Volume: 13, Issue: 4

Preface

Autoimmune Diseases in the Bioinformatics Paradigm

Quan-Zhen Li, Edward K. Wakeland

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Page 205-207

Research Highlight

Metagenome-wide Association Studies Potentiate Precision Medicine for Rheumatoid Arthritis

Yigang Tong

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最近深圳华大基因研究院的王俊、李英睿教授和中国医学科学院北京协和医院张烜教授研究团队在Nature杂志发表一篇人体微生物菌群和类风湿关节炎（RA）之间关系的研究论文，他们采用宏基因组鸟枪法测序和元基因组关联分析（metagenome-wide association study, MGWAS），对正常人群和未经药物治疗的RA病人大型队列进行研究，分析这两类人群粪便、牙菌斑和唾液样本中微生物的元基因组特征，发现二者之间不论是肠道微生物和还是口腔微生物均存在显著差异。通过对RA患者进行抗风湿药物（disease-modifying antirheumatic drugs, DMARDs）治疗，对比治疗前后元基因组差异，发现对治疗有效地患者，其不正常菌群结构得到部分校正，提示人体微生物菌群可能用于风湿性关节炎的辅助诊断和预后判断。该研究还发现，正常人和RA患者在体内氧化还原环境、铁硫锌等矿物元素的转运和代谢方面也存在较大差异，提示微生物菌群及其相关的代谢产物可能在RA的发病机制中发挥重要作用。 虽然微生物组与RA等自身免疫性疾病的关系已经有过报道，本研究首次从人体三个不同的身体部位（肠道、牙菌斑和唾液）比较正常人和大型队列RA患者的微生物菌群。这项研究表明，身体不同部位的微生物组可能作为生物标志物用于RA患者分级以及用于诊断和预后；其次，本文还显示出元基因组关联分析对于RA诊断治疗的意义，可能为类风湿关节炎的个性化临床治疗方案提供基础；最后，本研究还提示，人为修饰人体第二基因组即微生物组，可能有助于治疗某些类似RA的慢性疾病，从而弥补人体先天基因组的不足。

Page 208-209

Review Article

Autoantigen Microarray for High-throughput Autoantibody Profiling in Systemic Lupus Erythematosus

Honglin Zhu, Hui Luo, Mei Yan, Xiaoxia Zuo, Quan-Zhen Li

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the production of autoantibodies to a broad range of self-antigens. Profiling the autoantibody repertoire using array-based technology has emerged as a powerful tool for the identification of biomarkers in SLE and other autoimmune diseases. Proteomic microarray has the capacity to hold large number of self-antigens on a solid surface and serve as a high-throughput screening method for the determination of autoantibody specificities. The autoantigen arrays carrying a wide variety of self-antigens, such as cell nuclear components (nucleic acids and associated proteins), cytoplasmic proteins, phospholipid proteins, cell matrix proteins, mucosal/secreted proteins, glomeruli, and other tissue-specific proteins, have been used for screening of autoantibody specificities associated with different manifestations of SLE. Arrays containing synthetic peptides and molecular modified proteins are also being utilized for identification of autoantibodies targeting to special antigenic epitopes. Different isotypes of autoantibodies, including IgG, IgM, IgA, and IgE, as well as other Ig subtypes, can be detected simultaneously with multi-color labeled secondary antibodies. Serum and plasma are the most common biologic materials for autoantibody detection, but other body fluids such as cerebrospinal fluid, synovial fluid, and saliva can also be a source of autoantibody detection. Proteomic microarray as a multiplexed high-throughput screening platform is playing an increasingly-important role in autoantibody diagnostics. In this article, we highlight the use of autoantigen microarrays for autoantibody exploration in SLE.

Page 210-218

Review Article

Biomarkers for Primary Sjögren’s Syndrome

Weiqian Chen, Heng Cao, Jin Lin, Nancy Olsen, Song Guo Zheng

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease with exocrine gland dysfunction and multi-organ involvement. Recent progress in understanding the pathogenesis of pSS offers an opportunity to find new biomarkers for the diagnosis and assessment of disease activity. Screening noninvasive biomarkers from the saliva and tears has significant potential. The need for specific and sensitive biomarker candidates in pSS is significant. This review aims to summarize recent advances in the identification of biomarkers of Sjögren syndrome, trying to identify reliable, sensitive, and specific biomarkers that can be used to guide treatment decisions.

Page 219-223

Review Article

Biomarkers of An Autoimmune Skin Disease—Psoriasis

Shan Jiang, Taylor E. Hinchliffe, Tianfu Wu

Psoriasis is one of the most prevalent autoimmune skin diseases. However, its etiology and pathogenesis are still unclear. Over the last decade, omics-based technologies have been extensively utilized for biomarker discovery. As a result, some promising markers for psoriasis have been identified at the genome, transcriptome, proteome, and metabolome level. These discoveries have provided new insights into the underlying molecular mechanisms and signaling pathways in psoriasis pathogenesis. More importantly, some of these markers may prove useful in the diagnosis of psoriasis and in the prediction of disease progression once they have been validated. In this review, we summarize the most recent findings in psoriasis biomarker discovery. In addition, we will discuss several emerging technologies and their potential for novel biomarker discovery and diagnostics for psoriasis.

Page 224-233

Review Article

MicroRNAs Regulating Signaling Pathways: Potential Biomarkers in Systemic Sclerosis

Yisha Li, Jing Huang, Muyao Guo, Xiaoxia Zuo

Systemic sclerosis (SSc) is a multisystem fibrotic and autoimmune disease. Both genetic and epigenetic elements mediate SSc pathophysiology. This review summarizes the role of one epigenetic element, known as microRNAs (miRNAs), involved in different signaling pathways of SSc pathogenesis. The expression of key components in transforming growth factor-β (TGF-β) signaling pathway has been found to be regulated by miRNAs both upstream and downstream of TGF-β. We are specifically interested in the pathway components upstream of TGF-β, while miRNAs in other signaling pathways have not been extensively studied. The emerging role of miRNAs in vasculopathy of SSc suggests a promising new direction for future investigation. Elucidation of the regulatory role of miRNAs in the expression of signaling factors may facilitate the discovery of novel biomarkers in SSc and improve the understanding and treatment of this disease.
系统性硬化症是一个表现为多系统纤维化的自身免疫性疾病，其病理生理学改变是有遗传因子和表观遗传学因子共同介导的。本综述总结了表观遗传学因子中的一种——microRNA在参与系统性硬化症致病机制的信号通路中的作用。其中TGF-β信号通路的上游和下游参与分子均受到不同microRNA的调控，特别是microRNA对TGF-β上游分子的调控，对于系统性硬化症的发病机制研究有更加重要的意义。另外，最新的研究提示microRNA参与系统性硬化症微血管病的发病机制，未来在这个方向上有望出现更多有价值的发现。最后，本综述总结microRNA对信号分子的调控作用以及其参与信号通路的方法，目的是为了促进诊断该疾病的生物标志物的发展，从而提高对该疾病的认识和治疗。

Page 234-241

Review Article

Applications of Next-generation Sequencing in Systemic Autoimmune Diseases

Yiyangzi Ma, Na Shi, Mengtao Li, Fei Chen, Haitao Niu

Systemic autoimmune diseases are a group of heterogeneous disorders caused by both genetic and environmental factors. Although numerous causal genes have been identified by genome-wide association studies (GWAS), these susceptibility genes are correlated to a relatively low disease risk, indicating that environmental factors also play an important role in the pathogenesis of disease. The intestinal microbiome, as the main symbiotic ecosystem between the host and host-associated microorganisms, has been demonstrated to regulate the development of the body’s immune system and is likely related to genetic mutations in systemic autoimmune diseases. Next-generation sequencing (NGS) technology, with high-throughput capacity and accuracy, provides a powerful tool to discover genomic mutations, abnormal transcription and intestinal microbiome identification for autoimmune diseases. In this review, we briefly outlined the applications of NGS in systemic autoimmune diseases. This review may provide a reference for future studies in the pathogenesis of systemic autoimmune diseases.
系统性自身免疫病是由遗传和环境因素导致的一类涉及到全身脏器的自身免疫性疾病。虽然已经通过全基因组关联分析法（GWAS）确定了很多致病基因，但这些易感基因只在某种程度上参与了疾病的发病，而不能单独引发疾病，这表明环境因素在系统性自身免疫疾病的发病机制中也可能起重要作用。肠道微生物是与人类共生的主要微生物，并已被证实能调节人体免疫系统发育成熟，同时也可能与系统性自身免疫疾病中的基因突变有关。下一代基因测序技术（NGS）具有高通量和精确性的特点，它为探讨自身免疫病的基因突变、转录异常、肠道微生物鉴定等方面提供了强有力的工具。本文介绍了下一代基因测序技术在系统性自身免疫疾病研究方面的应用，同时也为将来更好地应用该技术研究系统性自身免疫病的发病机制提供了参考。

Page 242-249

Original Research

Novel Y-chromosome Short Tandem Repeat Variants Detected Through the Use of Massively Parallel Sequencing

David H. Warshauer, Jennifer D. Churchill, Nicole Novroski, Jonathan L. King, Bruce Budowle

Massively parallel sequencing (MPS) technology is capable of determining the sizes of short tandem repeat (STR) alleles as well as their individual nucleotide sequences. Thus, single nucleotide polymorphisms (SNPs) within the repeat regions of STRs and variations in the pattern of repeat units in a given repeat motif can be used to differentiate alleles of the same length. In this study, MPS was used to sequence 28 forensically-relevant Y-chromosome STRs in a set of 41 DNA samples from the 3 major U.S. population groups (African Americans, Caucasians, and Hispanics). The resulting sequence data, which were analyzed with STRait Razor v2.0, revealed 37 unique allele sequence variants that have not been previously reported. Of these, 19 sequences were variations of documented sequences resulting from the presence of intra-repeat SNPs or alternative repeat unit patterns. Despite a limited sampling, two of the most frequently-observed variants were found only in African American samples. The remaining 18 variants represented allele sequences for which there were no published data with which to compare. These findings illustrate the great potential of MPS with regard to increasing the resolving power of STR typing and emphasize the need for sample population characterization of STR alleles.

Page 250-257

Original Research

An Old Story Retold: Loss of G1 Control Defines A Distinct Genomic Subtype of Esophageal Squamous Cell Carcinoma

Qiyan Wang, Jian Bai, Amir Abliz, Ying Liu, Kenan Gong, Jingjing Li, Wenjie Shi, Yaqi Pan, Fangfang Liu, Shujuan Lai, Haijun Yang, Changdong Lu, Lixin Zhang, Wei Chen, Ruiping Xu, Hong Cai, Yang Ke, Changqing Zeng

Esophageal squamous cell carcinoma (ESCC) has a high mortality rate. To determine the molecular basis of ESCC development, this study sought to identify characteristic genome-wide alterations in ESCC, including exonic mutations and structural alterations. The clinical implications of these genetic alterations were also analyzed. Exome sequencing and verification were performed for nine pairs of ESCC and the matched blood samples, followed by validation with additional samples using Sanger sequencing. Whole-genome SNP arrays were employed to detect copy number alteration (CNA) and loss of heterozygosity (LOH) in 55 cases, including the nine ESCC samples subjected to exome sequencing. A total of 108 non-synonymous somatic mutations (NSSMs) in 102 genes were verified in nine patients. The chromatin modification process was found to be enriched in our gene ontology (GO) analysis. Tumor genomes with TP53 mutations were significantly more unstable than those without TP53 mutations. In terms of the landscape of genomic alterations, deletion of 9p21.3 covering CDKN2A/2B (30.9%), amplification of 11q13.3 covering CCND1 (30.9%), and TP53 point mutation (50.9%) occurred in two-thirds of the cases. These results suggest that the deregulation of the G1 phase during the cell cycle is a key event in ESCC. Furthermore, six minimal common regions were found to be significantly altered in ESCC samples and three of them, 9p21.3, 7p11.2, and 3p12.1, were associated with lymph node metastasis. With the high correlation of TP53 mutation and genomic instability in ESCC, the amplification of CCND1, the deletion of CDKN2A/2B, and the somatic mutation of TP53 appear to play pivotal roles via G1 deregulation and therefore helps to classify this cancer into different genomic subtypes. These findings provide clinical significance that could be useful in future molecular diagnoses and therapeutic targeting.
为了解食管鳞状细胞癌的基因组变异特征并从中确定关键促癌突变，我们以外显子组测序及全基因组SNPs分型为主，从不同方面解析了其肿瘤基因组变异。整合点突变与大片段变异数据发现，大部分患者（65.45%）中都包含p53通路的体细胞变异，通过破坏其细胞周期调控功能而参与肿瘤的发生发展。与临床数据的相关性分析结果表明，肿瘤基因组的整体不稳定性及部分共有变异区域与淋巴结转移显著相关，并在一定程度上影响患者的术后生存情况。

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