Dataset Information

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.

ABSTRACT: Human complement C4 is complex, with multiple layers of diversity. The aims of this study were to elucidate the copy number variations (CNVs) of C4A and C4B in relation to disease risk in systemic lupus erythematosus (SLE), and to compare the basis of race-specific C4A deficiency between East Asians and individuals of European descent.The East Asian study population included 999 SLE patients and 1,347 healthy subjects. Variations in gene copy numbers (GCNs) of total C4, C4A, and C4B, as well as C4-Long and C4-Short genes, were determined and validated using independent genotyping technologies. Genomic regions with C4B96 were investigated to determine the basis of the most basic C4B protein occurring concurrently with C4A deficiency.In East Asians, high GCNs of total C4 and C4A were strongly protective against SLE, whereas low and medium GCNs of total C4 and C4A, and the absence of C4-Short genes, were risk factors for SLE. Homozygous C4A deficiency was infrequent in East Asian subjects, but had an odds ratio (OR) of 12.4 (P?=?0.0015) for SLE disease susceptibility. Low serum complement levels were strongly associated with low GCNs of total C4 (OR 3.19, P?=?7.3?×?10(-7) ) and C4B (OR 2.53, P?=?2.5?×?10(-5) ). Patients with low serum complement levels had high frequencies of anti-double-stranded DNA antibodies (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 found to be prevalent in European Americans with C4A deficiency, which was in linkage disequilibrium with HLA-DRB1*0301, was scarce in East Asians. Instead, most East Asian subjects with C4A deficiency were found to have a recombinant haplotype with bimodular C4-Long and C4-Short genes, encoding C4B1 and C4B96, which was linked to HLA-DRB1*1501. DNA sequencing revealed an E920K polymorphism in C4B96.C4 CNVs and deficiency of C4A both play an important role in the risk and manifestations of SLE in East Asian and European populations.

SUBMITTER: Chen JY

PROVIDER: S-EPMC5114127 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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 Ji Yih JY Wu Yee Ling YL Mok Mo Yin MY Wu Yeong-Jian Jan YJ Lintner Katherine E KE Wang Chin-Man CM Chung Erwin K EK Yang Yan Y Zhou Bi B Wang Huanyu H Yu Dennis D Alhomosh Alaaedin A Jones Karla K Spencer Charles H CH Nagaraja Haikady N HN Lau Yu Lung YL Lau Chak-Sing CS Yu C Yung CY

Arthritis & rheumatology (Hoboken, N.J.) 20160601 6

<h4>Objective</h4>Human complement C4 is complex, with multiple layers of diversity. The aims of this study were to elucidate the copy number variations (CNVs) of C4A and C4B in relation to disease risk in systemic lupus erythematosus (SLE), and to compare the basis of race-specific C4A deficiency between East Asians and individuals of European descent.<h4>Methods</h4>The East Asian study population included 999 SLE patients and 1,347 healthy subjects. Variations in gene copy numbers (GCNs) of t ...[more]

PMID: 26814708

Similar Datasets

Project description:Objectives Low copy numbers and deletion of complement C4 genes are potent risk factors for systemic lupus erythematosus (SLE). However, it is not known whether this genetic association affects the clinical outcome. We investigated C4 copy number variation and its relationship to clinical and serological features in a Northern European lupus cohort. Methods We genotyped the C4 gene locus using polymerase chain reaction (PCR)-based TaqMan assays in 169 patients with SLE classified according to the 1997 revised American College of Rheumatology (ACR) criteria and in 520 matched controls. In the patient group the mean C4 serum protein concentrations nephelometrically measured during a 12-month period prior to genetic analysis were compared to C4 gene copy numbers. Severity of disease was classified according to the intensity of the immunosuppressive regimens applied and compared to C4 gene copy numbers, too. In addition, we performed a TaqMan based analysis of three lupus-associated single-nucleotide polymorphisms (SNPs) located inside the major histocompatibility complex (MHC) to investigate the independence of complement C4 in association with SLE. Results Homozygous deficiency of the C4A isotype was identified as the strongest risk factor for SLE (odds ratio (OR)?=?5.329; p?=?7.7?×?10-3) in the case-control comparison. Moreover, two copies of total C4 were associated with SLE (OR?=?3.699; p?=?6.8?×?10-3). C4 serum levels were strongly related to C4 gene copy numbers in patients, the mean concentration ranging from 0.110?g/l (two copies) to 0.256?g/l (five to six copies; p?=?4.9?×?10-6). Two copies of total C4 and homozygous deletion of C4A were associated with a disease course requiring cyclophosphamide therapy (OR?=?4.044; p?=?0.040 and OR?=?5.798; p?=?0.034, respectively). Homozygous deletion of C4A was associated with earlier onset of SLE (median 24 vs. 34 years; p?=?0.019) but not significant after correction for multiple testing. SNP analysis revealed a significant association of HLA-DRB1*0301 with SLE (OR?=?2.231; p?=?1.33?×?10-5). Conclusions Our findings confirm the important role of complement C4 genes in the development of SLE. Beyond the impact on the susceptibility for lupus, C4 copy numbers may be related to earlier onset and a more severe course of the disease. The association of homozygous deletion of C4A and SLE is accompanied by the presence of HLA-DRB1*0301 without a proven pathophysiological mechanism.

Project description:Systemic lupus erythematosus is a chronic autoimmune disease with multifactorial ethiopathogenesis. The complement system is involved in both the early and late stages of disease development and organ damage. To better understand autoantibody mediated complement consumption the GAPAID consortium examined ex vivo immune complex formation on autoantigen arrays. We recruited patients with SLE (n=211), with other systemic autoimmune diseases (n=65) and non-autoimmune control subjects (n=149) in two rheumatology tertiary care centers. Standard clinical and laboratory data were collected from all subjects and serum complement levels were determined in SLE patients. The genotype of SNP rs1143679 in the ITGAM gene was also determined. On-chip formation of immune complexes was examined using a functional immunoassay on autoantigen microarray. The amount of antigen-bound IgM, IgG and complement C4 and C3 was quantified on autoantigens comprising nucleic acids, proteins and lipids. Our results show that the relatively high complement consumption of nucleic acids is further increased upon binding of IgM and IgG. This is true even when serum complement levels are decreased due to complement consumption in SLE patients. A negative correlation between serum complement levels and ex vivo complement deposition on nucleic acid autoantigens is demonstrated. On the contrary, most protein and lipid autoantigens show positive correlation with C4 and C3 levels. Genetic analysis reveals that the non-synonymous variant rs1143679 in complement receptor type 3 is associated with an increased production of anti-dsDNA IgG antibodies. Notwithstanding, homozygous carriers of the previously reported susceptible allele (AA) have lower levels of dsDNA specific IgM among SLE patients. Regarding organ involvement we find that besides anti-C1q IgG, low levels of dsDNA specific IgM and low complement C4 binding to C1q are also associated with renal injury. In summary, nucleic acids maintain a skewed complement deposition balance when bound by IgG and IgM, depleting the early classical complement pathway from other physiological processes. Dysfunction of the receptor responsible for complement-mediated apoptotic debris removal promotes the development of autoantibodies targeting nucleic acids. These observations provide serological and genetic evidence for complement-mediated clearance deficiency of apoptotic debris in lupus.

Dataset Information

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.

Publications

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.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets