Editors' ChoiceMultiple Sclerosis

Harvesting HLA Region for Multiple Sclerosis Effects

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Science Translational Medicine  11 Dec 2013:
Vol. 5, Issue 215, pp. 215ec206
DOI: 10.1126/scitranslmed.3008081

The human leukocyte antigen (HLA) region is one of the most complex regions of the human genome. What’s more, the HLA region has an extremely high rate of genetic variation, with an extremely extensive and long-range linkage disequilibrium (correlation between genetic variants). Further complicating things, there are HLA “classical alleles,” such as class I (which take peptides from within the cell and present them to T cells) and class II (which take antigens from outside the cell and present them to T cells) alleles, as well as additional genes that perform other biological functions in the region. These factors make identifying which genetic variants and biological mechanisms are actually influencing risk challenging when a significant association is present.

In multiple sclerosis (MS), the strongest genetic signals have mapped to the HLA region; the strongest classical allele association has been demonstrated for the class II allele, HLA-DRB1*15:01. Patsopoulos and colleagues replicate this finding and other class II allele associations in the region, such as DRB1*03:01, *13:03, *04:04, *04:01, and *14:01. Interestingly, when controlling for the DRB1 associations the DQB1 and DQA1 alleles do not appear to confer risk, which is counter to some earlier work. Beyond the class II alleles, the authors also examined evidence for class I association, replicating HLA-A*02:01 and DPB1*03:01, as well as confirming HLA-B associations at B*37:01 and B*38:01. For these classical alleles, the authors engaged in a series of amino acid tests in order to further narrow down the potential binding positions that might alter risk. These tests are consistent with the disease model that an inflammatory demyelination process is being induced by altered T cells, on the basis of differences in binding driven by these amino acid changes.

Beyond these classical associations, the authors also established the presence of a risk haplotype that spans the HLA region that does not appear to be associated with any of the classical HLA alleles activity. This long-range haplotype appears to act independently of the other HLA associations in the region, which is also known to harbor associations to other autoimmune diseases such as Inflammatory Bowel Disease and Sjogren’s syndrome. Fine-mapping within this region is beset by the challenges described above, but the authors note that three genes in this region—TNF, LTA, and LTB—are ligands for TNFR SF1A, a previously established risk gene for MS.

N. A. Patsopoulos et al., Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects. PLOS Gen. 9, e1003026 (2013). [Full Text]

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