Identification of quantitative trait loci for murine autoimmune pancreatitis
Identification of quantitative trait loci for murine autoimmune pancreatitis
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DOI：
10.1136/jmg.2011.089730
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发表时间：
2011-08-01
影响因子：
4
通讯作者：
Jaster, Robert
中科院分区：
文献类型：
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作者：
Asghari, Farahnaz;Fitzner, Brit;Jaster, Robert
背景和目的自身免疫性胰腺炎（AIP）是一种罕见但临床相关的胰腺炎症原因。以MRL/Mp小鼠作为自发性AIP模型，研究了该病的遗传基础。方法以MRL/MpJ亲本小鼠和Cast（健康对照）、BXD2（胶原诱导关节炎易感小鼠）和NZM（红斑狼疮模型小鼠）为材料，建立AIP高级杂交系，鉴定AIP的数量性状位点（QTL）。选择这一概念来确定一般自身免疫性疾病相关位点和AIP特异性QTL。因此，本研究通过胰腺组织病理学变化评分对G4代远交系小鼠进行表型表征，并采用单核苷酸多态性（SNP）阵列进行基因分型。使用HAPPY的R实现对数据进行分析。结果鉴定出5个与AIP严重程度相关的qtl。其中两个映射到4号染色体，一个分别映射到2号、5号和6号染色体。6号染色体上的QTL显示出最高的LOD评分（5.4），在其峰值区域包含c型凝集素结构域家族4成员a2，该区域编码树突状细胞的受体蛋白，该蛋白先前与自身免疫性疾病（如干燥综合征）有关。其他QTL的AIP候选基因包括异质核糖核蛋白A3；核因子，红系衍生2，似2；干燥综合征抗原B；泛素蛋白连接酶E3组分n-识别蛋白3。结论本研究确定了小鼠AIP的qtl和候选基因。它们的功能作用及其与人类AIP的相关性将进一步研究。
Background and aims Autoimmune pancreatitis (AIP) represents a rare but clinically relevant cause of pancreatic inflammation. Using MRL/Mp mice as a model of spontaneous AIP, the genetic basis of the disease was studied.Methods To identify quantitative trait loci (QTL) of AIP, an advanced intercross line was studied, originating from MRL/MpJ parental mice and the following three mouse strains: Cast (healthy controls), BXD2 (susceptible to collagen induced arthritis), and NZM (a model of lupus erythematosus). This concept was chosen to identify both general autoimmune disease associated loci and AIP specific QTL. Therefore, generation G4 of outbred intercross mice was characterised phenotypically by scoring histopathological changes of the pancreas and genotyped with single nucleotide polymorphism (SNP) arrays. Data were analysed with the R implementation of HAPPY.Results Five QTLs, correlating with the severity of AIP, were identified. Two of them mapped to chromosome 4 and one to chromosomes 2, 5, and 6, respectively. The QTL on chromosome 6 displays the highest LOD score (5.4) and contains the C-type lectin domain family 4 member a2 in its peak region, which encodes a receptor protein of dendritic cells that has previously been implicated in autoimmune diseases such as Sjogren's syndrome. AIP candidate genes of other QTL's include heterogeneous nuclear ribonucleoprotein A3; nuclear factor, erythroid derived 2, like 2; Sjogren syndrome antigen B; and ubiquitin protein ligase E3 component n-recognin 3.Conclusions This study has identified QTLs and putative candidate genes of murine AIP. Their functional role and relevance to human AIP will be studied further.