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: −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.

Understanding HLA associations from SNP summary association statistics

“…Moreover, the most protective, susceptible alleles were identical in both methods, illustrating the usefulness of the DISH method in looking for the most significant alleles in HLA fine-mapping studies. The observed associations of HLA-DRB1 alleles with RA or SLE in DISH-based and HMM-based approaches were supported by previous studies 15,16 that tested for the association for sequenced HLA-DRB1 alleles.…”

Genetic Variations of NLR family genes in Behcet’s Disease

“…Another study showed that the two SNPs rs4774 and rs6498122 of CIITA were associated with oral lichen planus (OLP) 28 . CIITA//rs8048002 was found to be associated with RA in a Swedish cohort 29 . CIITA//rs12932187 and rs11074938 were found to be susceptibility markers of nasal passages inflammation in asthma patients in a Japanese population 30 .…”

Association of hyperlipidaemia, inflammation and serological status and coronary heart disease among patients with rheumatoid arthritis: data from the National Veterans Health Administration

“… 5 26 Seropositivity with either positive RF or anti-CCP or antinuclear antibodies had been associated with higher mortality from CHD even in patients without articular symptoms. 27 28 This comparison of autoantibody-positive RA to autoantibody-negative RA is relevant given that the genetic contribution of HLA-DRB1 shared epitope is restricted to autoantibody-positive RA, 29 30 which had also been associated with higher cardiovascular mortality rate. 31 Like the aforementioned studies, our study showed an association between seropositivity and MI risk.…”