Contributions
Abstract: EP1356
Type: ePoster
Abstract Category: Clinical aspects of MS - 6 MS and gender
Background: Multiple sclerosis (MS) is an autoimmune disease that affects women more than twice as often as men, a difference that is still increasing. Still, sex-related underlying differences in gene expression in MS patients and healthy controls (HCs) have only been scarcely investigated.
Objective: To analyze differentially expressed genes in women and men with untreated MS by comparing them with HCs of the same sex.
Methods: We included 30 women with relapsing-remitting (RR) MS and 28 HC women and 17 men with RRMS and 30 HC men. RNA was extracted from whole blood and gene expression levels measured by Affymetrix Gene 2.0 ST array. Data normalization and analyses were performed in Partek Genomics Suite and the enrichment of annotated genes was investigated using the database DAVID. We applied false discovery rate (FDR) (q< 0.01, ±2-fold) on p-values to adjust for multiple comparisons.
Results: We found no differences between MS and healthy men and only PDK4 was higher expressed in MS women than in HC women (2.2-fold, q=1.75x10-9). Next we analyzed gene expression at ±1.3-fold difference by ANCOVA adjusted for age and scan-date (p< 0.05) and observed 21 differentially expressed genes in women with MS and HCs, including a higher expression of HLA-DRB1, -DQA1, -DQB1, -DRA and -DRB5 in MS women. At the same conditions 158 genes were differentially expressed between men with MS and HCs, however only HLA-DRB1 and -DRB5 were significantly up-regulated in MS men compared to healthy individuals.
Functional annotation clustering, using the highest stringency, of all 21 genes identified 7 clusters of which 4 had significantly enriched (FDR< 0.01) pathways and enrichment scores from 6.63 to 3.47. These 4 clusters consisted primarily of the above mentioned HLA-genes. In men functional annotation clustering of the 158 genes resulted in 8 clusters with the highest enrichment score of 2.13 encompassing genes from the type 1 interferon signaling pathway and a cluster with granzyme proteins, however these clusters were not significant after FDR correction.
Conclusion: Interestingly, of the HLA-genes only HLA-DRB1 and -DRB5 were higher expressed in both MS men and women. Most likely this reflects an effect of the MS-associated HLA-DRB1*15:01 genotype. Of interest, the most differentially expressed gene in MS women (PDK4) is a mitochondrial protein involved in regulating the conversion of pyruvate to acetyl-CoA, and is inducible by several steroid hormones.
Disclosure:
Hannah-Marie Laigaard has nothing to disclose.
Annette Oturai has served on scientific advisory boards for Biogen and Genzyme; has received support for congress participation from Biogen, Novartis, Genzyme, and TEVA; has received speaker honoraria from, Biogen, Novartis, and TEVA.
Cecilie Ammitzbøl has received support for congress participation from Biogen, Merck, Genzyme, and TEVA.
Lars Börnsen has received support for congress participation from Biogen, Merck, Genzyme, and TEVA.
Per Soelberg Sørensen has received personal compensation for serving on advisory boards for Biogen, Merck, Novartis, Teva, MedDay Pharmaceuticals, and GSK; on steering committees or independent data monitoring boards in trials sponsored by Merck, Teva, GSK, and Novartis; has received speaker honoraria from Biogen, Merck, Teva, Sanofi-Aventis, Genzyme, and Novartis.
Finn Sellebjerg has served on scientific advisory boards for Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Teva, has been on the steering committee of a clinical trial sponsored by Merck Serono, and served as consultant for Biogen Idec and Novo Nordisk; has received support for congress participation from Biogen Idec, Novartis, Sanofi Aventis and Teva; has received speaker honoraria from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Schering-Plough.
Helle Bach Søndergaard has received support for congress participation from Biogen, Genzyme and Teva.
Abstract: EP1356
Type: ePoster
Abstract Category: Clinical aspects of MS - 6 MS and gender
Background: Multiple sclerosis (MS) is an autoimmune disease that affects women more than twice as often as men, a difference that is still increasing. Still, sex-related underlying differences in gene expression in MS patients and healthy controls (HCs) have only been scarcely investigated.
Objective: To analyze differentially expressed genes in women and men with untreated MS by comparing them with HCs of the same sex.
Methods: We included 30 women with relapsing-remitting (RR) MS and 28 HC women and 17 men with RRMS and 30 HC men. RNA was extracted from whole blood and gene expression levels measured by Affymetrix Gene 2.0 ST array. Data normalization and analyses were performed in Partek Genomics Suite and the enrichment of annotated genes was investigated using the database DAVID. We applied false discovery rate (FDR) (q< 0.01, ±2-fold) on p-values to adjust for multiple comparisons.
Results: We found no differences between MS and healthy men and only PDK4 was higher expressed in MS women than in HC women (2.2-fold, q=1.75x10-9). Next we analyzed gene expression at ±1.3-fold difference by ANCOVA adjusted for age and scan-date (p< 0.05) and observed 21 differentially expressed genes in women with MS and HCs, including a higher expression of HLA-DRB1, -DQA1, -DQB1, -DRA and -DRB5 in MS women. At the same conditions 158 genes were differentially expressed between men with MS and HCs, however only HLA-DRB1 and -DRB5 were significantly up-regulated in MS men compared to healthy individuals.
Functional annotation clustering, using the highest stringency, of all 21 genes identified 7 clusters of which 4 had significantly enriched (FDR< 0.01) pathways and enrichment scores from 6.63 to 3.47. These 4 clusters consisted primarily of the above mentioned HLA-genes. In men functional annotation clustering of the 158 genes resulted in 8 clusters with the highest enrichment score of 2.13 encompassing genes from the type 1 interferon signaling pathway and a cluster with granzyme proteins, however these clusters were not significant after FDR correction.
Conclusion: Interestingly, of the HLA-genes only HLA-DRB1 and -DRB5 were higher expressed in both MS men and women. Most likely this reflects an effect of the MS-associated HLA-DRB1*15:01 genotype. Of interest, the most differentially expressed gene in MS women (PDK4) is a mitochondrial protein involved in regulating the conversion of pyruvate to acetyl-CoA, and is inducible by several steroid hormones.
Disclosure:
Hannah-Marie Laigaard has nothing to disclose.
Annette Oturai has served on scientific advisory boards for Biogen and Genzyme; has received support for congress participation from Biogen, Novartis, Genzyme, and TEVA; has received speaker honoraria from, Biogen, Novartis, and TEVA.
Cecilie Ammitzbøl has received support for congress participation from Biogen, Merck, Genzyme, and TEVA.
Lars Börnsen has received support for congress participation from Biogen, Merck, Genzyme, and TEVA.
Per Soelberg Sørensen has received personal compensation for serving on advisory boards for Biogen, Merck, Novartis, Teva, MedDay Pharmaceuticals, and GSK; on steering committees or independent data monitoring boards in trials sponsored by Merck, Teva, GSK, and Novartis; has received speaker honoraria from Biogen, Merck, Teva, Sanofi-Aventis, Genzyme, and Novartis.
Finn Sellebjerg has served on scientific advisory boards for Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Teva, has been on the steering committee of a clinical trial sponsored by Merck Serono, and served as consultant for Biogen Idec and Novo Nordisk; has received support for congress participation from Biogen Idec, Novartis, Sanofi Aventis and Teva; has received speaker honoraria from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Schering-Plough.
Helle Bach Søndergaard has received support for congress participation from Biogen, Genzyme and Teva.