Gene copy-number variations (CNVs) of complement C4 and C4A deficiency in genetic risk and pathogenesis of juvenile dermatomyositis.
Gene copy-number variations (CNVs) of complement C4 and C4A deficiency in genetic risk and pathogenesis of juvenile dermatomyositis.
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DOI：
10.1136/annrheumdis-2015-207762
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发表时间：
2016-09
影响因子：
27.4
通讯作者：
Yu CY
中科院分区：
文献类型：
--
作者：
Lintner KE;Patwardhan A;Rider LG;Abdul-Aziz R;Wu YL;Lundström E;Padyukov L;Zhou B;Alhomosh A;Newsom D;White P;Jones KB;O'Hanlon TP;Miller FW;Spencer CH;Yu CY
补体介导的肌肉和皮肤血管病变是幼年皮肌炎(JDM)的临床特征。我们评估补体C4及其亚型C4a和C4b的基因拷贝数变异(CNV)在JDM的遗传风险和发病机制中的作用。研究人群包括105名JDM患者和500名健康的欧洲美国人。用Southern杂交和聚合酶链式反应检测C4、C4a、C4b和人类白细胞抗原-DRB1基因拷贝数(GCNS)。用流式细胞仪检测红细胞活化产物C4D的含量。利用PAX基因全血RNA对19例JDM患者和7例正常对照进行了基因表达谱芯片检测。通过定量聚合酶链式反应验证所选基因的差异表达水平。JDM组和对照组的GCNs显著降低，GCN组总C4和C4a的分布存在差异。在HLADR3阳性的受试者中，JDM患者C4a的Gcn仍然较低(p=0.015)。纯合子或杂合子C4a缺乏组为40.0%，对照组为18.2%[优势比(OR)=3.0(1.87~4.79)，p=8.2×10−6]。JDM组E-C4D水平高于对照组(P=0.004)。在JDM中，C4a缺乏的受试者E-C4D水平较高(p=0.0003)，确诊时多种血清肌酶水平升高的频率较高(p=0.004)。血液RNA芯片图谱显示，在JDM患者中，I型干扰素刺激基因上调，T细胞和趋化因子功能基因转录丰度较低，但在C4a缺乏或DR3阳性患者中这一点不那么明显。补体C4a缺乏似乎是JDM遗传风险和发病机制的重要因素，特别是在DR3阳性背景的患者中。
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. 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. 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. 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.