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

Abstract 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: 20.2-0.5) or when stratifying for anti-citrullinated protein antibodies (ACPA) presence (ACPA positive disease: n = 2945, AP = 0.3, 95%CI: 20.05-0.6, ACPA negative: n = 2268, AP = 20.2, 95%CI: 21.0-0.6). 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

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

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

Summary data of the interaction analysis for <i>HLA-DRB1</i> SE allelic groups and SNP rs3087456 for the Swedish cohort.

<p>Additive interaction is presented as attributable proportion (AP) with 95% confidence interval (CI). For additional analysis see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032861#pone.0032861.s005" target="_blank">Table S5</a>. SE = shared epitope; ACPA+ = anti citrullinated protein antibody positive RA patients.</p

Risk of developing RA for combinations of the <i>HLA-DRB1</i> SE and rs3087456 alleles in Swedish.

<p>British. Dutch and Norwegian cohorts.</p><p>Results for additive (add.) and multiplicative (mult.) interaction is displayed as significance (P value) of deviation from expected risk given no interaction. AP = attributable proportion; SE = shared epitope; OR = odds ratio; ACPA+ = anti citrullinated protein antibody positive RA patients; CI = confidence interval.</p

Summary data for interaction analysis between <i>CIITA</i> rs4781019 and <i>HLA-DRB1</i> SE.

<p>The table presents the best result after analysis of interaction between the <i>CIITA</i> locus and <i>HLA-DRB1</i>. Dominant and recessive (for the risk allele) genetic models were tested for each SNP, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032861#pone.0032861.s004" target="_blank">Table S4</a> for complete results. AP = attributable proportion; SE = shared epitope; ACPA+ = anti citrullinated protein antibody positive RA patients.</p

A novel sarcoidosis risk locus for Europeans on chromosome 11q13.1.

Rationale: Sarcoidosis is a complex inflammatory disease with a heterogeneous clinical picture. Among others, an acute and chronic clinical course can be distinguished, for which specific genetic risk factors are known. Objectives: To identify additional risk loci for sarcoidosis and its acute and chronic subforms, we analyzed imputed data from a genomewide association scan for these phenotypes. Methods: After quality control, the genome-wide association scan comprised nearly 1.3 million imputed single-nucleotide polymorphisms based on an Affymetrix 6.0 Gene Chip dataset of 564 German sarcoidosis cases, including 176 acute and 354 chronic cases and 1,575 control subjects. Measurements and Main Results: We identified chromosome 11q13.1 (rs479777) as a novel locus influencing susceptibility to sarcoidosis with genome-wide significance. The marker was significantly associated in three distinct German case-control populations and in an additional German family sample with odds ratios ranging from 0.67 to 0.77. This finding was further replicated in two independent European case-control populations from the Czech Republic (odds ratio, 0.75) and from Sweden (odds ratio, 0.79). In a meta-analysis of the included European case-control samples the marker yielded a P value of 2.68 x 10(-18). The locus was previously reported to be associated with Crohn disease, psoriasis, alopecia areata, and leprosy. For sarcoidosis, fine-mapping and expression analysis suggest KCNK4, PRDX5, PCLB3, and most promising CCDC88B as candidates for the underlying risk gene in the associated region. Conclusions: This study provides striking evidence for association of chromosome 11q13.1 with sarcoidosis in Europeans, and thus identified a further genetic risk locus shared by sarcoidosis, Crohn disease and psoriasis