Conserved 33-kb haplotype in the MHC class III region regulates chronic arthritis

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.arthritis | major histocompatibility complex | congenic mapping | haplotype | inflammation

Reply to Liu et al.: Translation of rat congenic data to humans on a conserved MHC-III haplotype associated with rheumatoid arthritis

“…In our study, higher Ltb and Ncr3 expression and lower Lst1 expression correlate with reduced arthritis severity in rats (1). Following these findings, we compared expression of these genes in a cohort of patients with rheumatoid arthritis (RA) and healthy controls and found that the expression of LTB, LST1, and NCR3 was higher in RA cases, but patients with mild RA showed higher NCR3 expression and lower LST1 expression than patients with severe RA (1).…”

“…We previously identified a conserved 33-kb haplotype comprising five genes, lymphotoxin-α (Lta), Tnf, lymphotoxin-β (Ltb), leukocytespecific transcript 1 (Lst1), and natural cytotoxicity-triggering receptor 3 (Ncr3), in the MHC class-III region regulating arthritis in rats (1). In our study, higher Ltb and Ncr3 expression and lower Lst1 expression correlate with reduced arthritis severity in rats (1).…”

“…We previously identified a conserved 33-kb haplotype comprising five genes, lymphotoxin-α (Lta), Tnf, lymphotoxin-β (Ltb), leukocytespecific transcript 1 (Lst1), and natural cytotoxicity-triggering receptor 3 (Ncr3), in the MHC class-III region regulating arthritis in rats (1). In our study, higher Ltb and Ncr3 expression and lower Lst1 expression correlate with reduced arthritis severity in rats (1). Following these findings, we compared expression of these genes in a cohort of patients with rheumatoid arthritis (RA) and healthy controls and found that the expression of LTB, LST1, and NCR3 was higher in RA cases, but patients with mild RA showed higher NCR3 expression and lower LST1 expression than patients with severe RA (1).…”

“…Second, a cohort of patients with RA in this study consists of only nonresponders to methotrexate (MTX) therapy (2, 4), whereas we included patients with a broader spectrum of treatments and disease activity (1). Because gene expression profiles differ between patients responding and not responding to MTX (5), it is not surprising that findings from two different cohorts could not be cross-replicated.…”

Rheumatoid arthritis: identifying and characterising polymorphisms using rat models

“…Initially, genetic linkage analysis (Box 1) is performed to identify the many different QTLs that regulate various arthritis phenotypes, including disease onset and severity, and also subphenotypes, such as CD4:CD8 T-cell ratio, and the presence of α­ 1 -acid glycoprotein (a marker of the systemic inflammatory response) and of cartilage oligomeric matrix protein (a marker of cartilage destruction) (Kawahito et al, 1998; Lorentzen et al, 1998; Olofsson et al, 2003b; Remmers et al, 1996). The contribution of some of these QTLs to disease phenotypes has been reproduced in congenic strains (see Box 2) (Bäckdahl et al, 2003; Olofsson et al, 2003a; Remmers et al, 2002) and further analysed through the generation of smaller sub-congenic fragments, to narrow down the arthritis-associated loci (Haag et al, 2015; Lorentzen et al, 2007; Rintisch et al, 2010; Yau et al, 2016). The aim of this approach is to arrive at a genetic region that is linked to a disease but that contains a minimal number of genes, making it feasible to map and analyse different candidate genes and polymorphisms.…”