Genetics and pathophysiology of systemic lupus erythematosus in global populations

全球人群系统性红斑狼疮的遗传学和病理生理学

• 批准号: 10928015
• 负责人: Laura Lewandowski
• 金额: $ 96.23万
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10928015
• 关键词: Acceleration; Adult; Affect; Age; Autoimmune Diseases; Bioinformatics; Biological; Biological Process; Childhood; Clinical; Collaborations; Collection; Complex; Country; DNA Repair Gene; Data; Data Analyses; Disease; Disparity; Equilibrium; European ancestry; Event; Family; Foundations; Functional disorder; Genes; Genetic; Genetic Risk; Genetic Structures; Genetic study; Genome; Goals; Heritability; Individual; International; Investigation; Life; Link; Lupus; Maps; Methodology; Molecular Diagnosis; Movement; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; Natural History; Nephritis; Onset of illness; Parents; Pathogenesis; Pathway Analysis; Pathway interactions; Patient Selection; Patients; Phenotype; Population; Population Heterogeneity; Predisposition; Process; Proteins; Protocols documentation; Reporting; Research; Research Personnel; Risk; Role; Sample Size; Sampling; Severity of illness; Siblings; Single Nucleotide Polymorphism; Site; Susceptibility Gene; System; Systemic Lupus Erythematosus; Testing; Twin Multiple Birth; Validation; Variant; Work; adolescent patient; age group; bioinformatics pipeline; causal variant; clinical phenotype; cohort; early onset; exome sequencing; genetic architecture; genetic association; genetic variant; genome sequencing; genome wide association study; genome-wide; health disparity; human disease; insight; molecular phenotype; next generation sequencing; novel; participant enrollment; patient stratification; polygenic risk score; protein function; rare variant; risk variant; targeted treatment; tool; transmission process; variant of interest; whole genome

This unit is focused on understanding how rare genetic variants contribute to systemic lupus erythematosus (SLE) pathogenesis in a diverse cohort of early-onset SLE patients. We also aim to understand the genetic architecture of childhood-onset SLE (cSLE) in a large cohort of patients worldwide. We have established collaborations with cSLE researchers in four countries. In doing so, we were able to perform whole genome sequencing on more than 500 childhood and adult onset SLE patients worldwide, and in many cases also collect samples from unaffected relatives. Using this collection, we are beginning to identify rare variants which may be important to refine the heterogenous clinical phenotype of cSLE into precise molecular phenotypes. Additionally, with whole genome data, we can better understand the comprehensive genetic architecture of these patients. With these data, we will be able to define the burden of both rare and common variants in these patients and try to understand the balance in different pediatric age groups and ancestral backgrounds. Defining the genetic architecture of SLE will help us to further understand the role of genetics in disease onset and severity in the pathogenesis of this complex disease. Our study aims to include patients of diverse ages and ancestral backgrounds, as previous studies have focused on mostly patients of European ancestry and of very early onset of disease. In addition, through collaboration, we are aiming to understand more about the clinical spectrum of cSLE. Rare Variant Analysis of childhood-onset SLE Whole genome data have remarkable capacity for discovery of variation causing disease across the genome. Yet whole genome sequencing (WGS) studies yield massive amounts of variant data, and it can be difficult to identify causative variants. Trio analysis of unaffected parents and affected patients or multiplex families allows more effective variant prioritization. We have collected and sequenced 443 cSLE patients and 170 parents, of which 50 were parent/patient trios from diverse ancestral backgrounds. We have prioritized rare variants through bioinformatic pipelines to first focus on those with a large effect on protein function. We have identified the first variants of interest. We are in the process of sequencing 270 additional SLE patients and we are continuing analysis of these samples over the coming year. We are currently growing our collaborative network to include more cSLE patients nationally and internationally. Additional sequencing efforts will allow us to increase sample size, which increases potential for discovery but also for validation of important variants. Sequencing patients across a wider age range will help us understand more about the genetic contribution of SLE along the continuum of age at disease onset. Importantly, the foundation for analysis of whole genome data in a diverse cSLE cohort has been established with this initial data analysis. Therefore, subsequent studies will be accelerated by benefitting from the robust methodology we have developed. Pathway Analysis of Rare Variants Enriched in cSLE In addition, we will conduct pathway analysis at the cohort level to understand not only individual variants, but important biologic processes that contribute to SLE pathogenesis. Historically, studies have focused on unrelated individuals who share variants in individual genes. However, this approach doesnt consider that rare variants in SLE could cluster in genes participating in related biological processes. We performed genome sequencing in a diverse cohort of cSLE patients and parental controls, and describe a network-of-pathways approach to identify biological pathways enriched in genes with rare variants that may contribute to cSLE pathogenesis. Network analysis is a useful approach to identify biological pathways and specific genes that could contribute to cSLE risk. Ongoing detailed analysis of the specific variants identified in each pathway will allow us to prioritize key genes and pathways for further study. In total, this analysis may contribute to advancing the understanding of cSLE beyond a broad clinical phenotype and towards a more precise molecular diagnosis. Genetic Architecture of SLE The pathogenesis of SLE is not fully understood but thought to be triggered by environmental events in a genetically susceptible individual. Whole exome sequencing (WES) and WGS are powerful tools for researchers elucidating genetic variants linked to human diseases. Many genome-wide association studies (GWAS) have been done in SLE, however only a few WES/WGS studies reported rare, highly penetrant genetic variants with a large impact on protein function. In addition to rare variant analysis, whole genome data can be mined for common variants described to confer risk for SLE by studying common variants. To understand the genetic architecture of cSLE, we first used transmission disequilibrium testing (TDT) for the families for whom we had complete trios (n=42). TDT is a family-based genetic association analysis that employs robust methodology, and our group was the first to use it to analyze whole genome sequencing data in SLE. We used both single nucleotide variant (SNV) based analysis to assess common variation and a gene-based analysis to detect rare variants. Our SNV-based analysis did not return any genome-wide significant SNVs. The rare variant gene-based TDT analysis identified many novel genes significantly enriched in cSLE patients, including HNRNPUL2, a DNA repair protein, and DNAH11, a ciliary movement protein, among others. Our approach identified several novel SLE susceptibility genes in an ancestrally diverse childhood-onset lupus cohort, adding to the evidence that the cSLE population is enriched in rare variants which contribute to disease. Another approach to understand genetic architecture is to assess the burden of known rare and common SLE risk variants in our cSLE population. A cumulative genetic risk score can describe the burden of common risk variants carried within a cohort of patients. Previous studies have determined that earlier onset of disease is associated with higher polygenic risk score (PRS). A study in cSLE showed that a higher score is associated with severe manifestations such as nephritis. No studies compiling a PRS from whole genome data in cSLE patients have been completed to date. This will be the first study to investigate the burden of both rare and common variants in a cSLE patient cohort compared to unaffected relatives. The current paradigm for genetic risk in cSLE is that the burden of rare and common SLE risk variants is inversely related in patients, with younger and more severe patients having a higher burden of rare, damaging variants but a low burden of common milder variants. Inversely, adolescent patients and those with milder phenotypes are expected to have a higher burden of common SLE risk variants and few rare variants. However, the actual distribution and balance between rare and common variants in cSLE patients have not been reported. We have completed an assessment of the burden of common risk variants for SLE in our diverse cohort of 83 cSLE patients using a weighted polygenic risk score. We will map the balance of known common and rare SLE risk variants in our cSLE cohort using whole genome data. We will compare the burden of common variants of the patients to those of their unaffected parents. We have performed WGS on 545 SLE patients and 170 unaffected relatives to date. Sequencing patients across a wider age range will help us understand more about the genetic contribution of SLE along the continuum of age at disease onset. Importantly, the foundation for analysis of whole genome data in a diverse cSLE cohort has been established with this initial data analysis.

该单元的重点是了解罕见的遗传变异如何在多种早期发作的SLE患者队列中对全身性红斑狼疮（SLE）发病机理有何贡献。我们还旨在了解全球大量患者的儿童期SLE（CSLE）的遗传结构。我们已经与四个国家的CSLE研究人员建立了合作。在此过程中，我们能够对全球500多名儿童和成人发作SLE患者进行整个基因组测序，并且在许多情况下还从未受影响的亲戚那里收集样本。使用此集合，我们开始识别稀有变体，这些变体对于将CSLE的异源临床表型提高到精确的分子表型中可能很重要。 此外，借助整个基因组数据，我们可以更好地了解这些患者的全面遗传结构。有了这些数据，我们将能够定义这些患者中稀有和常见变体的负担，并试图了解不同的小儿年龄组和祖先背景的平衡。定义SLE的遗传结构将有助于我们进一步了解遗传学在疾病发作和严重程度中在这种复杂疾病的发病机理中的作用。 我们的研究旨在包括不同年龄和祖先背景的患者，因为先前的研究集中在主要的欧洲血统患者和疾病早期发作。此外，通过协作，我们的目标是更多地了解CSLE的临床范围。 儿童期SLE的罕见变体分析 整个基因组数据具有显着的发现导致整个基因组疾病的变异的能力。然而，整个基因组测序（WGS）研究产生了大量的变异数据，并且很难识别因果变异。对未受影响的父母和受影响的患者或多重家族的三人分析可以更有效的变异优先级。我们已经收集并测序了443名CSLE患者和170名父母，其中50名来自不同祖先背景的父母/患者三重奏。我们已经通过生物信息学管道优先考虑稀有变体，以首先关注对蛋白质功能有很大影响的人。我们已经确定了感兴趣的第一个变体。我们正在对270名SLE患者进行测序，并且在来年我们将继续对这些样本进行分析。我们目前正在发展协作网络，以在国内和国际上包括更多的CSLE患者。其他的测序工作将使我们能够增加样本量，从而增加发现的潜力，也可以验证重要变体。在更广泛的年龄范围内对患者进行测序将有助于我们更多地了解SLE在疾病发作时年龄连续体的遗传贡献。重要的是，通过此初始数据分析，已经确定了各种CSLE队列中整个基因组数据的基础。因此，通过从我们开发的强大方法中受益，随后的研究将得到加速。 富含CSLE的稀有变体的途径分析 此外，我们将在队列水平进行途径分析，不仅了解单个变体，而且了解有助于SLE发病机理的重要生物学过程。从历史上看，研究集中于无关的个体，这些个体在单个基因中共享变体。但是，这种方法不认为SLE中的罕见变体可以聚集在参与相关生物过程的基因中。我们在各种CSLE患者和父母对照组中进行了基因组测序，并描述了一种识别富含稀有变异基因的生物学途径，这些方法可能有助于CSLE发病机理。网络分析是一种有用的方法，可以识别可能导致CSLE风险的生物学途径和特定基因。对每种途径中确定的特定变体的持续详细分析将使我们能够优先考虑关键基因和进一步研究的途径。总的来说，这种分析可能有助于推进对CSLE的理解，而不是广泛的临床表型和更精确的分子诊断。 SLE的遗传结构 SLE的发病机理尚未完全理解，但被认为是由遗传易感人群中的环境事件触发的。整个外显子组测序（WES）和WGS是阐明与人类疾病相关的遗传变异的研究人员的强大工具。在SLE中进行了许多全基因组关联研究（GWAS），但是只有少数WES/WGS研究报告了罕见的高度渗透遗传变异型，对蛋白质功能有很大影响。除了罕见的变体分析外，还可以针对所描述的常见变体开采整个基因组数据，以通过研究常见变体赋予SLE风险。 为了了解CSLE的遗传结构，我们首先使用了具有完整三重奏的家族（n = 42）的家庭使用传播不平衡测试（TDT）。 TDT是一种基于家庭的遗传关联分析，它采用了鲁棒的方法论，我们的小组是第一个使用它来分析SLE中整个基因组测序数据的人。我们使用基于单核苷酸变体（SNV）分析来评估常见变异和基于基因的分析来检测稀有变体。我们的基于SNV的分析没有返回任何全基因组明显的SNV。罕见的基因基因TDT分析鉴定了许多新型基因，这些基因在包括HnRNPUL2，DNA修复蛋白和纤毛运动蛋白等的DNAH11等中显着富集了CSLE。我们的方法确定了祖先多样化的童年发作的狼疮队列中的几个新型SLE敏感性基因，这增加了证据表明，CSLE种群富含有助于疾病的稀有变体。 了解遗传结构的另一种方法是评估我们CSLE人群中已知稀有和常见的SLE风险变体的负担。累积遗传风险评分可以描述一群患者中带来的常见风险变异的负担。先前的研究已经确定疾病的早期发作与较高的多基因风险评分（PRS）有关。 CSLE的一项研究表明，更高的分数与诸如肾炎等严重表现有关。迄今为止，尚无研究CSLE患者中整个基因组数据中的PR的研究。与未受影响的亲戚相比，这将是首次研究CSLE患者队列中稀有变体和常见变体负担的负担。 CSLE遗传风险的当前范例是，稀有和常见的SLE风险变体的负担成反比，年轻和更严重的患者的负担较高，具有稀有，有害变体的负担，但普通较温和的变体负担较低。相反，青春期患者和患有温和表型的患者预计将承担较高的常见SLE风险变体负担，少数稀有变体负担。但是，尚未报道CSLE患者的罕见变体和常见变异之间的实际分布和平衡。我们已经完成了使用加权多基因风险评分的83名CSLE患者队列中SLE的常见风险变体负担的评估。我们将使用整个基因组数据在我们的CSLE队列中绘制已知常见和稀有SLE风险变体的平衡。我们将将患者常见变体的负担与未受影响的父母的负担进行比较。 迄今为止，我们已经对545名SLE患者和170名未受影响的亲戚进行了WGS。在更广泛的年龄范围内对患者进行测序将有助于我们更多地了解SLE在疾病发作时年龄连续体的遗传贡献。重要的是，通过此初始数据分析，已经确定了各种CSLE队列中整个基因组数据的基础。

项目成果

Towards development of treat to target (T2T) in childhood-onset systemic lupus erythematosus: PReS-endorsed overarching principles and points-to-consider from an international task force.

• DOI: 10.1136/ard-2022-223328
• 发表时间: 2023-06
• 期刊: Annals of the rheumatic diseases
• 影响因子: 27.4

PReS-endorsed international childhood lupus T2T task force definition of childhood lupus low disease activity state (cLLDAS).

PReS 认可的国际儿童狼疮 T2T 工作组对儿童狼疮低疾病活动状态 (cLLDAS) 的定义。

• DOI: 10.1016/j.clim.2023.109296
• 发表时间: 2023
• 期刊: Clinical immunology (Orlando, Fla.)
• 作者: Smith,EMD;Aggarwal,A;Ainsworth,J;Al-Abadi,E;Avcin,T;Bortey,L;Burnham,J;Ciurtin,C;Hedrich,CM;Kamphuis,S;Lambert,L;Levy,DM;Lewandowski,L;Maxwell,N;Morand,E;Ozen,S;Pain,CE;Ravelli,A;SaadMagalhaes,C;Pilkington,C;S
• 通讯作者: S

Principles of pediatric lupus nephritis in a prospective contemporary multi-center cohort.

• DOI: 10.1177/09612033211028658
• 发表时间: 2021-09
• 期刊: Lupus
• 影响因子: 2.6

Use of EuroLupus Cyclophosphamide Dosing for the Treatment of Lupus Nephritis in Childhood-onset Systemic Lupus Erythematosus in North America.

• DOI: 10.3899/jrheum.210428
• 发表时间: 2022-06
• 期刊: The Journal of rheumatology
• 作者: Cannon LA;Wenderfer SE;Lewandowski LB;Cooper JC;Goilav B;Knight AM;Hersh AO;Ardoin SP;Sadun RE;CARRA Lupus Nephritis Workgroup
• 通讯作者: CARRA Lupus Nephritis Workgroup

Mammalian Chromosome Analysis and Sorting by Flow Cytometry.

通过流式细胞术进行哺乳动物染色体分析和分选。

• DOI: 10.1002/cpz1.785
• 发表时间: 2023
• 期刊: Current protocols
• 作者: Mukhopadhyay,Risani;Varshitha,DV;Telford,WilliamG;Sanders,ClaireK;Chakraborty,Uttara
• 通讯作者: Chakraborty,Uttara