A Genomewide Screen in Multiplex Rheumatoid Arthritis Families Suggests Genetic Overlap with Other Autoimmune Diseases

Jawaheer, Damini; Seldin, Michael F.; Amos, Christopher I.; Chen, Wei V.; Shigeta, Russell; Monteiro, Joanita; Kern, Marlene; Criswell, Lindsey A.; Albani, Salvatore; Nelson, J. Lee; Clegg, Daniel O.; Pope, Richard M.; Schroeder, Harry W.; Bridges, S. Louis; Pisetsky, David S.; Ward, Ryk; Kastner, Daniel L.; Wilder, Ronald L.; Pincus, Theodore; Callahan, Leigh F.; Flemming, Donald J.; Wener, Mark H.; Gregersen, Peter K.

doi:10.1086/319518

Cited by 329 publications

(283 citation statements)

References 26 publications

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“…One factor that encourages pursuit of these studies is the fact that at least 95% of all included families have available for analysis the genotype of at least one parent and, in most cases, both, adding statistical power to the relatively small subtype cohorts. This contrasts substantially with the experience in adult RA patients, for whom larger sibpair cohorts are available, but overall, parents are available in Ͻ50% of the families (18,19).…”

Section: Discussionmentioning

confidence: 83%

A genome‐wide scan for juvenile rheumatoid arthritis in affected sibpair families provides evidence of linkage

Thompson¹,

Moroldo²,

Guyer³

et al. 2004

Arthritis & Rheumatism

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Methods. Genotype data collected for HLA-DR and 386 microsatellite markers were subjected to multipoint nonparametric linkage analysis. Following analysis of the entire set of families, additional analyses were performed after a priori stratification by disease onset type, age at onset, disease course, and selected HLA-DRB1 alleles. Conclusion. These data support the hypothesis that multiple genes, including at least 1 in the HLA region, influence susceptibility to JRA. These findings for JRA are consistent with findings for other autoimmune diseases and support the notion that common genetic regions contribute to an autoimmune phenotype.Collectively, the varied conditions that constitute juvenile rheumatoid arthritis (JRA) represent the most common chronic rheumatic inflammatory conditions of childhood. Current estimates indicate that as many as 50,000 children in the US have been diagnosed with some form of JRA (1). The diagnosis of JRA is complicated by the heterogeneous nature of the clinical phenotypes and has broadly been defined by the American College of Rheumatology (ACR) (2) based on systemic involvement (fevers, rash, and involvement of other organ systems besides the musculoskeletal system) and mode of disease onset (pauciarticular [Յ4 joints] versus polyarticular [Ն5 joints]).Evidence suggests that JRA is a complex genetic disorder that is influenced by multiple genetic and environmental factors. The sibling risk ratio for a full sibling of a child with JRA is estimated to be 15 (3). These results are consistent with other autoimmune disorders, such as type 1 diabetes (4).

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Section: Discussionmentioning

confidence: 83%

A genome‐wide scan for juvenile rheumatoid arthritis in affected sibpair families provides evidence of linkage

Thompson¹,

Moroldo²,

Guyer³

et al. 2004

Arthritis & Rheumatism

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“…29 The region on the short arm of chromosome 16 coincides with one of the best supported non-HLA regions from the recently published meta-analysis of the original American, British and Canadian linkage screens in multiple sclerosis. 30 Our study thus shows both overlap and differences with previous screens in multiple sclerosis and other autoimmune complex traits.…”

Section: Discussionmentioning

confidence: 87%

A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis

et al. 2002

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“…Our group (the European Consortium on Rheumatoid Arthritis Families [see Appendix A]), a Japanese group, the North American Rheumatoid Arthritis Consortium, and a British group have performed genome scans with different marker sets and an average marker spacing ranging from 10 cM to 12 cM (7)(8)(9)(10)(11). Linkage to the region on chromosome 6 that contains HLA class II genes was confirmed, but no consistent evidence for non-HLA regions was found.…”

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confidence: 99%

Dense genome‐wide linkage analysis of rheumatoid arthritis, including covariates

Fortéa¹,

Bükülmez²,

Petit-Teixeira³

et al. 2004

Arthritis & Rheumatism

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Objective. Rheumatoid arthritis (RA) is a heterogeneous disease that exhibits a complex genetic component. Previous RA genome scans confirmed the involvement of the HLA region and generated data on suggestive signals at non-HLA regions, albeit with few overlaps in findings between studies. The present study was undertaken to detect potential RA gene regions and to estimate the number of true RA gene regions, taking into account the heterogeneity of RA, through performance of a dense genome scan.Methods. In a study of 88 French Caucasian families (105 RA sibpairs), 1,088 microsatellite markers were genotyped (3.3-cM genome scan), and a multipoint model-free linkage analysis was performed. The statistical assessment of the results relied on 10,000 computer simulations. A covariate-based multipoint model-free linkage analysis was performed on the locations of regions with suggestive evidence for linkage.Results. Involvement of the HLA region was strongly confirmed (P ‫؍‬ 6 ؋ 10 ؊5 ), and 19 non-HLA regions showed suggestive evidence for linkage (P < 0.05); 9 of these overlapped with regions suggested in other published RA genome scans. A routine 12-cM genome scan with the same families would have detected only 7 of the 19 regions, including only 4 of the 9 overlapping regions. From the 10,000 computer simulations, we estimated that 8 ؎ 4 regions (mean ؎ SD) were true-positives. RA covariate-based analysis provided additional linkage evidence for 3 regions, with age at disease onset, erosions, and HLA-DRB1 shared epitope as covariates.Conclusion. The results of this study provide evidence of 19 non-HLA RA gene regions, with an estimate of 8 ؎ 4 as true-positives, and provide additional evidence for 3 regions from covariate-based analysis.

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A Genomewide Screen in Multiplex Rheumatoid Arthritis Families Suggests Genetic Overlap with Other Autoimmune Diseases

Cited by 329 publications

References 26 publications

A genome‐wide scan for juvenile rheumatoid arthritis in affected sibpair families provides evidence of linkage

A genome‐wide scan for juvenile rheumatoid arthritis in affected sibpair families provides evidence of linkage

A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis

Dense genome‐wide linkage analysis of rheumatoid arthritis, including covariates

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