G.O.4 Search for SNPs modifiers in DMD with different corticosteroids response by candidate genes targeted resequencing

Abstract Corticosteroid treatment is an established therapy for DMD patients, with proven efficacy in delaying the loss of the ambulation. However the response to corticosteroids is not the same for all DMD individuals, some patients having no appreciable benefit. Considering the considerable side effects of this therapy, it would be desirable to identify biomarkers able to predict the response to corticosteroids. We have carried out a targeted exon sequencing in 243 genes (identified within the BIO-NMD consortium) which are connected to DMD pathways (identified using the MedScan informatics tools developed by ARIADNE), preceded by a targeted specific enrichment step. For target enrichment Agilent’s SureSelect in solution approach was selected. Sixteen DMD patients (eight high responders and eight low responders) were processed using 5500xl SOLiD™ Sequencer. Quality filtering was carried out on the SNP calls returned by LifeScope using quality filters, SNPs in introns were discarded. After quality filtering, 735 SNPs were identified across all samples. We applied two novel statistical methods for analysing variance in the two DMD groups: the multidimensional scaling, and the discriminant analysis, both used to determine which variables discriminate between two (or more) naturally occurring groups. Using both tools we were able to identify 34 SNPs which are differently represented in the two categories (responders/low responders) and do discriminate patients. These SNPs belong to 23 genes, several of which encode for the structural proteins vinculins, integrins, and laminins. In order to validate this data, and to confer robustness and specificity to our identified SNPs, 84 additional DMD patients as well as other non-DMD individuals are now being studied to increase the statistical power of the data. Validated SNPs may represent pharmacogenetic biomarkers for corticosteroid therapy response.