Study of the functional mechanisms underlying the association of CBLB with MS

Recently, we conducted a two-step genome-wide association study on about 6 million genotyped/ imputed variants to detect associations with Multiple Sclerosis (MS) (Sanna et al., 2010). Variant rs9657904 within the CBLB gene, was found associated with MS (P=1.60x10-10). Other markers spanning the region from the 5' UTR gene to IVS3 showed a degree of association similar to that of rs9657904; in particular rs7649466 (r2 = 0.85 with rs9657904) falls in the 5' UTR region of CBLB. CBL proteins are RING-family E3 ubiquitin ligases that act as negative regulators of many receptor tyrosine kinases. E3 ubiquitin ligase Casitas B cell lymphoma-b (Cbl-b) has been recently highlighted as a negative regulator of T-cell activation and its dysfunction usually results in autoimmunity (Schmitz et al, 2009; Loeser et al., 2007)