Genome-Wide Pharmacogenomic Study Of Response To Cannabinoids In MS Spasticity Patients (P1.185)

OBJECTIVE: to identify genetic determinants of lack of response to THC:CBD spray in patients with MS spasticity (MSS). BACKGROUND: THC:CBD oromucosal spray is increasingly being used to treat resistant spasticity in patients with multiple sclerosis but a proportion of individuals do not respond. METHODS: After prospective observational clinical follow-up in MSS patients on a ‘trial of therapy’ with THC:CBD spray, we performed a Genome Wide Association Study. Affymetrix 6.0 chips and Plink software were used to identify single nucleotide polymorphisms that could predict response. RESULTS: 36 MSS patients were evaluable: 25 responders (-20% on spasticity 0-10 Numerical Rating Scale score after 4 weeks, 69%), 9 non-responders, and 2 patients who did not tolerate treatment. 703,436 SNPs were analyzed. Five SNPs had p-values below 10^-5, corresponding to 3 distinct signals in chromosomes 4, 5 and 6. Signal 1 (rs10018930 and rs10033229, p=6.55 10^-6) in chromosome 4 was located within the large first intron of the ELOVL fatty acid elongase 6 gene (ELOVL6), encoding an enzyme that catalyzes synthesis of saturated and monounsaturated fatty acids. Allele frequency (identical in both markers) was 12% and 67% among responders and non-responders, respectively. Signal 2 in chromosome 5 was located at two DNase clusters 20kb downstream the gene SEMA6A, which encodes a member of the semaphoring family previously implicated in MS. This signal encompasses two different SNPs (rs11241390, p=3.23 10^-6; rs17139724, p=5.21 10^-7) both monomorphic in responders and with allele frequencies in non-responders of 39% and 44% respectively. Signal 3 was observed in chromosome 6 (rs7763280, p=5.48 10^-6) within the genomic sequence of the LYRM4 gene transcripts variants 1 and 3, a gene associated with inflammatory bowel disease, an autoimmune disorder that shares pathogenic pathways with MS. Allele frequency was 32% and 94% among responders and non-responders. CONCLUSIONS: This is the first GWAS on response of MSS patients to cannabinoids. Some results may be extrapolated to pharmacological response to cannabinoids in treatment of other diseases. Disclosure: Dr. Ruiz has nothing to disclose. Dr. Gonzalez-Perez has nothing to disclose. Dr. Garcia-Sanchez has nothing to disclose. Dr. Saez - Goni has nothing to disclose. Dr. Rus Hidalgo has nothing to disclose. Dr. Lucas has nothing to disclose. Dr. Alcina has nothing to disclose. Dr. Matesanz has nothing to disclose. Dr. Izquierdo Ayuso has nothing to disclose.