Epistatic modeling in rheumatoid arthritis: An application of the Risch theory

Rigby, Alan S.; Voelm, Lianne; Silman, Alan J.

doi:10.1002/gepi.1370100504

Cited by 36 publications

(24 citation statements)

References 30 publications

(16 reference statements)

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“…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).…”

mentioning

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

Arthritis & Rheumatism

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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.

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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

Arthritis & Rheumatism

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“…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).…”

mentioning

confidence: 99%

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

Newton¹,

Harney²,

Timms³

et al. 2004

Arthritis & Rheumatism

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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.

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“…Under the recessive model, the prevalence is 1.3% and the recurrence risk to female siblings is 4.3%. These recurrence risks fall within the range of risks provided in the summary manuscript of Rigby et al 14 We used the package Analyze 46 to perform linkage analyses and homogeneity tests. 47 …”

Section: Linkage Analysismentioning

confidence: 99%

“…Estimation of the genetic contribution of HLA suggests that less than 40% of RA susceptibility can be attributed to MHC-linked genes. 14,15 Multiple studies have reported a possible association or linkage with a variety of non-MHC genes and loci, most notably the T cell receptor B chain. Positive population associations with TCRB alleles have been reported by some groups, 16,17 but not others.…”

Section: Introductionmentioning

confidence: 99%

Genetic analysis of multiplex rheumatoid arthritis families

et al. 1999

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To examine the genetic contribution of HLA and non-HLA genes in the etiopathogenesis of rheumatoid arthritis (RA), 60 Caucasian multiplex families were identified and DNA analyzed for over 52 markers including DRB1, DQA1 and DQB1 alleles. Many of the markers were chosen because of close proximity to candidate genes suggested by previous studies or models of pathogenesis. Sibling pair analysis (SIBPAL), relative pair analysis (RELPAL) and linkage studies using two different models of inheritance suggested linkage for the MHC and two additional chromosomal regions: chromosome 2 (D2S443 near CD8 and IG ; 2p13-2p11.1), and chromosome 15 (CYP19-estrogen synthase; 15q15). No support was found for two chromosomal regions, 1p36 and 3q13, recently suggested by other studies. We used transmission disequilibrium testing (TDT), conditional logistic regression, and segregation analysis to study the contributions that the shared epitope and TNF-c have in contributing to risk for RA. These studies provide additional evidence that the association of HLA alleles in RA patients from multiplex families is similar to that observed in sporadic disease, suggest candidate regions for further analysis and find additional support for an association of TNF-c alleles with RA susceptibility.

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Epistatic modeling in rheumatoid arthritis: An application of the Risch theory

Cited by 36 publications

References 30 publications

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

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

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

Genetic analysis of multiplex rheumatoid arthritis families

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