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.

The immunogenetics of multiple sclerosis. The frequency of HLA-alleles class 1 and 2 is lower in Southern Brazil than in the European population

“…Haplotype studies have shown that, HLA-A*02 reduces susceptibility to the disease (protective effect) when associated with HLA-B*12 and HLA-Cw*05. The same occurred if this allele was associated with HLA-Cw*05 and HLA-B*44 11,12 . The presence of the allele Cw*05 in the haplotype reduce the expression of HLA-B12 and DRB1*15 and the susceptibility to the disease 11,13 .…”

“…The same occurred if this allele was associated with HLA-Cw*05 and HLA-B*44 11,12 . The presence of the allele Cw*05 in the haplotype reduce the expression of HLA-B12 and DRB1*15 and the susceptibility to the disease 11,13 . In light of the above, the aim of this study is to analyze the HLA class 1 and 2 profiles, with high resolutions technique, of MS patients of a Southern Brazil population to identify whether there is relationship between HLA type and susceptibility to MS in the Southern Brazilian population.…”

“…In recent years, researchers have turned their attention to HLA class I and its alleles. Initially performed with low resolution techniques, HLA typing showed that HLA-A*02 is negatively associated with the risk of MS (i.e., it is associated with a protective effect/reduction in susceptibility) regardless of the presence of the DRB1*15 allele 11 . Haplotype studies have shown that, HLA-A*02 reduces susceptibility to the disease (protective effect) when associated with HLA-B*12 and HLA-Cw*05.…”

The Role of HLA in MS Susceptibility and Phenotype

“…HLA-A*02 has been reported to confer protection against MS in multiple casecontrol studies (Bettencourt et al 2012;Bergamaschi et al 2010Bergamaschi et al , 2011Brynedal et al 2007;Burfoot et al 2008;Link et al 2010;Rubio et al 2002;Sawcer et al 2011;Silva et al 2009). However, a protective effect of HLA-A*02 was not observed in studies investigating transmission of HLA in MS families (Chao et al 2007), and recent reports suggest that HLA-A*02 might only exert protective effects in the absence of HLA-DRB1*15:01 (Link et al 2012). Other reported protective class I molecules include HLA-C*05 (or a variant in tight-linkage disequilibrium with it) (Yeo et al 2007), HLA-C*08 (Link et al 2010), HLA-B*44 (Bergamaschi et al 2011;Healy et al 2010), and HLA-B*52 (Benedek et al 2010).…”

“…There is also a robust literature showing that certain class II HLA types occur less frequently in MS patients than that in healthy individuals: these include HLA-DR1, HLA-DR4, HLA-DR6, HLA-DR7, HLA-DR9, HLA-DR11 and HLA-DR14 types (Balnyte et al 2012;Barcellos et al 2006;Cocco et al 2012Cocco et al , 2013DeLuca et al 2007;Dyment et al 2005;Fernandez et al 2009;Greer and Pender 2005;Kaimen-Maciel et al 2009;Link et al 2012;Masterman et al 2000;McDonnell et al 1999;Qiu et al 2011a;Stankovich et al 2009;Wu et al 2010a;Zhang et al 2011). It should be noted, however, that many of the studies from which this information is derived only reported HLA typing at the serotyping or two digit level and that some of these "protective" HLA types consist of many different alleles with markedly different amino acid sequences in regions forming the antigen-binding grooves of the HLA molecules, as discussed further below.…”