Variants underlying sex bias in Systemic Lupus Erythematosus

系统性红斑狼疮性别偏见的变异

基本信息

批准号：
10515344
负责人：
Laura Carrel
金额：
$ 20.14万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-11-01 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10515344
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 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 Repression Risk Assessment Role Sex Bias Sex Chromosomes System Systemic Lupus Erythematosus TLR7 gene Testing Validation Variant Woman X Chromosome X Inactivation causal variant dosage epigenetic regulation experimental study functional genomics gene function genetic architecture genetic variant genome annotation genome wide association study genome-wide analysis genomic data improved in silico individual variation 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

项目摘要

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.

抽象的全身性红斑狼疮（SLE）是一种自身免疫性疾病，对女性的偏见9：1。 SLE中的性偏见反映了男性和女性之间的荷尔蒙和性染色体差异。这提案着重于识别并在功能上建立X染色体上的遗传变异有助于SLE性偏见。当前使用全基因组了解狼疮的遗传结构的努力关联研究（GWAS）已确定与SLE相关的13个X连锁基因的变异。然而，这些基因座的病因变体仍然未知。这些GWAS基因座可能会导致SLE中的女性偏见它们影响基因对X染色体灭活（XCI）的反应方式，这是早期发育过程表观遗传学上，女性中的大多数X连锁基因为了维持与男性的剂量等效性。尽管XCI在女性的一个X上抑制了大多数基因，但某些基因逃脱了XCI，并从两者中表达主动XS。 XCI状态> 20％的人X基因是可变的，并从一个子集中逃脱了XCI XS，但在其他女性中被沉默。我们最近的数据表明，可变逃脱XCI的基因的遗传力在包括SLE在内的性偏见疾病中富含。我们假设x上的因果变体 SLE中的染色体基础异常X表达。该提议的目的是确定这些因果变体并直接评估它们对XCI的反应。为了解决这一假设，我们提出 AIM 1以X染色体上的细MAP因果变异并鉴定因果基因。结果的整合 EQTL和功能基因组注释将进一步完善基因座并与因果基因联系。关联效应将在男性和女性之间进行比较，以进一步区分受X失活影响的人。目标 2我们将在功能上评估映射到XQ28的变体，以改变基因对XCI和B细胞表达的反应。我们将执行多重报告基因测定作为调节性函数变体的初始屏幕潜在的。我们还将建立一个新型系统，通过编辑茎来在功能上评估X染色体变体将分化为B细胞并经历XCI的细胞。我们希望实验的结果将是首先在相关变体和X染色体灭活之间提供关键的功能联系，因此，将对了解SLE和狼疮生物学的机制产生深远的影响。