ArticleProceedings of the National Academy of Sciences of the United States of America2016
Conserved 33-kb haplotype in the MHC class III region regulates chronic arthritis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 23 citations in OpenAlex.
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- Genetic variability of three common NK and γδ T cell receptor genes (FCγ3R, NCR3, and DNAM-1) and their role in Polish patients with rheumatoid arthritis and ankylosing spondylitis.Immunologic research · 2024Article
- Glycan Activation of Clec4b Induces Reactive Oxygen Species Protecting against Neutrophilia and Arthritis.Antioxidants (Basel, Switzerland) · 2021Article
- Endophilin A2 deficiency protects rodents from autoimmune arthritis by modulating T cell activation.Nature communications · 2021Article
- Regulation of Inflammatory Response by Transmembrane Adaptor Protein LST1.Frontiers in immunology · 2021Article
- Rat models of human diseases and related phenotypes: a systematic inventory of the causative genes.Journal of biomedical science · 2020Review
- Genetic Variants in Preeclampsia: Lessons From Studies in Latin-American Populations.Frontiers in physiology · 2018Review
- Influence of hydrocarbon oil structure on adjuvanticity and autoimmunity.Scientific reports · 2017Article
- Effects of C2ta genetic polymorphisms on MHC class II expression and autoimmune diseases.Immunology · 2017Article
- MHC class II alleles associated with Th1 rather than Th17 type immunity drive the onset of early arthritis in a rat model of rheumatoid arthritis.European journal of immunology · 2017Article
- Cis-eQTLs regulate reduced LST1 gene and NCR3 gene expression and contribute to increased autoimmune disease risk.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Reply to Liu et al.: Translation of rat congenic data to humans on a conserved MHC-III haplotype associated with rheumatoid arthritis.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Rheumatoid arthritis: identifying and characterising polymorphisms using rat models.Disease models & mechanisms · 2016Review
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7 authors at 2 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
Abstract
Genome-wide association studies have revealed many genetic loci associated with complex autoimmune diseases. In rheumatoid arthritis (RA), the MHC gene HLA-DRB1 is the strongest candidate predicting disease development. It has been suggested that other immune-regulating genes in the MHC contribute to the disease risk, but this contribution has been difficult to show because of the strong linkage disequilibrium within the MHC. We isolated genomic regions in the form of congenic fragments in rats to test whether there are additional susceptibility loci in the MHC. By both congenic mapping in inbred strains and SNP typing in wild rats, we identified a conserved, 33-kb large haplotype Ltab-Ncr3 in the MHC-III region, which regulates the onset, severity, and chronicity of arthritis. The Ltab-Ncr3 haplotype consists of five polymorphic immunoregulatory genes: Lta (lymphotoxin-α), Tnf, Ltb (lymphotoxin-β), Lst1 (leukocyte-specific transcript 1), and Ncr3 (natural cytotoxicity-triggering receptor 3). Significant correlation in the expression of the Ltab-Ncr3 genes suggests that interaction of these genes may be important in keeping these genes clustered together as a conserved haplotype. We studied the arthritis association and the spliceo-transcriptome of four different Ltab-Ncr3 haplotypes and showed that higher Ltb and Ncr3 expression, lower Lst1 expression, and the expression of a shorter splice variant of Lst1 correlate with reduced arthritis severity in rats. Interestingly, patients with mild RA also showed higher NCR3 expression and lower LST1 expression than patients with severe RA. These data demonstrate the importance of a conserved haplotype in the regulation of complex diseases such as arthritis.
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