title: Importance of human leukocyte antigen (HLA) class I and II alleles on the risk of multiple sclerosis.
abstract: Multiple sclerosis (MS) is a complex disease of the central nervous system of unknown etiology. The human leukocyte antigen (HLA) locus on chromosome 6 confers a considerable part of the susceptibility to MS, and the most important factor is the class II allele HLA-DRB1*15:01. In addition, we and others have previously established a protective effect of HLA-A*02. Here, we genotyped 1,784 patients and 1,660 healthy controls from Scandinavia for the HLA-A, HLA-B, HLA-C and HLA-DRB1 genes and investigated their effects on MS risk by logistic regression. Several allele groups were found to exert effects independently of DRB1*15 and A*02, in particular DRB1*01 (OR = 0.82, p = 0.034) and B*12 (including B*44/45, OR = 0.76, p = 0.0028), confirming previous reports. Furthermore, we observed interaction between allele groups: DRB1*15 and DRB1*01 (multiplicative: OR = 0.54, p = 0.0041; additive: AP = 0.47, p = 4 × 10(-06)), DRB1*15 and C*12 (multiplicative: OR = 0.37, p = 0.00035; additive: AP = 0.58, p = 2.6 × 10(-05)), indicating that the effect size of these allele groups varies when taking DRB1*15 into account. Analysis of inferred haplotypes showed that almost all DRB1*15 bearing haplotypes were risk haplotypes, and that all A*02 bearing haplotypes were protective as long as they did not carry DRB1*15. In contrast, we found one class I haplotype, carrying A*02-C*05-B*12, which abolished the risk of DRB1*15. In conclusion, these results confirms a complex role of HLA class I and II genes that goes beyond DRB1*15 and A*02, in particular by including all three classical HLA class I genes as well as functional interactions between DRB1*15 and several alleles of DRB1 and class I genes.
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. jenny.link@ki.se
authors.forename: Jenny
authors.initials: J
authors.lastname: Link
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kockum
authors.forename: Aslaug R
authors.initials: AR
authors.lastname: Lorentzen
authors.forename: Benedicte A
authors.initials: BA
authors.lastname: Lie
authors.forename: Elisabeth G
authors.initials: EG
authors.lastname: Celius
authors.forename: Helga
authors.initials: H
authors.lastname: Westerlind
authors.forename: Marie
authors.initials: M
authors.lastname: Schaffer
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.forename: Boel
authors.initials: B
authors.lastname: Brynedal
authors.forename: Hanne F
authors.initials: HF
authors.lastname: Harbo
authors.forename: Jan
authors.initials: J
authors.lastname: Hillert
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D015234:HLA-A Antigens / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012537:Scandinavian and Nordic Countries
chemical_list: D015234:HLA-A Antigens; D015235:HLA-B Antigens; D059811:HLA-DRB1 Chains