Human gene variant influences disease

Multiple sclerosis associated genetic variants of CD226 impair regulatory T cell function.Piédavent-Salomon M, Willing A, Engler JB, Steinbach K, Bauer S, Eggert B, Ufer F, Kursawe N, Wehrmann S, Jäger J, Reinhardt S, Friese MA.Brain. 2015 Sep 10. pii: awv256. [Epub ahead of print]

Recent association studies have linked numerous genetic variants with an increased risk for multiple sclerosis, although their functional relevance remains largely unknown. Here we investigated phenotypical and functional consequences of a genetic variant in the CD226 gene that, among other autoimmune diseases, predisposes to multiple sclerosis. Phenotypically, effector and regulatory CD4+ memory T cells of healthy individuals carrying the predisposing CD226 genetic variant showed, in comparison to carriers of the protective variant, reduced surface expression of CD226 and an impaired induction of CD226 after stimulation. This haplotype-dependent reduction in CD226 expression on memory T cells was abrogated in patients with multiple sclerosis, as CD226 expression was comparable to healthy risk haplotype carriers irrespective of genetic variant. Functionally, FOXP3-positive regulatory T cells from healthy carriers of the genetic protective variant showed superior suppressive capacity, which was again abrogated inmultiple sclerosis patients. Mimicking the phenotype of human CD226 genetic risk variant carriers, regulatory T cells derived from Cd226-deficient mice showed similarly reduced inhibitory activity, eventually resulting in an exacerbated disease course of experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. Therefore, by combining human and mouse analyses we show that CD226 exhibits an important role in the activation of regulatory T cells, with its genetically imposed dysregulation impairing regulatory T cell function.

There are about 150 known MS susceptibility genes variants. But what do they do. It is difficult to work out in humans as you can’t manipulate the system. 

One way to work out what the variant does is to make a transgenic mouse that expresses the human disease associated variant and compare it with the non-MS associated gene variant.

In this study they show that the variant associated with protection from MS showed more regulatory cell function.

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