Investigating the HLA component in rheumatoid arthritis: An additive (dominant) mode of inheritance is rejected, a recessive mode is preferred

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134

Objective. The strongest known genetic association in rheumatoid arthritis (RA) is with HLA-DRB1 alleles that share a similar amino acid sequence, termed the shared epitope (SE). Although many studies have examined the association of the SE with disease severity, the results have been inconsistent, which may reflect the relatively small sample sizes or ethnic differences. The aim of this study was to assess the association of HLA-DRB1 SE alleles and genotype with the development of bony erosions in RA by meta-analysis.Methods. We identified English-language articles published between January 1, 1987 and June 1, 1999 through Medline, EMBase, and manual searches of 6 relevant journals. Included were studies in which molecular typing of HLA-DRB1 alleles was performed and in which the presence or absence of bony erosions was reported. Data were extracted from the studies, and erosions were coded as present or absent. Authors were contacted for missing information and data on individual patients.Results. A total of 29 studies and 3,240 patients were available for analysis. The summary odds ratios Conclusion. The SE is associated with the

Section: Discussionmentioning

confidence: 99%

Impact of shared epitope genotype and ethnicity on erosive disease: A meta‐analysis of 3,240 rheumatoid arthritis patients

Gorman¹,

Lum²,

Chen³

et al. 2004

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134

“…The heritability, estimated from twin studies, is 40-60% (2,3). Recurrence risk modeling suggests that the genetic susceptibility is encoded by a limited number of genes with significant genetic epistasis (4)(5)(6).…”

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confidence: 99%

The effect of HLA–DR on susceptibility to rheumatoid arthritis is influenced by the associated lymphotoxin α–tumor necrosis factor haplotype

Newton

Brown

Milicic

et al. 2003

Objective. HLA-DRB1, a major genetic determinant of susceptibility to rheumatoid arthritis (RA), is located within 1,000 kb of the gene encoding tumor necrosis factor (TNF). Because certain HLA-DRB1*04 subtypes increase susceptibility to RA, investigation of the role of the TNF gene is complicated by linkage disequilibrium (LD) between TNF and DRB1 alleles. By adequately controlling for this LD, we aimed to investigate the presence of additional major histocompatibility complex (MHC) susceptibility genes.Methods. We identified 274 HLA-DRB1*04-positive cases of RA and 271 HLA-DRB1*04-positive population controls. Each subject was typed for 6 singlenucleotide polymorphisms within a 4.5-kb region encompassing TNF and lymphotoxin ␣ (LTA). LTA-TNF haplotypes in these unrelated individuals were determined using a combination of family data and the PHASE software program.Results. Significant differences in LTA-TNF haplotype frequencies were observed between different subtypes of HLA-DRB1*04. The LTA-TNF haplotypes observed were very restricted, with only 4 haplotypes constituting 81% of all haplotypes present. Among individuals carrying DRB1*0401, the LTA-TNF 2 haplotype was significantly underrepresented in cases compared with controls (odds ratio 0.5 [95% confidence interval 0.3-0.8], P ‫؍‬ 0.007), while in those with DRB1*0404, the opposite effect was observed (P ‫؍‬ 0.007).Conclusion. These findings suggest that the MHC contains genetic elements outside the LTA-TNF region that modify the effect of HLA-DRB1 on susceptibility to RA.

“…Modeling studies suggest that the genetic susceptibility is encoded by a limited number of genes, with significant genetic epistasis, and there is evidence for more than one susceptibility gene within the MHC (6)(7)(8). The MHC is an extremely gene-dense region with Ͼ300 genes, of which ϳ50% are thought to have immunoregulatory functions (9).…”

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confidence: 99%

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

Newton¹,

Harney²,

Timms³

et al. 2004

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.