Importance of Human Leukocyte Antigen (HLA) Class I and II Alleles on the Risk of Multiple Sclerosis

Jenny Link,Ingrid Kockum,Marie Schaffer,Boel Brynedal,Lars Alfredsson,Benedicte A Lie,Elisabeth G Celius,Åslaug R Lorentzen,Tomas Olsson,Jan Hillert,Helga Westerlind,Hanne F Harbo,Jeong-Sun Seo

doi:10.1371/journal.pone.0036779

Jenny Link, Ingrid Kockum + Show 11 more

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https://doi.org/10.1371/journal.pone.0036779

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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.

Highlights

In the past few years, the number of genes known to influence the risk of multiple sclerosis (MS, OMIM:126200), a chronic inflammatory disease of the central nervous system, has increased dramatically
The aim of this study was to investigate the association to Multiple sclerosis (MS) of all three classical human leukocyte antigen (HLA) class I genes, HLA-A, HLA-B, HLA-C as well as the HLA class II gene, HLA-DRB1, in a Scandinavian cohort of 1,784 patients and 1,660 controls
All 3,444 individuals were genotyped for HLA-A, -B, -C, and -DRB1

Summary

Introduction

In the past few years, the number of genes known to influence the risk of multiple sclerosis (MS, OMIM:126200), a chronic inflammatory disease of the central nervous system, has increased dramatically. The discovery of the class II risk haplotype, later shown to be best represented by the HLA-DRB1*15:01 allele, was made almost 40 years ago and was only recently shown to be accompanied by an independent protective allele group in class I, HLA-A*02 [1,2,3,4,5,6]. In addition to these two established alleles a series of reports have suggested additional MS risk alleles as well as interactions between alleles [7]. Interactions have been implicated among DRB1 allele groups: DRB1*08, DRB1*10 and DRB1*01 were reported to interact with DRB1*15 in modifying susceptibility to MS [8,10]

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