THE ROLE OF THE PARP GENE IN SLE SUSCEPTIBILITY

PARP 基因在 SLE 易感性中的作用

• 批准号: 2902183
• 负责人: BETTY P TSAO
• 金额: $ 10万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2001-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2902183
• 关键词: DNA repair; apoptosis; clinical research; enzyme activity; enzyme structure; family genetics; genetic polymorphism; genetic promoter element; genetic susceptibility; human subject; nucleotidyltransferase; polymerase chain reaction; posttranslational modifications; protein biosynthesis; single strand conformation polymorphism; systemic lupus erythematosus

Cumulative evidence has suggested that genetic predisposition contributes to susceptibility to systemic lupus erythematosus (SLE). The search of SLE susceptibility genes has involved mainly testing functionally relevant genes as candidates in population-based association studies. Because positive association may occur as an artifact of population admixture, the addition of linkage analysis offers more compelling evidence for susceptibility genes based on physical locations. We previously reported evidence for linkage of SLE to a 15 cM region on chromosome 1q41-q42. Within this interval, there are several candidate genes including PARP and HLX1 which encode poly(ADP-ribose)polymerase (PARP) and a homeo box protein, respectively. Using a family-based association test, we have recently observed evidence for association of PARP (but not HLX1) alleles with SLE in 124 families containing offspring afflicted with SLE (p= 0.00008 by the multi-allele transmission-disequilibrium test), and thus suggesting a role of PARP in SLE susceptibility. Previously PARP was also implicated in SLE based on its lower than normal range of activity in SLE patients, its intermediate range of activity in unaffected family members of SLE patients, and its decreased mRNA levels in SLE patients. Abnormal DNA repair has been reported in SLE patients. These multiple lines of evidence has led us to hypothesize that PARP is an SLE susceptibility gene. PARP is activated by DNA strand breaks which transfers ADP-ribose residues from NAD to nuclear proteins involved in various chromatin functions including DNA repair. It is specifically cleaved by caspase-3 induced during apoptosis. This proposal tests whether allelic variation of PARP causes functional variation to account for heritable differences in SLE susceptibility primarily using EBV-transformed cell lines from SLE patients and their family members. This PARP polymorphism is a simple sequence repeat (SSR) within the promoter, and thus may affect levels of mRNA and protein expression. It is also likely that this polymorphism represents a marker in linkage disequilibrium with other polymorphism(s) influencing PARP activity. We propose to 1) study PARP expression in individuals homozygous for the SLE-associated allele and individuals with other alleles by comparing levels of protein, mRNA, promoter activity, and post-translational modification, 2) characterize allelic variation of PARP activity and the related DNA repair, 3) study allelic variation of apoptotic cleavage of PARP upon induction, and 4) define the structural basis of any observed variation of PARP. In summary, our proposed study will assess whether allelic variation of PARP causes quantitative variation in expression, enzyme activity, sensitivity as a substrate, and DNA repair which may contribute to SLE susceptibility. Results from this study will support (or refute) a role of PARP in SLE susceptibility.

累积证据表明，遗传易感性有助于对系统性红斑狼疮（SLE）的敏感性。 在基于人群的关联研究中，对SLE敏感性基因的搜索主要涉及与功能相关的基因作为候选者。 由于可能是作为种群混合物的伪像的阳性关联，因此链接分析的添加为基于物理位置的敏感性基因提供了更有说服力的证据。 我们先前报道了SLE与1q41-Q42染色体上15 cm区域连接的证据。 在此间隔内，有几个候选基因，包括PARP和HLX1，它们分别编码聚（ADP-核糖）聚合酶（PARP）和HONEO BOX蛋白。 使用基于家庭的关联测试，我们最近观察到了PARP（但不是HLX1）等位基因与SLE相关的证据，其中124个含有SLE的后代的家族（由多等位基因传输区传播区测试P = 0.00008），因此暗示了PARP在SLE敏感性中的作用。 以前的PAR在SLE患者中还基于其低于正常活性的SLE，其中间活性范围的SLE患者的活性范围以及SLE患者的mRNA水平降低。 SLE患者据报道了DNA的异常修复。这些多种证据使我们假设PARP是SLE敏感性基因。 PARP被DNA链断裂激活，这些断裂将ADP-核糖残基从NAD转移到参与包括DNA修复在内的各种染色质功能的核蛋白。 它被凋亡过程中caspase-3特别裂解。 该提案测试PARP的等位基因变化是否导致功能变化来解释SLE患者及其家人EBV转换的细胞系中SLE敏感性的可遗传差异。 该PARP多态性是启动子中简单的序列重复（SSR），因此可能影响mRNA和蛋白质表达的水平。 这种多态性也可能代表了连锁不平衡与影响PARP活性的其他多态性的标记。 我们提出1）研究个体中与SLE相关等位基因和其他等位基因的个体的个体中的PARP表达，通过比较蛋白质，mRNA，启动子活性和翻译后修饰的水平，2）表征PARP活性的等位基因变化和相关DNA修复的相关DNA修复，3）研究的构造构成构图的构造质量变化的变化，3）降低的构造和4个。 par。 总而言之，我们提出的研究将评估PARP的等位基因变化是否会导致表达，酶活性，敏感性作为底物和DNA修复的定量变化，这可能导致SLE敏感性。 这项研究的结果将支持（或驳斥）PARP在SLE敏感性中的作用。

项目成果

Familiality and co-occurrence of clinical features of systemic lupus erythematosus.

系统性红斑狼疮临床特征的家族性和共现性。

• DOI: 10.1002/art.10519
• 发表时间: 2002
• 期刊: Arthritis and rheumatism
• 作者: Tsao,BettyP;Grossman,JenniferM;Riemekasten,Gabriela;Strong,Noel;Kalsi,Jatinderpal;Wallace,DanielJ;Chen,Chung-Jen;Lau,ChakS;Ginzler,EllenM;Goldstein,Rose;Kalunian,KennethC;Harley,JohnB;Arnett,FrankC;Hahn,BevraH;Cantor,
• 通讯作者: Cantor,