The MHC class II transactivator gene (CIITA) is an important transcription factor regulating gene required for HLA class II MHC-restricted antigen presentation. Association with HLA class II variation, particularly HLA-DRB1*1501, has been well-established for multiple sclerosis (MS). In addition, the -168A/G CIITA promoter variant (rs3087456) has been reported to be associated with MS. Thus, a multi-stage investigation of variation within CIITA, DRB1*1501 and MS was undertaken in 6108 individuals. In stage 1,24 SNPs within CIITA were genotyped in 1320 cases and 1363 controls (n = 2683). Rs4774 (missense -1614G/C; G500A) was associated with MS (P = 4.9 3 10-3), particularly in DRB1*1501 1 individuals (P = 1 × 10-4). No association was observed for the 2168A/G promoter variant. In stage 2, rs4774 was genotyped in 973 extended families; rs4774*C was also associated with increased risk for MS in DRB1*15011 families (P = 2.3 × 10-2). In a third analysis, rs4774 was tested in cases and controls (stage 1) combined with one case per family (stage 2) for increased power. Rs4774*C was associated with MS (P = 1 × 10-3), particularly in DRB1*15011 cases and controls (P = 1 3 10-4). Results obtained from logistic regression analysis showed evidence for interaction between rs4774*C and DRB1*1501 associated with risk for MS (ratio of ORs 5 1.72, 95% CI 1.28-2.32, P = 3 × 10-4). Furthermore, rs4774*C was associated with DRB1*15011 MS when conditioned on the presence (OR = 1.67, 95% CI = 1.19-2.37, P = 1.9 × 10-3) and absence (OR = 1.49, 95% CI = 1.15-1.95, P = 2.3 × 10-3) of CLEC16A rs6498169*G, a putative MS risk allele adjacent to CIITA. Our results provide strong evidence supporting a role for CIITA variation in MS risk, which appears to depend on the presence of DRB1*1501.
ASJC Scopus subject areas
- Molecular Biology