CIITA gene variants are associated with rheumatoid arthritis in Scandinavian populations

Eike, Morten Christoph; Skinningsrud, Beate; Ronninger, Marcus; Stormyr, Alice; Kvien, Tore K; Joner, Geir; Njølstad, Pål R.; Førre, Ø; Flatø, Berit; Alfredsson, Lars; Padyukov, Leonid; Undlien, Dag E.; Lie, Benedicte A.

doi:10.1038/gene.2012.11

Cited by 22 publications

(19 citation statements)

References 30 publications

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“…Of these 22 SNPs, including rs3087456, only rs8048002 was significantly associated with RA after correction for multiple comparisons (ACPA negative patients, adjusted for 44 test: p = 0.013, data submitted elsewhere, Eike et al [17]). Rs3087456 was significantly associated with RA before adjusting for multiple comparisons.…”

Section: Resultsmentioning

confidence: 99%

Interaction Analysis between HLA-DRB1 Shared Epitope Alleles and MHC Class II Transactivator CIITA Gene with Regard to Risk of Rheumatoid Arthritis

et al. 2012

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HLA-DRB1 shared epitope (SE) alleles are the strongest genetic determinants for autoantibody positive rheumatoid arthritis (RA). One of the key regulators in expression of HLA class II receptors is MHC class II transactivator (CIITA). A variant of the CIITA gene has been found to associate with inflammatory diseases.We wanted to explore whether the risk variant rs3087456 in the CIITA gene interacts with the HLA-DRB1 SE alleles regarding the risk of developing RA. We tested this hypothesis in a case-control study with 11767 individuals from four European Caucasian populations (6649 RA cases and 5118 controls).We found no significant additive interaction for risk alleles among Swedish Caucasians with RA (n = 3869, attributable proportion due to interaction (AP) = 0.2, 95%CI: −0.2–0.5) or when stratifying for anti-citrullinated protein antibodies (ACPA) presence (ACPA positive disease: n = 2945, AP = 0.3, 95%CI: −0.05–0.6, ACPA negative: n = 2268, AP = −0.2, 95%CI: −1.0–0.6). We further found no significant interaction between the main subgroups of SE alleles (DRB1*01, DRB1*04 or DRB1*10) and CIITA. Similar analysis of three independent RA cohorts from British, Dutch and Norwegian populations also indicated an absence of significant interaction between genetic variants in CIITA and SE alleles with regard to RA risk.Our data suggest that risk from the CIITA locus is independent of the major risk for RA from HLA-DRB1 SE alleles, given that no significant interaction between rs3087456 and SE alleles was observed. Since a biological link between products of these genes is evident, the genetic contribution from CIITA and class II antigens in the autoimmune process may involve additional unidentified factors.

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Section: Resultsmentioning

confidence: 99%

Interaction Analysis between HLA-DRB1 Shared Epitope Alleles and MHC Class II Transactivator CIITA Gene with Regard to Risk of Rheumatoid Arthritis

et al. 2012

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“…An MHC2TA −168 A/G polymorphism is associated with MHC2TA gene expression [5]. Previous studies on the association between the MHC2TA −168 A/G polymorphism and RA have produced inconsistent results [5][6][7][8][9][10][11][12][13][14][15][16]. Therefore, we performed a meta-analysis to clarify the association.…”

Section: Discussionmentioning

confidence: 96%

“…Four studies were excluded because three did not contain genotype data for the MHC2TA polymorphism [8] and one was a review. Thus, 12 studies met the inclusion criteria [5][6][7][8][9][10][11][12][13][14][15][16]. One of the eligible studies contained data on two different country populations [6] and one contained data on three ethnically different populations [13], and these were treated independently (Fig.…”

Section: Studies Included In the Meta-analysismentioning

confidence: 99%

“…However, previous studies of the association between the MHC2TA −168 A/G polymorphism and RA have produced inconsistent results [5][6][7][8][9][10][11][12][13][14][15][16], which may reflect inadequate statistical power, racial/ethnic differences in the frequencies of alleles, or publication bias. To overcome the limitations of individual studies, resolve inconsistencies, and reduce the likelihood that random errors were responsible for falsepositive or false-negative associations, we performed a metaanalysis [17][18][19].…”

Section: Introductionmentioning

confidence: 98%

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Association between the functional MHC2TA −168 A/G polymorphism and susceptibility to rheumatoid arthritis: a meta-analysis

Lee

Bae

2015

Clin Rheumatol

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The aim of this study was to determine whether the functional major histocompatibility complex II transactivator (MHC2TA) -168 A/G polymorphism is associated with susceptibility to rheumatoid arthritis (RA). A meta-analysis was conducted to estimate the association between the MHC2TA-168 A/G polymorphism and RA. A total of 15 comparative studies, which included 14,158 patients and 13,642 controls, were included in the meta-analysis. Based on the meta-analysis, there was no association between RA and the MHC2TA -168 G allele in the study subjects (OR = 1.046, 95 % CI = 0.987-1.108, p = 0.130) or Caucasians (OR = 1.027, 95 % CI = 0.986-1.070, p = 0.193). However, the country-specific meta-analysis revealed an association between the MHC2TA -168 G allele and RA in the Swedish population (OR = 1.131, 95 % CI = 1.023-1.250, p = 0.016). A direct comparison between rheumatoid factor (RF)-positive and RF-negative patients revealed that the frequency of the G allele was significantly lower in RF-positive patients (OR = 0.783, 95 % CI = 0.628-0.975, p = 0.029) than in RF-negative patients. This meta-analysis demonstrated that the MHC2TA -168 A/G polymorphism is not associated with susceptibility to RA in Caucasians.

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“…The experimental findings in rats prompted further investigation of C2TA in humans and it was demonstrated that a single nucleotide polymorphism in the 5′ flanking region of type III promoter of C2TA is associated with susceptibility to RA, MS and myocardial infarction . C2TA disease association has since then been shown in different patient cohorts in not only RA and MS, but also T1D, coeliac disease and systemic lupus erythematosus, although disease associations could not be reproduced in some populations …”

Section: Introductionmentioning

confidence: 99%

Effects of C2ta genetic polymorphisms on MHC class II expression and autoimmune diseases

et al. 2016

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Antigen presentation by the MHC-II to CD4 T cells is important in adaptive immune responses. The class II transactivator (CIITA in human and C2TA in mouse) is the master regulator of MHC-II gene expression. It coordinates the transcription factors necessary for the transcription of MHC-II molecules. In humans, genetic variations in CIITA have been associated with differential expression of MHC-II and susceptibility to autoimmune diseases. Here we made use of a C2ta congenic mouse strain (expressing MHC-II haplotype H-2 ) to investigate the effect of the natural genetic polymorphisms in type I promoter of C2ta on MHC-II expression and function. We demonstrate that an allelic variant in the type I promoter of C2ta resulted in an increased expression of MHC-II on macrophages (72-151% higher mean florescence intensity) and conventional dendritic cells (13-65% higher mean florescence intensity) in both spleen and peripheral blood. The increase in MHC-II expression resulted in an increase in antigen presentation to T cells in vitro and increased T-cell activation. The differential MHC-II expression in B6Q.C2ta, however, did not alter the disease development in models of rheumatoid arthritis (collagen-induced arthritis and human glucose-6-phosphate-isomerase -peptide-induced arthritis), or multiple sclerosis (MOG protein-induced and MOG peptide-induced experimental autoimmune encephalomyelitis). This is the first study to address the role of an allelic variant in type I promoter of C2ta in MHC-II expression and autoimmune diseases; and shows that C2ta polymorphisms regulate MHC-II expression and T-cell responses but do not necessarily have a strong impact on autoimmune diseases.

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CIITA gene variants are associated with rheumatoid arthritis in Scandinavian populations

Cited by 22 publications

References 30 publications

Interaction Analysis between HLA-DRB1 Shared Epitope Alleles and MHC Class II Transactivator CIITA Gene with Regard to Risk of Rheumatoid Arthritis

Interaction Analysis between HLA-DRB1 Shared Epitope Alleles and MHC Class II Transactivator CIITA Gene with Regard to Risk of Rheumatoid Arthritis

Association between the functional MHC2TA −168 A/G polymorphism and susceptibility to rheumatoid arthritis: a meta-analysis

Effects of C2ta genetic polymorphisms on MHC class II expression and autoimmune diseases

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