Understanding MS genetics

Patsopoulos NA, Barcellos LF, Hintzen RQ, Schaefer C, van Duijn CM, Noble JA, Raj T; IMSGC; ANZgene, Gourraud PA, Stranger BE, Oksenberg J, Olsson T, Taylor BV, Sawcer S, Hafler DA, Carrington M, De Jager PL, de Bakker PI. Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects.PLoS Genet. 2013 Nov;9(11):e1003926. doi: 10.1371/journal.pgen.1003926. Epub 2013 Nov 21

The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leucocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles

So far there have been about 150 genes associated with susceptibility the first one known for about thirty to forty years was the HLA complex may by from HLA-A,HLA-B, HLA-C, and HLA-DR, HLA-DQ and HLA-DP with the D molecules made up of of two chains A and B eg. HLA-DQA or HLA-DQB. Even now we do not understand this susceptibility factor properly but there are many different variants in this region as we have described previously. This report shows the reason why because there are many different interacting elements some may be related to the target antigens that may trigger the disease preferentially being bound by certain HLA variants with seven being CD4 T cells targets and 2 differnet CD8 T cell targets. The thousand dollar question is what sits n those HLA molecules because this is key to finding the cause.

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