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Hybrid Mouse Diversity Panel Identifies Genetic Architecture Associated with the Acute Antisense Oligonucleotide-Mediated Inflammatory Response to a 2'-O-Methoxyethyl Antisense Oligonucleotide.

ABSTRACT: Although antisense oligonucleotides (ASOs) are well tolerated preclinically and in the clinic, some sequences of ASOs can trigger an inflammatory response leading to B cell and macrophage activation in rodents. This prompted our investigation into the contribution of genetic architecture to the ASO-mediated inflammatory response. Genome-wide association (GWA) and transcriptomic analysis in a hybrid mouse diversity panel (HMDP) were used to identify and validate novel genes involved in the acute and delayed inflammatory response to a single 75?mg/kg dose of an inflammatory 2'-O-methoxyethyl (2'MOE) modified ASO. The acute response was measured 6?h after ASO administration, via evaluation for increased plasma production of interleukin 6 (IL6), IL10, monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein-1? (MIP-1?). Delayed inflammation was evaluated by spleen weight increases after 96?h. We identified single nucleotide polymorphisms (SNPs) on chromosomes 16 and 17 associated with plasma MIP-1?, IL6, and MCP-1 levels, and one on chromosome 8 associated with increases in spleen weight. Systems genetic analysis utilizing transcriptomic data from HMDP strain macrophages determined that the acute inflammatory SNPs were expression quantitative trait locis (eQTLs) for CCAAT/enhancer-binding protein beta (Cebpb) and salt inducible kinase 1 (Sik1). The delayed inflammatory SNP was an eQTL for Rho guanine nucleotide exchange factor 10 (Arhgef10). In vitro assays in mouse primary cells and human cell lines have confirmed the HMDP finding that lower Sik1 expression increases the acute inflammatory response. Our results demonstrate the utility of using mouse GWA study (GWAS) and the HMDP for detecting genes modulating the inflammatory response to pro-inflammatory ASOs in a pharmacological setting.

SUBMITTER: Pirie E

PROVIDER: S-EPMC6765210 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Hybrid Mouse Diversity Panel Identifies Genetic Architecture Associated with the Acute Antisense Oligonucleotide-Mediated Inflammatory Response to a 2'-<i>O</i>-Methoxyethyl Antisense Oligonucleotide.

Pirie Elaine E Cauntay Patrick P Fu Wuxia W Ray Shayoni S Pan Calvin C Lusis Aldonis J AJ Hsiao Jill J Burel Sebastien A SA Narayanan Padma P Crooke Rosanne M RM Lee Richard G RG

Nucleic acid therapeutics 20190801 5

Although antisense oligonucleotides (ASOs) are well tolerated preclinically and in the clinic, some sequences of ASOs can trigger an inflammatory response leading to B cell and macrophage activation in rodents. This prompted our investigation into the contribution of genetic architecture to the ASO-mediated inflammatory response. Genome-wide association (GWA) and transcriptomic analysis in a hybrid mouse diversity panel (HMDP) were used to identify and validate novel genes involved in the acute ...[more]

PMID: 31368839

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Project description:Significant advances have been made in the discovery of genes affecting bone mineral density (BMD); however, our understanding of its genetic basis remains incomplete. In the current study, genome-wide association (GWA) and co-expression network analysis was used in the recently described Hybrid Mouse Diversity Panel (HMDP) to identify and functionally characterize novel BMD genes. In the HMDP, a GWA of total body, spinal and femoral BMD revealed four significant associations (-log10P > 5.39) affecting at least one BMD trait on chromosomes (Chrs.) 7, 11, 12 and 17. The associations implicated a total of 163 genes with each association harboring between 14 and 112 genes. This list was reduced to 26 functional candidates by identifying those genes that were regulated by local eQTL in bone or harbored potentially functional non-synonymous (NS) SNPs. This analysis revealed that the most significant BMD SNP on Chr. 12 was a NS SNP in the additional sex combs like-2 (Asxl2) gene that was predicted to be functional. The involvement of Asxl2 in the regulation of bone mass was confirmed by the observation that Asxl2 knockout mice had reduced BMD. To begin to unravel the mechanism though which Asxl2 influenced BMD, a gene co-expression network was created using cortical bone gene expression microarray data from the HMDP strains. Asxl2 was identified as a member of a co-expression gene module enriched for genes involved in the differentiation of myeloid cells. In bone, osteoclasts are bone-resorbing cell of myeloid origin, suggesting that Asxl2 may play a role in osteoclast differentiation. In agreement, the knockdown of Asxl2 in bone marrow macrophages impaired their ability to form osteoclasts. This study identifies a new regulator of BMD and osteoclastogenesis and highlights the power of GWA and systems genetics in the mouse for dissecting complex genetic traits. RNA from cortical bone (femoral diaphysis free of marrow) were profiled from 99 Hybrid Mouse Diversity Panel strains were profiled. Sixteen-week old male mice were used in this study. A total of 1-3 mice per strain were arrayed.

Dataset Information

Hybrid Mouse Diversity Panel Identifies Genetic Architecture Associated with the Acute Antisense Oligonucleotide-Mediated Inflammatory Response to a 2'-O-Methoxyethyl Antisense Oligonucleotide.

Publications

Hybrid Mouse Diversity Panel Identifies Genetic Architecture Associated with the Acute Antisense Oligonucleotide-Mediated Inflammatory Response to a 2'-<i>O</i>-Methoxyethyl Antisense Oligonucleotide.

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