Identification of potential genetic causal variants for rheumatoid arthritis by whole-exome sequencing

Liu, Ying; Leung, Elaine Lai‐Han; Pan, Hudan; Yao, Xiaojun; Huang, Qingchun; Wu, Min; Xu, Ting; Wang, Yuwei; Cai, Jun; Li, Runze; Liu, Wei; Liu, Liang

doi:10.18632/oncotarget.22630

Cited by 22 publications

(17 citation statements)

References 62 publications

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“…Moreover, the down-expression of HIPK2 also impairs the pro-apoptosis ability and induces drug resistance [32]. The role of HIPK2 in RA has not been researched in detail ever, a previous study using whole-exome sequencing technique demonstrated variants of gene HIPK2 may induce functional impact on RA pathogenesis [33]. Therefore, it is the first time to investigate the functional effects of HIPK2 protein, as well as the upstream regulator (miR-27b-3p), in RA development.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-27b-3p inhibits apoptosis of chondrocyte in rheumatoid arthritis by targeting HIPK2

Zhou

Chen³

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Background: Understanding the mechanism of chondrocytes degeneration could provide a new potential therapeutic idea for rheumatoid arthritis (RA) treatment. MicroRNA-27b-3p (miR-27b-3p) has been shown to regulate a variety of cell behaviors in various cell types. However, the role of miR-27b-3p in RA remains unknown. Materials and methods: Expression of miR-27b-3p and HIPK2 in cartilage tissues and chondrocytes was characterized using qRT-PCR and Western blot. MiR-27b-3p was overexpressed or suppressed in chondrocytes to observe the potential role of miR-27b-3p. Results: We found declined miR-27b-3p and elevated HIPK2 in RA tissues and cells using qRT-PCR. Dual-luciferase reporter assay validated HIPK2 is a direct target of miR-27b-3p, confirmed by Western blot results. Pearson correlation presented that there was a significantly negative correlation between miR-27b-3p and HIPK2 mRNA. Overexpression of miR-27b-3p significantly reduced the expression of pro-apoptotic protein c-caspase3 and increased the expression of anti-apoptotic Bcl-2; however, downregulation of miR-27b-3p has a significant effect of inducing apoptosis. Furthermore, overexpression of miR-27b-3p combined with recombinant HIPK2 protein showed the inhibitory effect of miR-27b-3p was abolished by HIPK2. Conclusion: We found declined miR-27b-3p and elevated HIPK2 in RA tissues and cells. Further in vitro studies demonstrated that miR-27b might inhibit chondrocyte apoptosis and thus attenuate RA development by directly inhibiting HIPK2 expression.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-27b-3p inhibits apoptosis of chondrocyte in rheumatoid arthritis by targeting HIPK2

Zhou

Chen³

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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“…Whole-genome or whole-exome sequencing, utilising high-performance HTS platforms, could also help to identify rare and population-specific pathogenic genetic variants. In particular, rare RA-associated germline variants were identified in the NCR3LG1 , RAP1GAP , CHCHD5 , HIPK2 , and DIAPH2 genes by whole-exome sequencing with Illumina HiSeq in a Han (Chinese ethnic group) patient cohort [ 56 ].…”

Section: Predisposition To Ra Depends On the Methods Of Analysis Ofmentioning

confidence: 99%

Genetic Polymorphisms Associated with Rheumatoid Arthritis Development and Antirheumatic Therapy Response

Mikhaylenko

Немцова

Bure

et al. 2020

IJMS

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Rheumatoid arthritis (RA) is the most common inflammatory arthropathy worldwide. Possible manifestations of RA can be represented by a wide variability of symptoms, clinical forms, and course options. This multifactorial disease is triggered by a genetic predisposition and environmental factors. Both clinical and genealogical studies have demonstrated disease case accumulation in families. Revealing the impact of candidate gene missense variants on the disease course elucidates understanding of RA molecular pathogenesis. A multivariate genomewide association study (GWAS) based analysis identified the genes and signalling pathways involved in the pathogenesis of the disease. However, these identified RA candidate gene variants only explain 30% of familial disease cases. The genetic causes for a significant proportion of familial RA have not been determined until now. Therefore, it is important to identify RA risk groups in different populations, as well as the possible prognostic value of some genetic variants for disease development, progression, and treatment. Our review has two purposes. First, to summarise the data on RA candidate genes and the increased disease risk associated with these alleles in various populations. Second, to describe how the genetic variants can be used in the selection of drugs for the treatment of RA.

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“…Previously, we have applied molecular docking to compare the protein structures of wild-type SAA1 and SAA1.2 [11]. The SAA1.2 mutation occurred in a-helix 3, and this mutation resulted in a protein conformation change, with a more compressed and condensed protein structure.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, using the whole exome sequencing method (WES), we identified multiple novel genes that were enriched with deleterious variants in 58 RA patients' peripheral blood mononuclear cells (PBMC) [11]. One novel deleterious mutation was in the SAA1 gene, creating an amino acid change (G90D) in the SAA1.2 protein isoform.…”

Section: Introductionmentioning

confidence: 99%

Serum amyloid A 1 protein isoforms induce Rheumatoid Arthritis

Leung

Lai

et al. 2020

Preprint

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Background: SAA1 in RA pathogenesis and its complications remains unknown, making early diagnosis and risk prevention difficult. This study is to determine the pathogenetic mechanisms of three different SAA1 protein isoforms in RA progression. Methods: We modified an experimental adenovirus infection protocol in order to successfully introduce SAA1.2, SAA1.3, SAA1.5 gene alleles into the rear knee joints of C57BL/6 mice. Micro-computed tomography (micro-CT) analysis was applied to determine changes in bone morphology and density. Immunohistochemistry (IHC), flow cytometry, ELISA and real-time PCR were used to investigate disease progression and cytokine alterations in the course of adenoviral SAA-induced knee joint inflammation and bone destruction. Results: The pathogenetic functions of SAA1.2, SAA1.3 and SAA1.5 protein isoforms in promoting the initiation and progression of RA were determined. We established that SAA1.2 was the most aggressive factor in RA induction and progression. Mechanistically, we found that the arthritis-inducing effect of SAA1.2 transcription in the knee joints and mutant SAA1 protein secretion in blood results in stimulation of immune responses, leading to CD8+ T cell and pro-inflammatory cytokine elevation, with subsequent synovial inflammation and bone destruction. Conclusions: These findings indicate that SAA1 protein isoforms, particularly SAA1.2, play a significant role in the induction and progression of RA and may have potential value in the early diagnosis and severity prediction for RA.

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Identification of potential genetic causal variants for rheumatoid arthritis by whole-exome sequencing

Cited by 22 publications

References 62 publications

MicroRNA-27b-3p inhibits apoptosis of chondrocyte in rheumatoid arthritis by targeting HIPK2

MicroRNA-27b-3p inhibits apoptosis of chondrocyte in rheumatoid arthritis by targeting HIPK2

Genetic Polymorphisms Associated with Rheumatoid Arthritis Development and Antirheumatic Therapy Response

Serum amyloid A 1 protein isoforms induce Rheumatoid Arthritis

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