The immunogenetics of multiple sclerosis: A comprehensive review

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and common cause of non-traumatic neurological disability in young adults. The likelihood for an individual to develop MS is strongly influenced by her or his ethnic background and family history of disease, suggesting that genetic susceptibility is a key determinant of risk. Over 100 loci have been firmly associated with susceptibility, whereas the main signal genome-wide maps to the class II region of the human leukocyte antigen (HLA) gene cluster and explains up to 10.5% of the genetic variance underlying risk. HLA-DRB1*15:01 has the strongest effect with an average odds ratio of 3.08. However, complex allelic hierarchical lineages, cis/trans haplotypic effects, and independent protective signals in the class I region of the locus have been described as well. Despite the remarkable molecular dissection of the HLA region in MS, further studies are needed to generate unifying models to account for the role of the MHC in disease pathogenesis. Driven by the discovery of combinatorial associations of Killer-cell Immunoglobulin-like Receptor (KIR) and HLA alleles with infectious, autoimmune diseases, transplantation outcome and pregnancy, multi-locus immunogenomic research is now thriving. Central to immunity and critically important for human health, KIR molecules and their HLA ligands are encoded by complex genetic systems with extraordinarily high levels of sequence and structural variation and complex expression patterns. However, studies to-date of KIR in MS have been few and limited to very low resolution genotyping. Application of modern sequencing methodologies coupled with state of the art bioinformatics and analytical approaches will permit us to fully appreciate the impact of HLA and KIR variation in MS.

Keywords: Genetics; Human leukocyte antigen; Killer-cell immunoglobulin-like receptor; Multiple sclerosis.

Figure 1

Global frequency distributions of MS predisposing alleles of HLA-DRB1

Figure 2

Extended DR haplotype structures for MS predisposing DRB1 alleles, showing additional functional DRB gene [black]. DRB pseudogenes may also be present [hatched]

Figure 3

Structure of the six most common KIR gene content haplotypes observed worldwide. The centromeric [Cen] and telomeric [Tel] motifs are labeled according to their association with the KIR A or B haplotype

Figure 4

Noncoding variation in HLA loci can impact expression, through promoter polymorphism [including intronic promoters], introduction of stop codons, via splice site variation, or through sequence disruption