title: CIITA variation in the presence of HLA-DRB1*1501 increases risk for multiple sclerosis.
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.
authors.affiliation: Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, University of California, Berkeley, CA 94720-7356, USA.
authors.forename: Paola G
authors.initials: PG
authors.lastname: Bronson
authors.forename: Stacy
authors.initials: S
authors.lastname: Caillier
authors.forename: Patricia P
authors.initials: PP
authors.lastname: Ramsay
authors.forename: Jacob L
authors.initials: JL
authors.lastname: McCauley
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Zuvich
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.forename: John D
authors.initials: JD
authors.lastname: Rioux
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Ivinson
authors.forename: Alastair
authors.initials: A
authors.lastname: Compston
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sawcer
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Barcellos
mesh_terms: D017951:Antigen Presentation / Q000235:genetics*; D014644:Genetic Variation; D006684:HLA-DR Antigens / Q000235:genetics* / Q000378:metabolism; D059811:HLA-DRB1 Chains; D006801:Humans; D016015:Logistic Models; D009103:Multiple Sclerosis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C489631:HLA-DRB1*15:01 antigen; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators