Genetics of Rheumatic Disease

Alex Clarke; Timothy J Vyse


Arthritis Res Ther. 2009;11(5):248 

In This Article

The MHC Region and Antigen Processing

The major histocompatibility complex (MHC) region on chromosome 6 contributes to the risk of almost all autoimmune diseases, and its role in immunity in mice was recognized over 60 years ago. In humans, the MHC locus is also known as the HLA (human leukocyte antigen) region, reflecting the initial identification of MHC gene products on the surface of white blood cells. The classical MHC extends over around 4 megabases, and comprises three clusters: class I, II, and III. Class I and II regions include genes that encode the α- and β-chains of the MHC I and II complexes, and flank the class III region, which contains an assortment of immunologically relevant genes. Despite extensive study, the mechanisms that link the MHC to disease are largely unknown, although it is supposed that variation in the MHC peptide binding cleft facilitates presentation of self-antigen to autoreactive lymphocytes.

These difficulties in understanding the MHC are not without reason; it contains some of the most polymorphic loci described in the genome, and has a highly complicated genetic architecture, with some regions exhibiting extended linkage disequilibrium.[13]

In RA, the MHC accounts for around a third of the genetic liability.[14] Alleles at HLA-DRB1 contribute much of this risk - for example, DRB1*0401 carries an OR of 3. GWA studies confirm the strong association with MHC variants; risk alleles confer an OR of around 2 to 3 in homozygotes,[15] with very high statistical significance (P < 10−100). Additional loci contributing to the risk of RA identified by high-density genotyping include HLA-DP in patients with anti-cyclic citrullinated peptide antibodies.[16] SLE not only has strongly associated alleles in the class II region, HLA-DR2 (DRB1*1501) and DR3 (DRB1*0301),[14] with ORs of 2,[17] but also risk variants in the class III cluster, which encodes genes such as TNF and the complement components C2, C4A and C4B. C4 is crucial in the classical and mannose-binding lectin pathways of complement activation, and complete deficiency of C4 or indeed other components of the classical pathway are rare, but strong, risk factors for SLE.[18] The C4 gene is subject to CNV and is of two isotypes, C4A and C4B. It is an attractive hypothesis that CNV at C4 affects expression and contributes to SLE risk. However, it remains to be established whether haplotypes carrying partial C4 deficiency exert their risk via an influence on complement or through other genetic variants that are in linkage disequilibrium. Other loci in the class III region have been implicated in SLE, including the SKIV2L gene, SNPs in which carry an OR of 2 in a family-based analysis.[19]SKIV2L encodes superkiller viralicidic activity 2-like, the human homologue of which is a DEAD box protein that may have nucleic acid processing activity. The second MHC III signal for SLE we will consider was identified in the International Consortium on the Genetics of Systemic Lupus Erythematosus (SLEGEN) GWA study.[17,20] The SNP rs3131379 in mutS homologue 5 (MSH5) has an OR of 1.82. There is evidence that MSH5 has a role in immunoglobulin class switch variation.[21] Again, further work is required to definitively implicate this gene rather than variants in linkage disequilibrium, which include HLA-DRB1*0301 and C4A deletions.

Clearly, HLA-B27 is the overwhelming association in AS, with an OR of 200 to 300. In the MHC, other genetic risk variants have been identified, including HLA-B60 (OR 3.6)[22] and various HLA-DR genes with relatively minor contributions.[23] The pathogenic mechanism for these risk alleles is unknown. Outside of the MHC, two significant genes have so far been identified in AS: ARTS1 and IL-23R,[24] the latter of which will be discussed below and has been associated with several different autoimmune diseases. ARTS1 has two identified functions. Its first is in the processing of peptide for presentation via MHC I. It is localised in the endoplasmic reticulum, and is upregulated by IFNγ. It acts as an amino-terminal aminopeptidase and in mice is essential for the display of the normal peptide repertoire. In its absence, many unstable and highly immunogenic MHC-peptide complexes are presented.[25] A hypothetical connection with HLA-B27 can thus be drawn. Its other function is to downregulate signalling by IL-1, IL-6, and TNFα through surface receptor cleavage.[26–28] The most associated SNP rs30187 risk allele has an OR of 1.4, and is of unknown functional significance.


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