title: Variability in the CIITA gene interacts with HLA in multiple sclerosis.
abstract: The human leukocyte antigen (HLA) is the main genetic determinant of multiple sclerosis (MS) risk. Within the HLA, the class II HLA-DRB1*15:01 allele exerts a disease-promoting effect, whereas the class I HLA-A*02 allele is protective. The CIITA gene is crucial for expression of class II HLA molecules and has previously been found to associate with several autoimmune diseases, including MS and type 1 diabetes. We here performed association analyses with CIITA in 2000 MS cases and up to 6900 controls as well as interaction analysis with HLA. We find that the previously investigated single-nucleotide polymorphism rs4774 is associated with MS risk in cases carrying the HLA-DRB1*15 allele (P=0.01, odds ratio (OR): 1.21, 95% confidence interval (CI): 1.04-1.40) or the HLA-A*02 allele (P=0.01, OR: 1.33, 95% CI: 1.07-1.64) and that these associations are independent of the adjacent confirmed MS susceptibility gene CLEC16A. We also confirm interaction between rs4774 and HLA-DRB1*15:01 such that individuals carrying the risk allele for rs4774 and HLA-DRB1*15:01 have a higher than expected risk for MS. In conclusion, our findings support previous data that variability in the CIITA gene affects MS risk, but also that the effect is modulated by MS-associated HLA haplotypes. These findings further underscore the biological importance of HLA for MS risk.
authors.affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Gyllenberg
authors.affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: F
authors.initials: F
authors.lastname: Piehl
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Alfredsson
authors.affiliation: Department of Clinical Neuroscience, Multiple Sclerosis Research Group, Karolinska Institutet, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Hillert
authors.affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: I L
authors.initials: IL
authors.lastname: Bomfim
authors.affiliation: Department of Medicine, Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Padyukov
authors.affiliation: Department of Clinical Sciences, Diabetes and Cardiovascular Disease, Genetic Epidemiology, Lund University Hospital, Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Orho-Melander
authors.affiliation: Department of Clinical Sciences, Diabetes and Cardiovascular Disease, Genetic Epidemiology, Lund University Hospital, Lund, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Lindholm
authors.affiliation: Department of Endocrinology, Skane University Hospital Lund, Lund University, Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Landin-Olsson
authors.affiliation: Department of Medicine, Lund University Hospital, Lund, Sweden.
authors.forename: Å
authors.initials: Å
authors.lastname: Lernmark
authors.affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Olsson
authors.affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: Kockum
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D015810:Linkage Disequilibrium; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D009687:Nuclear Proteins / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D006680:HLA Antigens; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators