Gene copy-number variations (CNVs) of complement<i>C4</i>and<i>C4A</i>deficiency in genetic risk and pathogenesis of juvenile dermatomyositis

Lintner, Katherine E.; Patwardhan, Anjali; Rider, Lisa G.; Abdul-Aziz, Rabheh; Wu, Yee Ling; Lundström, Emeli; Padyukov, Leonid; Zhou, Bi; Alhomosh, Alaaedin; Newsom, David L.; White, Peter; Jones, Karla; O’Hanlon, Terrance P.; Miller, Frederick W.; Spencer, Charles H.; Yu, C. Yung

doi:10.1136/annrheumdis-2015-207762

Cited by 45 publications

(38 citation statements)

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“…Additionally, these potentially ‘high-risk’ individuals who were in the treatment group of the APPLE trial demonstrated slower CIMT progression over the course of the trial. We also noted an association between low C4A GCN and myositis, an observation which was consistent with our earlier report on C4A deficiency in juvenile dermatomyositis 38…”

Section: Discussionsupporting

confidence: 93%

Elevated serum complement levels and higher gene copy number of complementC4Bare associated with hypertension and effective response to statin therapy in childhood-onset systemic lupus erythematosus (SLE)

et al. 2019

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ObjectiveSystemic lupus erythematosus (SLE) features high frequency of cardiovascular disease (CVD) and fluctuating complement levels. The clinical trial Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) aimed to evaluate whether atorvastatin treatment reduced the progression of atherosclerosis in 221 patients with childhood-onset SLE (cSLE), using carotid intima media thickness (CIMT) as surrogates. We leveraged APPLE biorepository and trial data to investigate the relationship between complement and CVD in cSLE.MethodsGene copy numbers (GCNs) for total C4, C4A and C4B were measured by TaqMan-based real-time PCR and Southern blotting, and analysed with laboratory and clinical parameters through Student’s t-test and χ2 analyses. Effects of total C4, C4A and C4B GCNs on the response to placebo or atorvastatin treatment and progression of CIMT were examined by regression analyses.ResultsAt baseline, C4 protein levels strongly correlated with GCNs of total C4 (p=1.8×10−6). Each copy of C4 gene increased mean serum C4 by 3.28 mg/dL. Compared with those without hypertension (N=142), individuals with hypertension demonstrated significantly elevated serum levels for C4 and C3 at baseline and serially (C4: P=5.0×10−25; C3: P=5.84×10−20). Individuals with ≥2 C4B genes had 2.5 times the odds of having hypertension (p=0.016) and higher diastolic blood pressure (p=0.015) compared with those with C4B deficiency. At the study end, subjects with ≥2 C4B and atorvastatin treatment had significantly slower increase in CIMT compared with those treated with placebo (p=0.018).ConclusionscSLE with hypertension had elevated serum levels of C4 and C3 and higher GCN of C4B; cSLE with ≥2 C4B genes would benefit from statins therapy to prevent atherosclerosis.

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Section: Discussionsupporting

confidence: 93%

Elevated serum complement levels and higher gene copy number of complementC4Bare associated with hypertension and effective response to statin therapy in childhood-onset systemic lupus erythematosus (SLE)

et al. 2019

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“…Specific HLA alleles are thought to target particular autoantigens, resulting in a breakdown in immunological tolerance to self-antigens. However, studies have shown that there are additional genetic features of the 8.1 AH that predispose individuals to immune-mediated diseases, such as NF-kappaB and TNF-alpha polymorphisms,18 19 and gene copy number variants of complement genes 20. The association of alleles independent of the 8.1 AH with anti-Mi-2 and anti-HMGCR, as well as finding that some autoantibodies do not have strong HLA associations, suggests that not all patients with IIM share a common genetic risk.…”

Section: Discussionmentioning

confidence: 99%

Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups

et al. 2019

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ObjectivesIdiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies.MethodsWe collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups.ResultsWe report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10–5. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10–53 and HLA-DRB1*03:01, p=3.25×10–9), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10–26) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10–11). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10–13) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10–6). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10–64) and position 9 of HLA-B (p=7.03×10–11). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies.ConclusionsThese findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.

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“…The coexistence of C4A deficiency with the HLA risk allele DRB1*0301 in European Americans with SLE and the HLA allele DRB1*1501 in East Asians with SLE and other autoimmune diseases continues to be a fascinating topic in studies aimed at determining whether C4 CNVs or C4A deficiency and DRB1 genetic variants are independent, additive, or confounding disease risk factors . The pathologic effects of genetic and/or acquired deficiencies of C4, C1q, C1r, and C1s on SLE risk and pathogenesis have been found to be overwhelming .…”

Section: Discussionmentioning

confidence: 99%

Effects of Complement C4 Gene Copy Number Variations, Size Dichotomy, and C4A Deficiency on Genetic Risk and Clinical Presentation of Systemic Lupus Erythematosus in East Asian Populations

Chen

Mok

et al. 2016

Arthritis & Rheumatology

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Objectives Human complement C4 is sophisticatedly complex with multiple layers of diversity. This study aims to elucidate the CNVs of C4A and C4B in disease risk of SLE, and compare the basis of race-specific C4A-deficiency in East-Asians (EA) and Europeans. Patients and Methods Our EA study-population included 999 SLE patients and 1,347 healthy subjects. Variations in gene copy-numbers (GCNs) for total C4, C4A, C4B, long and short genes were determined and validated rigorously by independent genotyping technologies. Genomic regions with C4B96 were investigated to determine the basis of the most basic C4B protein that is concurrent with C4A-deficiency. Results In EA, strong protective effects of high GCNs for total C4 and C4A against SLE were notable; low and medium GCNs for total C4 and C4A, and the absence of short genes were risk factors of SLE. Homozygous C4A-deficiency was infrequent but had an odds-ratio (OR) of 12.4 (p=0.0015). Patients who experienced very-low serum complement were associated with low GCNs of total C4 (OR=3.27, p=7.0×10−7) and C4B (OR=2.55, p=2.5×10−5). Patients with low complement had high frequencies of anti-dsDNA (OR=4.96, p=9.7×10−17), hemolytic anemia (OR=3.89, p=3.6×10−10) and renal disease (OR=2.18, p=8.5×10−6). The monomodular-short haplotype with C4A-deficiency and in linkage-disequilibrium with HLA-DRB1*0301 prevalent in European was scarce in EA. Instead, most EA-subjects with C4A-deficiency shared a recombinant haplotype with bimodular-LS encoding C4B1 and C4B96, which was linked to HLA-DRB1*1501. DNA sequencing revealed the E920K polymorphism for C4B96. Conclusion C4 CNVs and C4A-deficiency are important in the risk and manifestations of East-Asian and European SLE.

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

Cited by 45 publications

References 54 publications

Elevated serum complement levels and higher gene copy number of complementC4Bare associated with hypertension and effective response to statin therapy in childhood-onset systemic lupus erythematosus (SLE)

Elevated serum complement levels and higher gene copy number of complementC4Bare associated with hypertension and effective response to statin therapy in childhood-onset systemic lupus erythematosus (SLE)

Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups

Effects of Complement C4 Gene Copy Number Variations, Size Dichotomy, and C4A Deficiency on Genetic Risk and Clinical Presentation of Systemic Lupus Erythematosus in East Asian Populations

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