Combinations of susceptibility genes are important in MS susceptibility

Akkad DA, Olischewsky A, Reiner F, Hellwig K, Esser S, Epplen JT, Curk T, Gold R, Haghikia A. Combinations of Susceptibility Genes Are Associated with Higher Risk for Multiple Sclerosis and Imply Disease Course Specificity. PLoS One. 2015 ;10(5):e0127632. doi: 10.1371/journal.pone.0127632. eCollection 2015.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that predominantly affects young adults. The genetic contributions to this multifactorial disease were underscored by a genome wide association study (GWAS) conducted by the International Multiple Sclerosis Genetic Consortium in a multinational cohort prompting the discovery of 57 non-MHC MS-associated common genetic variants. Hitherto, few of these newly reported variants have been replicated in larger independent patient cohorts.We genotyped a cohort of 1033 MS patients and 644 healthy controls with a consistent genetic background for the 57 non-MHC variants reported to be associated with MS by the first large GWAS as well as the HLA DRB1*1501 tagging SNP rs3135388.  We robustly replicated three of the 57 non-MHC reported MS-associated single nucleotide polymorphisms (SNPs). In addition, our study revealed several genotype-genotype combinations with an evidently higher degree of disease association than the genotypes of the single SNPs. We further correlated well-defined clinical phenotypes, i.e. ataxia, visual impairment due to optic neuritis and paresis with single SNPs and genotype combinations, and identified several associations. The results may open new avenues for clinical implications of the MS associated genetic variants reported from large GWAS.

The International Multiple Sclerosis Genetic Consortium has identified about 150 genes involved in MS susceptibility by analysing many thousands of MSers and non-MSers. The first crop of genes was about 50. In this current study only 3 of  the original 57 were robustly replicated, although a number of the others looked like they associated with MS. Combinations of genes showed better associations than single genes and this is just what we heard last week with the twin studies which indicated traits are controlled by additive effects of genes and a big influence of environment. 

Will genetics lead to treatments in the future?  Time will tell.

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