Arth & Rheu：遗传性红斑狼疮的治疗关键在于个体化治疗

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来源：生物谷 2014-08-22 09:187 j3 _7 b) ?* ?$ o
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( c9 G( K, j5 ~# l1 {3 s+ J2014年8月22日 讯 /生物谷BIOON/ --医学研究人员利用DNA测序确定基因变异是引起年轻病人得红斑狼疮的原因。研究首次表明，通过使用DNA测序鉴别病人得狼疮的个人原因是可行的，因而应让医生对具体患者进行具体治疗。狼疮是一种慢性自身免疫性疾病，它影响了七百分之一的澳大利亚人，主要群体是年轻人和中年妇女。医学研究者们研究了一个年轻女孩的基因序列，结果显示当她四岁时由于狼疮而得了中风。
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“我们现在可以靶向治疗她的特殊疾病，通过治疗会使她在生活中受益。” Julia Ellyard博士说。研究人员在TREX1基因中发现了一个变异体，这种突变会引起病人细胞产生一种名为α干扰素的分子。临床试验在成人体内已经进行了α干扰素药物的试行。
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& j( }3 h9 o( g& Y9 GJeff Chaitow博士说他的一个年幼的病人现在才10岁，但仍然需要每天定期服用类固醇和免疫抑制药物。“新的靶向治疗的一个主要好处在于能控制她的病情，”他说。Carola Vinuesa教授表示，研究显示狼疮主要是由于一个或几个基因中有缺陷而导致的。她说：“这是个体化医疗的新时代，这项研究有可能解开狼疮的深入机理和由于个体遗传原因而导致的个体不同”。& k7 Q# t* D1 O& g5 W8 ]9 D. ?

. `0 I2 D; g5 B“红斑狼疮是一种异质性疾病，患者可以伴有很多不同的症状。我们相信有很多不同的狼疮遗传原因。理解这些个体中有缺陷的基因和通路有助于调整治疗方法。” Matthew Cook教授说，“该结果证明了个体化医疗的潜在好处，医生可以靶向治疗个体患者。我们乐观地认为这是一系列复杂的免疫疾病的一种新的诊断和治疗方法的证据和原则。”这项研究结果发表在《关节炎和风湿病学》期刊上。（生物谷Bioon.com）
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doi:10.1002/art.38824
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PMID:
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; Z& C- K3 t% F' M, _$ V3 @2 ?Whole exome sequencing in early-onset cerebral SLE identifies a pathogenic variant in TREX1& Q1 L. v. m& w+ v4 `5 C

& p% t' W5 z* }9 I6 [Julia I Ellyard1,*, Rebekka Jerjen1, Jaime L Martin1, Adrian Lee1, Matthew A Field2, Simon H Jiang1,3, Jean Cappello1, Svenja K Naumann1, T Daniel Andrews2, Hamish S Scott4, Marco G Casarotto5, Christopher C Goodnow2, Jeffrey Chaitow6, Virginia Pascual7, Paul Hertzog8, Stephen I Alexander9, Matthew C Cook2,10,† andCarola G Vinuesa1,† 7 k- R2 x( q  P" B% i! c% O3 V  Z+ M
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6 t$ D3 `5 v$ e: a- X) k/ {. vObjective: Systemic lupus erythematosus (SLE) is a chronic and heterogeneous autoimmune disease. Both twin and sibling studies indicate a strong genetic contribution to lupus, but in the majority of cases the pathogenic variant remains to be identified. The genetic contribution to disease is likely to be greatest in cases with early onset and severe phenotypes. Whole exome sequencing now offers the possibility of identifying rare alleles responsible for disease in such cases. Methods: We performed whole exome sequencing in a 4-year-old female with early-onset SLE and conducted biochemical analysis of the putative defect. Results: Whole exome sequencing of a 4-year-old female with cerebral lupus identified a rare, homozygous mutation in the Three Prime Repair Exonuclease 1 (TREX1) that was predicted to be highly deleterious. The TREX1 R97H mutant protein had a 20-fold reduction in exonuclease activity and was associated with an elevated IFN-α signature in the patient. The discovery and characterization of a pathogenic TREX1 in our proband has therapeutic implications: the patient is now a candidate for neutralizing anti-IFN-α therapy. Conclusion: Our study is the first to demonstrate that whole exome sequencing can be used to identify rare or novel deleterious variants as genetic causes of SLE and, through a personalized approach, improve therapeutic options. © 2014 American College of Rheumatology." o# N( w9 s4 H, u6 y2 j5 d% A7 Y