The relationship between extreme inter-individual variation in macrophage gene expression and genetic susceptibility to inflammatory bowel disease.

IF 3.8 2区 生物学 Q2 GENETICS & HEREDITY
Human Genetics Pub Date : 2024-03-01 Epub Date: 2024-02-29 DOI:10.1007/s00439-024-02642-9
Claire L O'Brien, Kim M Summers, Natalia M Martin, Dylan Carter-Cusack, Yuanhao Yang, Rasel Barua, Ojas V A Dixit, David A Hume, Paul Pavli
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Abstract

The differentiation of resident intestinal macrophages from blood monocytes depends upon signals from the macrophage colony-stimulating factor receptor (CSF1R). Analysis of genome-wide association studies (GWAS) indicates that dysregulation of macrophage differentiation and response to microorganisms contributes to susceptibility to chronic inflammatory bowel disease (IBD). Here, we analyzed transcriptomic variation in monocyte-derived macrophages (MDM) from affected and unaffected sib pairs/trios from 22 IBD families and 6 healthy controls. Transcriptional network analysis of the data revealed no overall or inter-sib distinction between affected and unaffected individuals in basal gene expression or the temporal response to lipopolysaccharide (LPS). However, the basal or LPS-inducible expression of individual genes varied independently by as much as 100-fold between subjects. Extreme independent variation in the expression of pairs of HLA-associated transcripts (HLA-B/C, HLA-A/F and HLA-DRB1/DRB5) in macrophages was associated with HLA genotype. Correlation analysis indicated the downstream impacts of variation in the immediate early response to LPS. For example, variation in early expression of IL1B was significantly associated with local SNV genotype and with subsequent peak expression of target genes including IL23A, CXCL1, CXCL3, CXCL8 and NLRP3. Similarly, variation in early IFNB1 expression was correlated with subsequent expression of IFN target genes. Our results support the view that gene-specific dysregulation in macrophage adaptation to the intestinal milieu is associated with genetic susceptibility to IBD.

Abstract Image

巨噬细胞基因表达的极端个体间变异与炎症性肠病遗传易感性之间的关系。
常驻肠巨噬细胞从血液单核细胞分化出来取决于巨噬细胞集落刺激因子受体(CSF1R)发出的信号。全基因组关联研究(GWAS)分析表明,巨噬细胞分化和对微生物的反应失调是慢性炎症性肠病(IBD)易感性的原因之一。在这里,我们分析了来自 22 个 IBD 家系和 6 个健康对照的受影响和未受影响兄弟姐妹/三人的单核细胞衍生巨噬细胞(MDM)的转录组变异。数据转录网络分析显示,在基础基因表达或对脂多糖(LPS)的时间反应方面,受影响个体和未受影响个体之间没有整体或同胞间的区别。然而,受试者之间单个基因的基础表达或 LPS 诱导表达的独立差异高达 100 倍。巨噬细胞中一对 HLA 相关转录本(HLA-B/C、HLA-A/F 和 HLA-DRB1/DRB5)表达的极端独立变化与 HLA 基因型有关。相关性分析表明了对 LPS 即时早期反应的变化所产生的下游影响。例如,IL1B 早期表达的变化与局部 SNV 基因型以及随后的目标基因(包括 IL23A、CXCL1、CXCL3、CXCL8 和 NLRP3)的峰值表达显著相关。同样,早期 IFNB1 表达的变化也与随后 IFN 靶基因的表达相关。我们的研究结果支持这样一种观点,即巨噬细胞对肠道环境适应的特异性基因失调与 IBD 的遗传易感性有关。
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来源期刊
Human Genetics
Human Genetics 生物-遗传学
CiteScore
10.80
自引率
3.80%
发文量
94
审稿时长
1 months
期刊介绍: Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology. Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted. The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.
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