Journal Article

<i>CIITA</i> variation in the presence of <i>HLA-DRB1*1501</i> increases risk for multiple sclerosis

Paola G. Bronson, Stacy Caillier, Patricia P. Ramsay, Jacob L. McCauley, Rebecca L. Zuvich, Philip L. De Jager, John D. Rioux, Adrian J. Ivinson, Alastair Compston, David A. Hafler, Stephen J. Sawcer, Margaret A. Pericak-Vance, Jonathan L. Haines, Stephen L. Hauser, Jorge R. Oksenberg and Lisa F. Barcellos

in Human Molecular Genetics

Volume 19, issue 11, pages 2331-2340
Published in print June 2010 | ISSN: 0964-6906
Published online March 2010 | e-ISSN: 1460-2083 | DOI:
CIITA variation in the presence of HLA-DRB1*1501 increases risk for multiple sclerosis

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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 × 10−3), particularly in DRB1*1501 +individuals (P = 1 × 10−4). No association was observed for the −168A/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*1501+ 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*1501+ cases and controls (P = 1 × 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 = 1.72, 95% CI 1.28–2.32, P = 3 × 10−4). Furthermore, rs4774*C was associated with DRB1*1501+ 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.

Journal Article.  6688 words.  Illustrated.

Subjects: Genetics and Genomics

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