Dissection of class III major histocompatibility complex haplotypes associated with rheumatoid arthritis

Abstract

Objective. We have previously identified a singlenucleotide polymorphism (SNP) haplotype involving the lymphotoxin ␣ (LTA) and tumor necrosis factor (TNF) loci (termed haplotype LTA-TNF2) on chromosome 6 that shows differential association with rheumatoid arthritis (RA) on HLA-DRB1*0404 and *0401 haplotypes, suggesting the presence of additional non-HLA-DRB1 RA susceptibility genes on these haplotypes. To refine this association, we performed a case-control association study using both SNPs and microsatellite markers in haplotypes matched either for HLA-DRB1*0404 or for HLA-DRB1*0401.Methods. Fourteen SNPs lying between HLA-DRB1 and LTA were genotyped in 87 DRB1*04-positive families. High-density microsatellite typing was performed using 24 markers spanning 2,500 kb centered around the TNF gene in 305 DRB1*0401 or *0404 cases and 400 DRB1*0401 or *0404 controls. Single-marker, 2-marker, and 3-marker minihaplotypes were constructed and their frequencies compared between the DRB1*0401 and DRB1*0404 matched case and control haplotypes.Results. Marked preservation of major histocompatibility complex haplotypes was seen, with chromosomes carrying LTA-TNF2 and either DRB1*0401 or DRB1*0404 both carrying an identical SNP haplotype across the 1-Mb region between TNF and HLA-DRB1. Using microsatellite markers, we observed two 3-marker minihaplotypes that were significantly overrepresented in the DRB1*0404 case haplotypes (P ‫؍‬ 0.00024 and P ‫؍‬ 0.00097).Conclusion. The presence of a single extended SNP haplotype between LTA-TNF2 and both DRB1*0401 and DRB1*0404 is evidence against this region harboring the genetic effects in linkage disequilibrium with LTA-TNF2. Two RA-associated haplotypes on the background of DRB1*0404 were identified in a 126-kb region surrounding and centromeric to the TNF locus.

High-density SNP analysis of 642 Caucasian families with rheumatoid arthritis identifies two new linkage regions on 11p12 and 2q33

“…Indeed, there is previous evidence that genes within the central MHC also contribute to disease risk, independent of DRB1. 10,11,48 The current data suggest that additional risk genes may also lie within the very broad linkage peak in this region, perhaps some of which lie outside of the MHC proper.…”

Animal models of rheumatoid arthritis: How informative are they?

“…Class II molecules are found on APCs and govern presentation of antigens to CD4+ T cells. RA susceptibility is associated with specific alleles within MHC class II, namely HLA DRB1 (Newton et al, 2004a;Newton et al, 2004b). The frequency of HLA DRB1 alleles is increased in patients with RA when compared to healthy controls (McInnes and Schett, 2007).…”

Does a central MHC gene in linkage disequilibrium with HLA-DRB1*0401 affect susceptibility to type 1 diabetes?

“…While we did not eliminate a role for HLA-DQB1*0302, a gene in the central MHC would explain our data. A central MHC effect contributing to susceptibility to T1DM has been described in HLA-DRB1*0404 patients 14 and HLA-DRB1*0301 patients. [6][7][8] Here IKBL þ 446*T and HLA-A2,B15 were used as haplotypic markers to identify an interactive effect between the class II alleles and the telomeric portion of the 62.1AH.…”