Contributions
Abstract: EP1461
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics
The Melanocortin 1 Receptor (MC1R) determines skin type and hair color. As the MC1R gene is highly polymorphic, there are several variants known, some of which result in diminished receptor function associated with reddish hair, but also risk for melanoma. The MC1R has also been implicated in diseases like Alzheimer's and Parkinson's. Notably, a relationship between the MC1R single nucleotide polymorphism (SNP) Arg160Trp and MS incidence has been found in a previous study.
In our study we investigated the impact of MC1R SNPs on clinical parameters of MS patients. We used data from a multicentric German registry with knowledge of the patients' MC1R status for 21 different SNPs including the most common variants Asp84Glu, Arg151Cys, Arg160Trp, Val92Met, Arg163gln. Variants with low allele frequency were excluded from analysis but information for all 21 SNPs was used to define a WT group. Baseline characteristics were distributed as follows: 986 patients, mean age of 34.31 years, 69.9% women, 45.4% CIS patients, 54.5% RRMS, 32.4% ever-smokers, 40.1% WT, 8.1% with the SNP Arg151Cys, 18.4% with Arg160Trp, 22.7% with Val92Met, 10.1% with Arg163Glu. The mean clinical scores were 1.50 (EDSS), 24.01 (MUSIC), and 39.11 (FSMC).
For baseline analysis of clinical scores, we specified a generalized linear mixed model, which allows for binary responses (e.g. dichotomized EDSS), adjustment for confounders (sex, age, smoking) and a random intercept to account for center variability. All patients were untreated at baseline (inclusion criterium). Upon testing we found a significant influence of Arg160Trp on EDSS (p=0.016) and MUSIC (p=0.027) with a trend in the FSMC score (p=0.064). There was no such relationship for the other variants tested.
To further test our hypothesis over time we chose a nested panel data model with three time points and adjustment for treatment (yes/no). We found an effect of the Arg160Trp variant on EDSS (p=0.008), MUSIC (p=0.011) and FSMC (p=0.042). Furthermore, carriers of this variant show an overall trend towards a higher annualized relapse rate (p=0.064). This is intriguing, as Arg160Trp has already been associated with MS incidence and Parkinson's severity, but also melanoma, where it is associated with high risk and bad prognosis.
Finally, we aim at validating these findings in other national cohorts. Taken together, this study suggests that MS patients with the MC1R SNP Arg160Trp, suffer from worse MS symptoms compared to WT patients.
Disclosure: Funding: This study was funded by the DFG (SFB128, A10 to KL and HW) and the IZKF Münster (to HW and NS).
Conflicts of interest:NS has received travel support from Genyzme and Novartis. PO, JB, TA, GA, TD, NM, KL have no conflicts to report. HW has received honoraria for acting as a member of Scientific Advisory Boards for Biogen, Sanofi-Genzyme, Merck Serono, Novartis, Evgen, MedDay Pharmaceuticals, Roche Pharma AG); speaker honoraria and travel support (Biogen, Sanofi-Genzyme, Merck Serono, Novartis, Roche Pharma AG, Alexion, Cognomed, F.Hoffmann-LA Roche Ltd, TEVA, WebMD Global, Gemeinnützige Hertie-Stiftung, Peervoice, Swiss Multiple Sclerosis Society); compensation as consultant (Biogen, Novartis, Sanofi-Genzyme, Abbvie, Actelion, IGES, GlaxoSmithKline GmbH, Roche Pharma AG, Swiss Multiple Sclerosis Society) an received research support by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgesellschaft (DFG), Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children's Foundation, Biogen, GlaxoSmithKline GmbH, Roche Pharma AG, Sanofi-Genzyme and Novartis.
Abstract: EP1461
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics
The Melanocortin 1 Receptor (MC1R) determines skin type and hair color. As the MC1R gene is highly polymorphic, there are several variants known, some of which result in diminished receptor function associated with reddish hair, but also risk for melanoma. The MC1R has also been implicated in diseases like Alzheimer's and Parkinson's. Notably, a relationship between the MC1R single nucleotide polymorphism (SNP) Arg160Trp and MS incidence has been found in a previous study.
In our study we investigated the impact of MC1R SNPs on clinical parameters of MS patients. We used data from a multicentric German registry with knowledge of the patients' MC1R status for 21 different SNPs including the most common variants Asp84Glu, Arg151Cys, Arg160Trp, Val92Met, Arg163gln. Variants with low allele frequency were excluded from analysis but information for all 21 SNPs was used to define a WT group. Baseline characteristics were distributed as follows: 986 patients, mean age of 34.31 years, 69.9% women, 45.4% CIS patients, 54.5% RRMS, 32.4% ever-smokers, 40.1% WT, 8.1% with the SNP Arg151Cys, 18.4% with Arg160Trp, 22.7% with Val92Met, 10.1% with Arg163Glu. The mean clinical scores were 1.50 (EDSS), 24.01 (MUSIC), and 39.11 (FSMC).
For baseline analysis of clinical scores, we specified a generalized linear mixed model, which allows for binary responses (e.g. dichotomized EDSS), adjustment for confounders (sex, age, smoking) and a random intercept to account for center variability. All patients were untreated at baseline (inclusion criterium). Upon testing we found a significant influence of Arg160Trp on EDSS (p=0.016) and MUSIC (p=0.027) with a trend in the FSMC score (p=0.064). There was no such relationship for the other variants tested.
To further test our hypothesis over time we chose a nested panel data model with three time points and adjustment for treatment (yes/no). We found an effect of the Arg160Trp variant on EDSS (p=0.008), MUSIC (p=0.011) and FSMC (p=0.042). Furthermore, carriers of this variant show an overall trend towards a higher annualized relapse rate (p=0.064). This is intriguing, as Arg160Trp has already been associated with MS incidence and Parkinson's severity, but also melanoma, where it is associated with high risk and bad prognosis.
Finally, we aim at validating these findings in other national cohorts. Taken together, this study suggests that MS patients with the MC1R SNP Arg160Trp, suffer from worse MS symptoms compared to WT patients.
Disclosure: Funding: This study was funded by the DFG (SFB128, A10 to KL and HW) and the IZKF Münster (to HW and NS).
Conflicts of interest:NS has received travel support from Genyzme and Novartis. PO, JB, TA, GA, TD, NM, KL have no conflicts to report. HW has received honoraria for acting as a member of Scientific Advisory Boards for Biogen, Sanofi-Genzyme, Merck Serono, Novartis, Evgen, MedDay Pharmaceuticals, Roche Pharma AG); speaker honoraria and travel support (Biogen, Sanofi-Genzyme, Merck Serono, Novartis, Roche Pharma AG, Alexion, Cognomed, F.Hoffmann-LA Roche Ltd, TEVA, WebMD Global, Gemeinnützige Hertie-Stiftung, Peervoice, Swiss Multiple Sclerosis Society); compensation as consultant (Biogen, Novartis, Sanofi-Genzyme, Abbvie, Actelion, IGES, GlaxoSmithKline GmbH, Roche Pharma AG, Swiss Multiple Sclerosis Society) an received research support by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgesellschaft (DFG), Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children's Foundation, Biogen, GlaxoSmithKline GmbH, Roche Pharma AG, Sanofi-Genzyme and Novartis.