed in 309 patients with AS and 309 control subjects, using a copy number variant (CNV) microarray. AS-associated CNV regions were replicated in 2 independent sets (625 patients and 891 control subjects) by quantitative polymerase chain reaction (PCR) and deletion-typing PCR.Results. In the CNV GWAS, 227 CNV regions were shown to be significantly associated with the risk of AS. Of the candidate CNV regions, 9 were successfully replicated in the first replication analysis: 1q32.2 (HHAT), 1p34.2 (BMP8A), 2q31.2 (PRKRA), 6p21.32 (HLA-DPB1), 11q22.1 (CNTN5), 13q13.1 (EEF1DP3), 14q24.2 (RGS6), 16p13.3, and 22q11.1 (IL17RA). The 5 deletion-type CNV regions, in 1q32.2, 2q31.2, 6p21.32, 13q13.1, and 16p13.3, were associated with an increased risk of AS, and the other 4 CNV regions were protective. In the second replication analysis, 4 CNV regions in 1q32.2, 2q31.2, 6p21.32, and 16p13.3 were replicated. Among patients with CNV regions in >4 risk-increasing loci, the risk was 18.0 times higher than that in patients without any deletions (odds ratio [OR] 17.98, P ‫؍‬ 2.3 ؋ 10 ؊7 ). Among patients with CNV regions in >2 protective loci, the risk was 5.2 times lower than that in those without any deletions (OR 0.19, P ‫؍‬ 4.0 ؋ 10 ؊10 ). The additive effects of simultaneous events were shown to be dependent on the frequency of CNV regions. Through deletion-typing PCR and sequencing, the exact sizes and breakpoint sequences were defined in 4 CNV regions. The mechanism of all 3 deletions was shown to be microhomology-based nonhomologous end joining.Conclusion. The results of this study can help to identify pathogenic mechanisms of AS and can easily be applied in the development of algorithms estimating the risk of AS.Ankylosing spondylitis (AS) is a chronic inflammatory disease that mainly affects the sacroiliac joints and spine. Nonsteroidal antiinflammatory drugs and tumor necrosis factor ␣ (TNF␣) inhibitors are effective in controlling the signs and symptoms of active AS (1). However, it is currently unclear whether these drugs can inhibit the progress of bony ankylosis (2). Therefore, there is a great need for further research on the etiology and pathophysiology of the disease, which will help in the development of better therapies.

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Deletion Variants of RABGAP1L, 10q21.3, and C4 Are Associated With the Risk of Systemic Lupus Erythematosus in Korean Women

Cited by 35 publications

References 26 publications

The complement system in systemic lupus erythematosus: an update

The complement system in systemic lupus erythematosus: an update

Gene copy-number variations (CNVs) of complementC4andC4Adeficiency in genetic risk and pathogenesis of juvenile dermatomyositis

Genome‐Wide Copy Number Variation Analysis Identifies Deletion Variants Associated With Ankylosing Spondylitis

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