Opposing effects of HLA–DRB1*13 alleles on the risk of developing anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis

Lundström, Emeli; Källberg, Henrik; Смольникова, М. В.; Ding, Bo; Rönnelid, Johan; Alfredsson, Lars; Klareskog, Lars; Padyukov, Leonid

doi:10.1002/art.24410

Cited by 64 publications

(67 citation statements)

References 30 publications

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“…We found no evidence to support a proposed interaction of HLA-DRB1*03 with HLA-DRB1*13. 61 HLA-DRB1*13 had a per-allele, HLA-DRB1 SE-adjusted OR of 1.17 (0.98-1.40), P ¼ 0.082. There was a marginal risk effect of HLA-DRB1*13 for ACPA-negative (OR 1.31 (1.04-1.65), P ¼ 0.021), but not for ACPApositive RA (OR 0.91 (0.72-1.15), P ¼ 0.44).…”

Section: Discussionmentioning

confidence: 98%

A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population

et al. 2011

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Previously-proposed rheumatoid arthritis (RA) HLA-DRB1 susceptibility and protective models were compared, based on amino acids at positions 67-74 and autoantibody combinations. 3 657 RA patients and 1 357 controls were studied using logistic regression, with secondary stratification by anti-citrullinated peptide antibodies(ACPA) and rheumatoid factor(RF). Susceptibility models were based on previously defined HLA-DRB1 shared epitope(SE) subgroups. 70 DERAA 74 , D 70 and I 67 protective models were compared, adjusting for HLA-DRB1 SE. A hierarchy of risk was observed within the HLA-DRB1 SE, particularly for ACPA-positive and RF-positive RA: HLA-DRB1*0401B*04044*0101B*1001 (*04044*0101: P ¼ 0.0003). HLA-DRB1*0401/*0404 compound heterozygosity conferred a risk similar to *0401 homozygosity (P ¼ 0.70). Protective effects of D 70 and I 67 were similar. Predictions of the D 70 model fitted the data better than those of the I 67 model. The protective effect of D 70 showed a gene-dose effect (OR 0.82, 95% CI 0.73-0.92, P ¼ 5.8 Â 10 À4 ), but was only seen in RA patients positive for RF or ACPA. HLA-DRB1 SE alleles were also associated with ACPA-negative, RF-positive RA (OR 1.42 (1.15-1.76), P ¼ 0.0012).In conclusion, HLA-DRB1 SE alleles show heterogeneity in RA susceptibility; their major effect appears to be mediated by ACPA positivity, but a significant association of HLA-DRB1 SE with RF-positive, ACPA-negative RA was also observed. D 70 specifically protected against antibody-positive RA.

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Section: Discussionmentioning

confidence: 98%

A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population

et al. 2011

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“…By contrast, variations in IRF518 and C-type lectin genes19 appear to be associated with ACPA-negative RA. Association of ACPA-negative disease with HLA-DRB1*03 haplotype was previously suggested20 21 but has not been replicated in a larger study 22. In at least one study23 an indication for an association of PTPN22 marker with ACPA-negative RA was presented based on 65 cases of RA.…”

Section: Introductionmentioning

confidence: 91%

A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis

Padyukov

Seielstad²,

Ong³

et al. 2010

Annals of the Rheumatic Diseases

242

187

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BackgroundRheumatoid arthritis (RA) can be divided into two major subsets based on the presence or absence of antibodies to citrullinated peptide antigens (ACPA). Until now, data from genome-wide association studies (GWAS) have only been published from ACPA-positive subsets of RA or from studies that have not separated the two subsets. The aim of the current study is to provide and compare GWAS data for both subsets.Methodsand results GWAS using the Illumina 300K chip was performed for 774 ACPA-negative patients with RA, 1147 ACPA-positive patients with RA and 1079 controls from the Swedish population-based case–control study EIRA. Imputation was performed which allowed comparisons using 1 723 056 single nucleotide polymorphisms (SNPs). No SNP achieved genome-wide significance (2.9 × 10–8) in the comparison between ACPA-negative RA and controls. A case–case association study was then performed between ACPA-negative and ACPA-positive RA groups. The major difference in this analysis was in the HLA region where 768 HLA SNPs passed the threshold for genome-wide significance whereas additional contrasting SNPs did not reach genome-wide significance. However, one SNP close to the RPS12P4 locus in chromosome 2 reached a p value of 2 × 106 and this locus can thus be considered as a tentative candidate locus for ACPA-negative RA.ConclusionsACPA-positive and ACPA-negative RA display significant risk allele frequency differences which are mainly confined to the HLA region. The data provide further support for distinct genetic aetiologies of RA subsets and emphasise the need to consider them separately in genetic as well as functional studies of this disease.

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“…40HLA-DRB1 shared epitope (SE) alleles are the major genetic 41 risk factors for this condition[1]. RA patients positive for42 anti-citrullinated protein antibodies (ACPAs Q5 ) constitute two 43 thirds of all RA cases and represent a group with higher disease 44 severity.…”

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confidence: 99%

Gene–gene interaction and RNA splicing profiles of MAP2K4 gene in rheumatoid arthritis

Shchetynsky

Protsyuk

Ronninger

et al. 2015

Clinical Immunology

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We performed gene-gene interaction analysis, with HLA-DRB1 shared epitope (SE) alleles for 195 SNPs within immunologically important MAP2K, MAP3K and MAP4K gene families, in 2010 rheumatoid arthritis (RA) patients and 2280 healthy controls. We found a significant statistical interaction for rs10468473 with SE alleles in autoantibody-positive RA. Individuals heterozygous for rs10468473 demonstrated higher expression of total MAP2K4 mRNA in blood, compared to A-allele homozygous. We discovered a novel, putatively translated, "cassette exon" RNA splice form of MAP2K4, differentially expressed in peripheral blood mononuclear cells from 88 RA cases and controls. Within the group of RA patients, we observed a correlation of MAP2K4 isoform expression with carried SE alleles, autoantibody, and rheumatoid factor profiles. TNF-dependent modulation of isoform expression pattern was detected in the Jurkat cell line. Our data suggest a genetic interaction between MAP2K4 and HLA-DRB1, and the importance of rs10468473 and MAP2K4 splice variants in the development of autoantibody-positive RA.

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Opposing effects of HLA–DRB1*13 alleles on the risk of developing anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis

Cited by 64 publications

References 30 publications

A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population

A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population

A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis

Gene–gene interaction and RNA splicing profiles of MAP2K4 gene in rheumatoid arthritis

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