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

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Abstract
Objective We have previously identified a single‐nucleotide polymorphism (SNP) haplotype involving the lymphotoxin α (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.