Conserved 33-kb haplotype in the MHC class III region regulates chronic arthritis.
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.
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
Anthony C Y
AC
Yau
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
Jonatan
J
Tuncel
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
Sabrina
0000-0003-3714-6268
S
Haag
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
Ulrika
U
Norin
Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, SE-171 76, Stockholm, Sweden;
Miranda
M
Houtman
Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, SE-171 76, Stockholm, Sweden;
Leonid
L
Padyukov
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Southern Medical University, Guangzhou 510515, China Rikard.Holmdahl@ki.se.
Rikard
R
Holmdahl
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006649:Histocompatibility Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000276:immunology; D053308:Lymphotoxin-beta / Q000235:genetics / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000235:genetics / Q000276:immunology; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
D006649:Histocompatibility Antigens; D047908:Intracellular Signaling Peptides and Proteins; C093604:LST1 protein, human; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D055628:Natural Cytotoxicity Triggering Receptor 3; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha
arthritis; congenic mapping; haplotype; inflammation; major histocompatibility complex