Contributions
Abstract: EP1468
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics
Background and aim:The genetic contribution to Multiple Sclerosis(MS) susceptibility is well established, with more than 30 HLA and 200 non-MHC variants linked to disease susceptibility; though, the mechanisms of increased risk due to these SNPs are unclear and studies exploring their association with gene(eQTL) and protein(pQTL) expression can help to shed light on their role in pathogenesis. We found that 3 MS risk variants, rs3809627, rs35218683 and rs6032662 correlated with mRNA levels of MAPK3, IFITM3 and CD40 in peripheral blood mononuclear cells. Here, we investigated the association of these SNPs with protein expression in monocytes from MS patients to better clarify their biological effect.
Methods: CD14+ cells were isolated from 118 RRMS patients treated with glatiramer acetate(n=54) or dymethylfumarate(n=64) and expression of MAPK3, IFITM3 and CD40 was measured with flow cytometry(CFM) as median fluorescence intensity(MFI). Array genotyping was performed, followed by imputation, and genotypes in rs3809627 and rs6032662 were obtained; rs34481144 was used as a tagging SNP(r2:0.48) for rs35218683. Association of MS-related and surrounding variants with protein expression was tested under a linear regression model, covarying for clinico-demographic characteristics (age, gender, therapy) and technical parameters (batches, CFM quality); significance was assessed with permutation testing. A colocalization analysis was performed to test overlap with MS signals.
Results: MS risk alleles rs3809627C, rs6032662C and rs34481144T, were associated to a lower expression of MAPK3, CD40 and IFITM3 compared to the alternative alleles(p< 0.01). When analyzing the nearby genomic regions, we found stronger pQTL signals in MAPK3 and IFITM3 region but we failed to identify any pQTL in the CD40 region after multiple testing correction. The posterior probability of colocalization with the MS signal was high for IFITM3(71.6%) while results for the MAPK3 region were inconclusive.
Conclusions: Our results suggest that the MS-risk region on chr11 likely modulate both gene and protein expression of IFITM3, an interferon induced protein with antiviral and anti-inflammatory properties. It is not clear whether the MAPK3 variant affects protein expression: the overlap in association may be coincidental. This effort prioritizes IFITM3 as a locus with a clear functional effect on downstream biology that we can pursue further as we develop strategies to reverse effects of risk variants
Disclosure: Dr Laura Ferrè, Dr Tina Roostaei, Dr Charles White, Dr Laura Martinez-Calvo, Dr Daniel Felsky, Dr Belinda Kaskow have noting to disclose. Dr Philip De Jager served as a member of advisory board for Celgene, Roche, Sanofi/Genzyme, received grant funding from Eisai, Roche, Biogen, Lundbeck and speaker honorarium from GlaxoSmithKline.
Abstract: EP1468
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics
Background and aim:The genetic contribution to Multiple Sclerosis(MS) susceptibility is well established, with more than 30 HLA and 200 non-MHC variants linked to disease susceptibility; though, the mechanisms of increased risk due to these SNPs are unclear and studies exploring their association with gene(eQTL) and protein(pQTL) expression can help to shed light on their role in pathogenesis. We found that 3 MS risk variants, rs3809627, rs35218683 and rs6032662 correlated with mRNA levels of MAPK3, IFITM3 and CD40 in peripheral blood mononuclear cells. Here, we investigated the association of these SNPs with protein expression in monocytes from MS patients to better clarify their biological effect.
Methods: CD14+ cells were isolated from 118 RRMS patients treated with glatiramer acetate(n=54) or dymethylfumarate(n=64) and expression of MAPK3, IFITM3 and CD40 was measured with flow cytometry(CFM) as median fluorescence intensity(MFI). Array genotyping was performed, followed by imputation, and genotypes in rs3809627 and rs6032662 were obtained; rs34481144 was used as a tagging SNP(r2:0.48) for rs35218683. Association of MS-related and surrounding variants with protein expression was tested under a linear regression model, covarying for clinico-demographic characteristics (age, gender, therapy) and technical parameters (batches, CFM quality); significance was assessed with permutation testing. A colocalization analysis was performed to test overlap with MS signals.
Results: MS risk alleles rs3809627C, rs6032662C and rs34481144T, were associated to a lower expression of MAPK3, CD40 and IFITM3 compared to the alternative alleles(p< 0.01). When analyzing the nearby genomic regions, we found stronger pQTL signals in MAPK3 and IFITM3 region but we failed to identify any pQTL in the CD40 region after multiple testing correction. The posterior probability of colocalization with the MS signal was high for IFITM3(71.6%) while results for the MAPK3 region were inconclusive.
Conclusions: Our results suggest that the MS-risk region on chr11 likely modulate both gene and protein expression of IFITM3, an interferon induced protein with antiviral and anti-inflammatory properties. It is not clear whether the MAPK3 variant affects protein expression: the overlap in association may be coincidental. This effort prioritizes IFITM3 as a locus with a clear functional effect on downstream biology that we can pursue further as we develop strategies to reverse effects of risk variants
Disclosure: Dr Laura Ferrè, Dr Tina Roostaei, Dr Charles White, Dr Laura Martinez-Calvo, Dr Daniel Felsky, Dr Belinda Kaskow have noting to disclose. Dr Philip De Jager served as a member of advisory board for Celgene, Roche, Sanofi/Genzyme, received grant funding from Eisai, Roche, Biogen, Lundbeck and speaker honorarium from GlaxoSmithKline.