Complement C4 gene copy number variations and polymorphisms, autoantibodies, and clinical manifestations of juvenile dermatomyositis– a multi-center study

Samantha L. Coss, R. Aziz, Danlei Zhou, Bi Zhou, K. Miller, Yee-Ling Wu, S. Ardoin, E. Oberle, K. Driest, O. Al Ahmed, A. Patwardhan, S. Akoghlanian, V. Sivaraman, F. Barbar‐Smiley, Joanne Drew, C. Spencer, L. Pachman, Gabrielle Morgan, Gulnara Mamyrova, R. Curiel, O. Jones, Terry O’Hanlon, L. Rider, F. Miller, L. Padyukov, I. Lundberg, A. Notarnicola, J. Vencovský, B. Stibůrková, O. Kryštůfková, Chack-Yung Yu
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Abstract

Juvenile dermatomyositis (JDM) is an autoimmune myopathy characterized by rash and muscle weakness. Complement C4 gene copy number (GCN) variation is a known risk factor for JDM. JDM patients often develop autoantibodies. We investigated the relationship between C4 GCN, clinical features, and antibody development. Subjects were recruited (n=255) from the US, Sweden, and the Czech Republic. C4 GCN was determined by real time PCR. Comparative analyses were performed via student’s t test or Mann Whitney U test. Correlation was assessed via linear regression or Fisher’s exact test. All studies were IRB approved, and informed consent was obtained. C4 GCN correlated with muscle pathology and extra-muscular disease at diagnosis. Lower C4A and C4L GCN were associated with a higher number of abnormal muscle enzymes (p=0.0062 and p=0.0029), while the opposite was true for C4S (p=0.024). Higher C4S GCN correlated with lower muscle strength scores (p=0.039). Lower C4L correlated with abnormal MRI (p= 0.042). C4B GCN correlated with dysphagia (p=0.035). Higher GCN of C4S was a risk factor for arthritis (p=0.032), systemic symptoms (p=0.020), and dysphagia (p=0.0078). C4 GCN was associated with myositis-specific (MSA) and myositis-associated (MAA) antibodies. Patients with homozygous C4A deficiency were more likely to test positive for anti-NXP2 (OR 20.0, p=0.011), and C4A GCN was lower in anti-NXP2 positive subjects (p=0.030). A higher C4B GCN correlated with positive MAA (p=0.043). Here, we show that low C4A/C4L GCN and high C4B/C4S GCN correlate with worse muscle disease, extra-muscular pathology, and autoantibodies. Our data suggest that complement C4 may play a key role in the ongoing pathogenesis of JDM. Supported by grants from NIH (R21 AR070509) and the CureJM Foundation
补体C4基因拷贝数变异和多态性、自身抗体和青少年皮肌炎的临床表现——一项多中心研究
青少年皮肌炎(JDM)是一种以皮疹和肌肉无力为特征的自身免疫性肌病。补体C4基因拷贝数(GCN)变异是已知的JDM危险因素。JDM患者经常产生自身抗体。我们研究了C4 GCN、临床特征和抗体发展之间的关系。受试者从美国、瑞典和捷克共和国招募(n=255)。C4 GCN采用real - time PCR检测。比较分析采用学生t检验或Mann Whitney U检验。通过线性回归或Fisher精确检验评估相关性。所有研究均经IRB批准,并获得知情同意。C4 GCN与诊断时的肌肉病理和肌外疾病相关。较低的C4A和C4L GCN与较高的异常肌酶数量相关(p=0.0062和p=0.0029),而C4S则相反(p=0.024)。C4S GCN越高,肌力评分越低(p=0.039)。低C4L与MRI异常相关(p= 0.042)。C4B GCN与吞咽困难相关(p=0.035)。C4S GCN增高是关节炎(p=0.032)、全身症状(p=0.020)和吞咽困难(p=0.0078)的危险因素。C4 GCN与肌炎特异性(MSA)和肌炎相关(MAA)抗体相关。纯合子C4A缺乏症患者更容易检测出抗nxp2阳性(OR为20.0,p=0.011),抗nxp2阳性患者的C4A GCN较低(p=0.030)。较高的C4B GCN与MAA阳性相关(p=0.043)。在这里,我们发现低C4A/C4L GCN和高C4B/C4S GCN与更严重的肌肉疾病、肌肉外病理和自身抗体相关。我们的数据表明,补体C4可能在JDM的持续发病机制中发挥关键作用。由NIH (R21 AR070509)和curem基金会资助
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