Grigoryev Dmitry N, Dalal Jignesh, Becker Mara L, Ye Shui Q
Division of Experimental and Translational Genetics, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, MO, USA.
BMC Hematol. 2014 Mar 22;14(1):7. doi: 10.1186/2052-1839-14-7.
Chronic graft-versus-host disease (cGVHD) is a major factor of morbidity and mortality for allogeneic stem cell transplantation (aSCT). The skin and internal organ involvement is the most common systemic complication of cGVHD and closely resembles systemic sclerosis (SSc). Circulating lymphocytes characterize the autoimmune nature of both conditions. Therefore we hypothesized that the common clinical manifestation (systemic organ and skin injury) and the common underlying players (lymphocytes) justify the combined meta-analysis of these diseases.
The aSCT and SSc datasets were uploaded from Gene Expression Omnibus (GEO), a public functional genomics data repository. The available microarray studies of peripheral blood mononuclear cells (PBMCs) and isolated lymphocytes were limited to well established microarray platforms (Affymetrix, Agilent, Canvac, and Illumina) and experimental settings with ≥10 patients per group. The resulting pools of data were merged by unique gene identifier and analyzed by the expression genome-wide association studies (eGWAS) coupled with the subtraction of the cGVHD+ and cGVHD- molecular signatures. The eGWAS was applied to 47 and 50 lymphocyte profiles from aSCT and SSc patients, respectively. The identified 35 candidates were represented by 8 known cGVHD genes (including CXCR4, LTBR and PML) and 28 new candidate genes (including SEPX1 and DNJGB1). The further mutual subtraction of cGVHD+ and cGVHD- candidates and pathway analysis identified a list of 25 genes. Seven of these genes belong to the fibroblast development and function pathway, consisting of the well known cGVHD genes CCND1, JUN, and FOS, and the new molecular targets MMP2, FOSB, TNFAIP8, and DUSP1. These genes become primary candidates for a potential link of systemic effects of cGVHD and SSc.
We designed a new approach for meta-analysis by combining data from different diseases using common clinical manifestation as a linker. This allowed us to power up the insufficient standalone meta-analysis of aSCT microarray studies, by adding SSc samples to the data pool. This new method has successfully identified novel molecular targets for systemic effects of both aSCT and SSc. We believe that this approach is generalizable and can be applied to an array of diseases with common clinical manifestations.
慢性移植物抗宿主病（cGVHD）是异基因干细胞移植（aSCT）发病和死亡的主要因素。皮肤和内脏器官受累是cGVHD最常见的全身并发症，与系统性硬化症（SSc）极为相似。循环淋巴细胞是这两种疾病自身免疫性质的特征。因此，我们推测共同的临床表现（全身器官和皮肤损伤）以及共同的潜在因素（淋巴细胞）证明了对这些疾病进行联合荟萃分析的合理性。
aSCT和SSc数据集从公共功能基因组学数据存储库基因表达综合数据库（GEO）上传。外周血单核细胞（PBMC）和分离淋巴细胞的现有微阵列研究仅限于成熟的微阵列平台（Affymetrix、Agilent、Canvac和Illumina）以及每组≥10名患者的实验设置。通过独特的基因标识符合并所得数据集，并通过全基因组表达关联研究（eGWAS）以及减去cGVHD +和cGVHD -分子特征进行分析。eGWAS分别应用于aSCT和SSc患者的47个和50个淋巴细胞谱。鉴定出的35个候选基因由8个已知的cGVHD基因（包括CXCR4、LTBR和PML）和28个新的候选基因（包括SEPX1和DNJGB1）代表。对cGVHD +和cGVHD -候选基因的进一步相互减法和通路分析确定了一个25个基因的列表。这些基因中的7个属于成纤维细胞发育和功能通路，由已知的cGVHD基因CCND1、JUN和FOS以及新的分子靶点MMP2、FOSB、TNFAIP8和DUSP1组成。这些基因成为cGVHD和SSc全身效应潜在联系的主要候选基因。
我们设计了一种新的荟萃分析方法，以共同的临床表现为纽带合并来自不同疾病的数据。通过将SSc样本添加到数据池中，这使我们能够增强aSCT微阵列研究中单独进行的不足的荟萃分析。这种新方法已成功鉴定出aSCT和SSc全身效应的新分子靶点。我们相信这种方法具有普遍性，可应用于一系列具有共同临床表现的疾病。
