Polygenic susceptibility in rheumatoid arthritis.

Wordsworth, P; Bell, James B.

doi:10.1136/ard.50.6.343

Cited by 124 publications

(66 citation statements)

References 43 publications

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“…8 -11 RA is considered to be an autoimmune. The genetic regulation of autoimmune diseases is poorly understood and at least three models have been proposed, a multiplicative model, 12 a polygenic threshold liability model 13 and a heterogeneity model. 14 Recently, two whole-genome scans, involving a wide range of RA families in Europe and US, identified linkage to several chromosomal regions, including the MHC class II region.…”

Section: Introductionmentioning

confidence: 99%

Both common and unique susceptibility genes in different rat strains with pristane-induced arthritis

Nordquist

Holmberg

et al. 2002

Eur J Hum Genet

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Pristane-induced arthritis (PIA) in rats is an animal model for rheumatoid arthritis (RA). We have previously identified seven quantitative trait loci (QTLs), which regulate arthritis development using a cross between the susceptible DA strain and the resistant E3 strain of rats (Pia2 -8). In the present study the inbred rat strain LEW.1F was used as the susceptible strain in a cross with the E3 strain. The results confirmed the locus Pia4 on chromosome 12, which previously was shown to be associated with PIA, and also with experimental allergic encephalomyelitis, in crosses between the rat strains E3 and DA. On chromosome 1, linked to the albino locus, we identified a novel QTL, Pia9 in the LEW.F1 cross. This locus was associated with arthritis severity in the early phase of disease. A locus on chromosome 16, denoted Pia11, was also associated with arthritis severity in the early phase of the disease. A suggestive locus was detected on chromosome 14, which was associated with arthritis severity at the time when PIA progresses into a chronic phase. Using a congenic LEW.1F strain, which carries E3 alleles at the Pia9 locus, we confirmed that the E3 allele significantly suppresses arthritis severity during the early phase of the disease. The results revealed synergistic effects between different susceptibility loci using ANOVA analysis. These interactions were influenced by gender. Rats with Pia9 alleles from LEW.1F and Pia11 alleles from E3, were shown to suffer from much more severe arthritis in the early stage of the disease. On the other hand, the Pia9 and the suggestive locus on chromosome 14 affected only males during the chronic phase of the disease. These findings provide clues to how genetic factors by themselves, and in interaction with each other, regulate the development of a disease, which displays many similarities to RA.

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Section: Introductionmentioning

confidence: 99%

Both common and unique susceptibility genes in different rat strains with pristane-induced arthritis

Nordquist

Holmberg

et al. 2002

Eur J Hum Genet

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“…There is a rather low, but clearly significant, genetic association of RA [29]. So far only MHC genes have been identified, albeit without a deeper knowledge of their biological role or interacting autoantigens [30].…”

Section: Nd MImentioning

confidence: 99%

A vridine-induced arthritis in rats; a T cell-dependent chronic disease influenced both by MHC genes and by non-MHC genes

Vingsbo

Jönsson

Holmdahl

1995

Clinical and Experimental Immunology

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SUMMARYAvrtdine is a potent synthetic adjuvant that can induce arthritis in most rat strains. The clinical appearance and histopathology of avridine-induced arthritis show great similarity to other arthritis models such as collagen-induced arthritis. In LEW and DA rats the avridine-induccd arthritis is severe and long lasting. To investigate a possible genetic influence on the disease we compared LEW, DA and E3 rats, which are of different genetic origins, for their ability to develop arthritis after injection ofa lowdoseofavridined 5mg rat). The E3 rat was shown to be resistant. whereas ail of the DA rats developed arthritis. Recombinant inbred strains derived from DA and E3 parentals varied in susceptibility to avridine. Only strains sharing RTl"^' with DA developed arthritis, indicating a role for the MHC genes. The MHC association was further analysed in a series of !^wis congenic strains using the l-5mg avridine dose. All strains developed arthritis. LEW,1C and LEW.IW developed only acute arthritis, whereas LEW.IA, LEW. LEW,ID, LEW.IN and LEW.IF developed chronic arthritis. In particular, the LEW.IF rats developed a chronic severe arthritis of high incidence. The chronic arthritis showed an aaive. erosive joint inflammation several months after induction. Nude rats are resistant to avridine-induced arthritis, indicating a T celi dependence of the disease which supports the importance of MHC. However, non-MHC genes are also crucial to arthritis development. Recombinants between DA and E3, sharing RTI^'' with DA, showed either a lower incidence or a lower severity of disease than the DA rats. The E3 rat and the recombinants with RTI" were completely resistant, whereas LEW.IW, also RTI", were highly susceptible.

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“…It is surprising, though, that even with a relatively high amount of missing genotypes (up to 30%), the effect on the confidence region is negligible, demonstrating a high robustness of the method in this regard. A parallel experiment, but without [Wordsworth and Bell, 1991]. Although it is thought that there are multiple susceptibility loci contributing to the trait [Wordsworth and Bell, 1991;John et al, 1997;Gregersen, 1999;Fisher et al, 2003], linkage analysis studies have successfully mapped only one locus, HLA Ã DRB1, on chromosome 6 [Mackay et al, 2002;Fisher et al, 2003].…”

Section: Missing Genotypesmentioning

confidence: 99%

“…A parallel experiment, but without [Wordsworth and Bell, 1991]. Although it is thought that there are multiple susceptibility loci contributing to the trait [Wordsworth and Bell, 1991;John et al, 1997;Gregersen, 1999;Fisher et al, 2003], linkage analysis studies have successfully mapped only one locus, HLA Ã DRB1, on chromosome 6 [Mackay et al, 2002;Fisher et al, 2003]. The failure of identifying additional trait-predisposing loci is believed to be due to their small contributions [Gregersen, 1999;Fisher et al, 2003].…”

Section: Missing Genotypesmentioning

confidence: 99%

A two‐step procedure for constructing confidence intervals of trait loci with application to a rheumatoid arthritis dataset

Papachristou

Lin

2005

Genetic Epidemiology

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Preliminary genome screens are usually succeeded by fine mapping analyses focusing on the regions that signal linkage. It is advantageous to reduce the size of the regions where follow-up studies are performed, since this will help better tackle, among other things, the multiplicity adjustment issue associated with them. We describe a two-step approach that uses a confidence set inference procedure as a tool for intermediate mapping (between preliminary genome screening and fine mapping) to further localize disease loci. Apart from the usual Hardy-Weiberg and linkage equilibrium assumptions, the only other assumption of the proposed approach is that each region of interest houses at most one of the diseasecontributing loci. Through a simulation study with several two-locus disease models, we demonstrate that our method can isolate the position of trait loci with high accuracy. Application of this two-step procedure to the data from the Arthritis Research Campaign National Repository also led to highly encouraging results. The method not only successfully localized a well-characterized trait contributing locus on chromosome 6, but also placed its position to narrower regions when compared to their LOD support interval counterparts based on the same data.

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Polygenic susceptibility in rheumatoid arthritis.

Cited by 124 publications

References 43 publications

Both common and unique susceptibility genes in different rat strains with pristane-induced arthritis

Both common and unique susceptibility genes in different rat strains with pristane-induced arthritis

A vridine-induced arthritis in rats; a T cell-dependent chronic disease influenced both by MHC genes and by non-MHC genes

A two‐step procedure for constructing confidence intervals of trait loci with application to a rheumatoid arthritis dataset

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