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Low copy numbers of complement C4 and homozygous deficiency of C4A may predispose to severe disease and earlier disease onset in patients with systemic lupus erythematosus.
Jüptner, M; Flachsbart, F; Caliebe, A; Lieb, W; Schreiber, S; Zeuner, R; Franke, A; Schröder, J O.
Afiliación
  • Jüptner M; 1 First Clinic of Internal Medicine, University Hospital of Kiel, Kiel, Germany.
  • Flachsbart F; 2 Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
  • Caliebe A; 3 Institute of Medical Informatics and Statistics, Christian-Albrechts-University of Kiel, Kiel, Germany.
  • Lieb W; 4 Institute of Epidemiology, Christian-Albrechts-University of Kiel, Kiel, Germany.
  • Schreiber S; 1 First Clinic of Internal Medicine, University Hospital of Kiel, Kiel, Germany.
  • Zeuner R; 1 First Clinic of Internal Medicine, University Hospital of Kiel, Kiel, Germany.
  • Franke A; 2 Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
  • Schröder JO; 1 First Clinic of Internal Medicine, University Hospital of Kiel, Kiel, Germany.
Lupus ; 27(4): 600-609, 2018 Apr.
Article en En | MEDLINE | ID: mdl-29050534
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Complemento C4a / Eliminación de Gen / Dosificación de Gen / Variaciones en el Número de Copia de ADN / Homocigoto / Lupus Eritematoso Sistémico Tipo de estudio: Diagnostic_studies / Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adult / Aged / Female / Humans / Male / Middle aged País/Región como asunto: Europa Idioma: En Revista: Lupus Asunto de la revista: REUMATOLOGIA Año: 2018 Tipo del documento: Article País de afiliación: Alemania

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Complemento C4a / Eliminación de Gen / Dosificación de Gen / Variaciones en el Número de Copia de ADN / Homocigoto / Lupus Eritematoso Sistémico Tipo de estudio: Diagnostic_studies / Etiology_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adult / Aged / Female / Humans / Male / Middle aged País/Región como asunto: Europa Idioma: En Revista: Lupus Asunto de la revista: REUMATOLOGIA Año: 2018 Tipo del documento: Article País de afiliación: Alemania