title: 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.
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. marcus.ronninger@ki.se
authors.forename: Marcus
authors.initials: M
authors.lastname: Ronninger
authors.forename: Maria
authors.initials: M
authors.lastname: Seddighzadeh
authors.forename: Morten Christoph
authors.initials: MC
authors.lastname: Eike
authors.forename: Darren
authors.initials: D
authors.lastname: Plant
authors.forename: Nina A
authors.initials: NA
authors.lastname: Daha
authors.forename: Beate
authors.initials: B
authors.lastname: Skinningsrud
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.forename: Tore K
authors.initials: TK
authors.lastname: Kvien
authors.forename: Rene E M
authors.initials: RE
authors.lastname: Toes
authors.forename: Benedicte A
authors.initials: BA
authors.lastname: Lie
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
mesh_terms: D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000208:ethnology / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D015331:Cohort Studies; D004843:Epistasis, Genetic; D000939:Epitopes / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D008297:Male; D009426:Netherlands; D009664:Norway; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013548:Sweden; D015534:Trans-Activators / Q000235:genetics*; D006113:United Kingdom; D044465:White People / Q000235:genetics
chemical_list: D000939:Epitopes; D059811:HLA-DRB1 Chains; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators