多种自身免疫性疾病的基因重叠也许能揭示一般疗法——基因专家带头研究遗传结构，着眼于再利用现有的药物

正文：

有科学家分析研究了包含10种自身免疫性疾病的基因，这些基因始于童年，现已发现22种全组基因信号由两个或多个疾病共享。这些共享的基因位点也许能揭示潜在的新型靶向治疗，在某些情况下用于非自身免疫系统障碍的现有药物也可用于治疗。

自身免疫系统疾病，比如1型糖尿病、节段性肠炎和幼年特发性关节炎，共同影响着7 - 10%的西半球人口。

“我们所做的不止是发现一组疾病的相关联基因，”研究带头人，医学博士，费城儿童医院应用基因组学中心主任Hakon Hakonarson, 说到。“我们鉴定了这些疾病的生物相关系的基因，每种基因的网络与通路，这对靶向治疗的研究非常有用。”

该论文发表于《自然医学》杂志上。

这个国际研究小组使用了一种元分析技术，该技术包括，含有自身免疫性疾病6035例和10700例病例对照研究，研究对象都是欧洲人。这项研究的首席分析师，Yun (Rose) Li，宾夕法尼亚大学和应用基因组学中心的博士研究生，指导老师为Hakonarson和他的研究小组。应用高度创新和综合的方法来分析这些疾病的致病机理。

该研究包含临床上明显的发生在儿童时期的10种自身免疫性疾病：1型糖尿病、脂泻病、幼年特发性关节炎、常见变异型免疫缺陷病、系统性红斑狼疮、节段性回肠炎、溃疡性结肠炎、牛皮癣、自我免疫性甲状腺炎和强直性脊柱炎。

由于这些疾病当中许多都有家族遗传倾向，以及有的病人有不止一种的自身免疫性疾病，临床医生一直疑虑着这些情况是否暗示着共享基因遗传倾向。以前的全基因组关联研究已经鉴定了上百种自身免疫性疾病的易感基因在很大程度上影响成年人。

目前的研究是一个发病于儿童的多种疾病的同步系统分析。该研究小组在检查疾病时发现了27种全基因组基因点，包括5种新型的基因点。这些27种信号中，22种由两种或两种以上的自身免疫性疾病共同拥有，其中的17种由至少三种以上的自身免疫性疾病共同拥有。

“许多研究者发现的基因信号都存在于与细胞的激活、细胞增殖及免疫过程中重要的信令方式有关的生物通路中。在中新型的信号中，有一种与CD40LG基因相邻，这是尤其引人注目的”，Hakonarson说到，“该基因编码了CD40的受体的配体，这与节段性回肠炎疾病相关。这个配合基体也许能揭示另一种有前景的药物靶向治疗。”

在这27种研究人员发现的基因之中，许多都有自身免疫性疾病过程生物相关性，Hakonarson说，“不仅要着眼于全体基因的整体表达，我们还把研究焦点放在了这些基因在特定的细胞类型和组织中，是如何调整塔们的表达的，以便发现特定疾病的直接相关的表达模式。比如，在这些疾病中，我们发现基因在B细胞中表达得较强。在红斑狼疮和幼年特发性关节炎中，最显著的就是B细胞机能障碍，我们可以设计一种治疗法案来降低这些细胞的过度表达。”

他还说到，“研究小组发现的粒度级别，将给研究者们提供一个更好的特定自身免疫系统疾病靶向基因网络与通路研究方向。通过再利用现有的药物，再结合我们的研究，也许能够找到一种能够很好的调节的药物。”

文章来源：

该文资料来源于费城儿童医院。

文章来源：Science Daily

翻译：“觅健”社区

转载请注明来源“觅健”社区

Genetic overlapping in multiple autoimmune diseases may suggest common therapies

Genomics expert leads analysis of genetic architecture, with eye on repurposing existing drugs

• Date:

• August 24, 2015

• Source:

• Children's Hospital of Philadelphia

• Summary:

• Scientists who analyzed the genes involved in 10 autoimmune diseases that begin in childhood have discovered 22 genome-wide signals shared by two or more diseases. These shared gene sites may reveal potential new targets for treating many of these diseases, in some cases with existing drugs already available for non-autoimmune disorders.

Scientists who analyzed the genes involved in 10 autoimmune diseases that begin in childhood have discovered 22 genome-wide signals shared by two or more diseases. These shared gene sites may reveal potential new targets for treating many of these diseases, in some cases with existing drugs already available for non-autoimmune disorders.

Autoimmune diseases, such as type 1 diabetes, Crohn's disease, and juvenile idiopathic arthritis, collectively affect 7 to 10 percent of the population in the Western Hemisphere.

"Our approach did more than finding genetic associations among a group of diseases," said study leader, Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children's Hospital of Philadelphia (CHOP). "We identified genes with a biological relevance to these diseases, acting along gene networks and pathways that may offer very useful targets for therapy."

The paper appears online today in Nature Medicine.

The international study team performed a meta-analysis, including a case-control study of 6,035 subjects with automimmune disease and 10,700 controls, all of European ancestry. The study's lead analyst, Yun (Rose) Li, an M.D./Ph.D. graduate student at the University of Pennsylvania and the Center for Applied Genomics, mentored by Hakonarson and his research team, applied highly innovative and integrative approaches in supporting the study of pathogenic roles of the genes uncovered across multiple diseases.

The research encompassed 10 clinically distinct autoimmune diseases with onset during childhood: type 1 diabetes, celiac disease, juvenile idiopathic arthritis, common variable immunodeficiency disease, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, psoriasis, autoimmune thyroiditis and ankylosing spondylitis.

Because many of these diseases run in families and because individual patients often have more than one autoimmune condition, clinicians have long suspected these conditions have shared genetic predispositions. Previous genome-wide association studies have identified hundreds of susceptibility genes among autoimmune diseases, largely affecting adults.

The current research was a systematic analysis of multiple pediatric-onset diseases simultaneously. The study team found 27 genome-wide loci, including five novel loci, among the diseases examined. Of those 27 signals, 22 were shared by at least two of the autoimmune diseases, and 19 of them were shared by at least three of them.

Many of the gene signals the investigators discovered were on biological pathways functionally linked to cell activation, cell proliferation and signaling systems important in immune processes. One of the five novel signals, near the CD40LG gene, was especially compelling, said Hakonarson, who added, "That gene encodes the ligand for the CD40 receptor, which is associated with Crohn's disease, ulcerative colitis and celiac disease. This ligand may represent another promising drug target in treating these diseases."

Many of the 27 gene signals the investigators uncovered have a biological relevance to autoimmune disease processes, Hakonarson said. "Rather than looking at overall gene expression in all cells, we focused on how these genes upregulated gene expression in specific cell types and tissues, and found patterns that were directly relevant to specific diseases. For instance, among several of the diseases, we saw genes with stronger expression in B cells. Looking at diseases such as lupus or juvenile idiopathic arthritis, which feature dysfunctions in B cells, we can start to design therapies to dial down over-expression in those cells."

He added that "the level of granularity the study team uncovered offers opportunities for researchers to better target gene networks and pathways in specific autoimmune diseases, and perhaps to fine tune and expedite drug development by repurposing existing drugs, based on our findings."

Story Source:

The above post is reprinted from materials provided by Children's Hospital of Philadelphia. Note: Materials may be edited for content and length.