Variants underlying sex bias in Systemic Lupus Erythematosus

系统性红斑狼疮性别偏见的变异

• 批准号: 10380322
• 负责人: Laura Carrel
• 金额: $ 24.06万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380322
• 关键词: Address; Affect; Age-Years; Alleles; American; Autoimmune Diseases; B-Lymphocytes; Biological Assay; Biology; CRISPR/Cas technology; Candidate Disease Gene; Cells; Data; Developmental Process; Diagnosis; Disease; Epigenetic Process; Female; Female of child bearing age; Gene Expression; Gene Frequency; Genes; Genetic; Heritability; Heterogeneity; Hormonal; Human; Human Genome; Immune; Individual; Investigation; Knowledge; Link; Linkage Disequilibrium; Lupus; Lymphocyte; Maintenance; Maps; Mus; Patients; Prevalence; RNA; Rapid screening; Regulation; Reporter; Reporter Genes; Risk Assessment; Role; Sex Bias; Sex Chromosomes; System; Systemic Lupus Erythematosus; TLR7 gene; Testing; Validation; Variant; Woman; X Chromosome; X Inactivation; base; causal variant; dosage; epigenetic regulation; epigenetic silencing; experimental study; functional genomics; gene function; genetic architecture; genetic variant; genome annotation; genome wide association study; genomic data; improved; in silico; insight; male; men; new therapeutic target; novel; novel strategies; overexpression; public health relevance; response; risk prediction; risk variant; stem cells; therapeutic development; therapeutic target; trait

ABSTRACT Systemic Lupus Erythematosus (SLE) is an autoimmune disorder that is heavily biased 9:1 towards females. Sex bias in SLE reflects both hormonal and sex chromosome differences between men and women. This proposal focuses on identifying and functionally establishing genetic variants on the X chromosome that contribute to SLE sex bias. Current efforts to understand the genetic architecture of lupus using genome-wide association studies (GWAS) have identified variants at 13 X-linked genes that are associated with SLE. However, causative variants at these loci remain unknown. These GWAS loci may contribute to female bias in SLE if they influence how genes respond to X chromosome inactivation (XCI), the early developmental process that epigenetically silences most X-linked genes in females in order to maintain dosage equivalence with males. Although XCI represses most genes on one X in females, some genes escape XCI and are expressed from both active and inactive Xs. XCI states for >20% of human X genes are variable, and escape XCI from a subset of Xs, but are silenced in other females. Our recent data indicate that heritability at genes that variably escape XCI is enriched in sex-biased disorders including SLE. We hypothesize that causal variants on the X chromosome underlie aberrant inactive X expression in SLE. The objective of this proposal is to identify these causal variants and directly evaluate their response to XCI. To address this hypothesis, we propose in Aim 1 to fine map causal variants on the X chromosome and identify causal genes. Integration of results with eQTL and functional genome annotation will further refine loci and link to causal genes. Association effects will be compared between males and females to further differentiate those likely influenced by X inactivation. In Aim 2 we will functionally evaluate variants mapping to Xq28 for altered gene response to XCI and B cell expression. We will perform multiplex reporter gene assays as an initial screen for functional variants with regulatory potential. We will also establish a novel system to functionally evaluate X chromosome variants by editing stem cells that will be differentiated to B cells and undergo XCI. We expect that results from experiments will be the first to provide a critical functional link between associated variants and X chromosome inactivation, and as such will have a profound impact on understanding mechanisms of SLE and lupus biology.

摘要 系统性红斑狼疮（SLE）是一种自身免疫性疾病，严重偏向女性9：1。 SLE中的性别偏见反映了男性和女性之间的激素和性染色体差异。这 该提案的重点是识别和功能上建立X染色体上的遗传变异， 有助于SLE性别偏见。目前的努力，以了解遗传结构的狼疮使用全基因组 关联研究（GWAS）已经鉴定了与SLE相关的13个X连锁基因的变体。然而，在这方面， 在这些基因座的致病变异仍然未知。这些GWAS基因座可能导致SLE的女性偏倚， 它们影响基因如何对X染色体失活（XCI）做出反应，这是一个早期发育过程， 表观遗传学沉默大多数X连锁基因的女性，以保持剂量相当于男性。 虽然XCI抑制了女性中一个X上的大多数基因，但一些基因逃脱了XCI，并在两个X上表达 活跃和不活跃的X。>20%的人类X基因的XCI状态是可变的，并且从人类X基因的子集中逃逸XCI。 X，但在其他女性中沉默。我们最近的数据表明，在基因的遗传性，不逃避XCI 富含性别偏见疾病包括SLE我们假设X染色体上的因果变异 SLE中染色体异常失活X表达的基础。本建议的目的是确定 这些致病变异体，并直接评估他们对XCI的反应。为了解决这个问题，我们建议在 目的1精细定位X染色体上的致病变异体并鉴定致病基因.将结果与 eQTL和功能基因组注释将进一步细化基因座并与致病基因联系起来。关联效应将 在男性和女性之间进行比较，以进一步区分那些可能受到X失活影响的人。在Aim中 我们将在功能上评估定位到Xq28的变体对XCI和B细胞表达的改变的基因应答。 我们将进行多重报告基因测定，作为对具有调节性的功能变体的初步筛选。 潜力我们还将建立一个新的系统，通过编辑茎功能评估X染色体变异 将分化为B细胞并经历XCI的细胞。我们希望实验的结果将是 首先提供相关变异体和X染色体失活之间的关键功能联系， 因此将对理解SLE和狼疮生物学机制产生深远影响。