The double-faced association of the PRKCA gene with multiple sclerosis

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system characterized by chronic inflammation and progressive neurological dysfunction. The Protein Kinase C Alpha (PRKCA) gene, spanning 508 kb on 17q24.2, was associated with MS in Finnish, Canadian, and UK populations, in which specific risk haplotypes were identified. In this study, we analyzed the role of PRKCA in MS susceptibility in an Italian cohort of 358 cases and 662 controls. An association analysis was performed by genotyping 3 microsatellites and 20 single nucleotide polymorphisms (SNPs) covering the whole gene. Single-marker analysis demonstrated a nominal evidence of association for one allele of the microsatellite mapping in the promoter region of the gene, showing a protective effect (P=0.033; OR=0.12, 95% CI=0.015-0.94). Moreover, a risk haplotype composed of 7 SNPs, spanning a 43-kb-long region of PRKCA, was found (P=0.00074; OR=1.57, 95% CI=1.24-1.99). Interestingly, this haplotype includes an exon characterizing an alternative PRKCA transcript. The expression of both PRKCA wild-type and of its alternative isoform was significantly down-regulated in peripheral blood mononuclear cells of MS patients compared to controls (P=0.00097 and P=0.044, respectively). However, stratification of expression data according to the presence/absence of the risk haplotype did not reveal any significant difference, suggesting that a fine mapping of the 43-kb region is needed to identify the actual risk variant. In conclusion, the identification of both protective and risk alleles in different regions of PRKCA suggests the existence of multiple mechanisms linking genetic variations in this gene to the pathogenesis of MS.