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. 2010 Jun 1;19(11):2331-40.
doi: 10.1093/hmg/ddq101. Epub 2010 Mar 8.

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

Paola G Bronson  1 , 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; International Multiple Sclerosis Genetics Consortium; Stephen L Hauser, Jorge R Oksenberg, Lisa F Barcellos
Affiliations

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

Paola G Bronson et al. Hum Mol Genet. .

Abstract

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 x 10(-3)), particularly in DRB1*1501 +individuals (P = 1 x 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 x 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 x 10(-3)), particularly in DRB1*1501+ cases and controls (P = 1 x 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 x 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 x 10(-3)) and absence (OR = 1.49, 95% CI = 1.15-1.95, P = 2.3 x 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.

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Figures

Figure 1.
Figure 1.
R2 plot illustrating the LD structure of CIITA SNP variants in healthy controls; darker gray indicates higher r2 between pairs of SNPs. LD, linkage disequilbrium; SNP, single nucleotide polymorphism.
See this image and copyright information in PMC

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