Contributions
Abstract: P960
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Genetics /Epigenetics and Pharmacogenetics
Introduction: Intrathecal synthesis of immunoglobulins can often be observed in patients with multiple sclerosis (MS) and clinically isolated syndrome (CIS) and the amount of intrathecal immunoglobulin synthesis in an individual patient remains relatively stable over time. We could previously show an association between the IgG index and genetic variants located around the immunoglobulin heavy chain locus (IGHC) on chromosome 14 using a genome wide association study (GWAS). The variants corresponded to different allotypes that code for structurally distinct immunoglobulin heavy chains. The aim of this study was to confirm the previously described association by genotyping the single nucleotide polymorphism (SNP) rs74093865, which is in strong linkage disequilibrium (r2 0.9) with the lead SNP rs10136766 from our previous study and to further investigate the effect of this genetic variant on intrathecal synthesis of IgA and IgM.
Methods: DNA samples from 785 MS or CIS patients with available data on intrathecal immunoglobulin synthesis, who were not part of our previous study, were obtained and genotyped for the rs74093865 using a TaqMan SNP genotyping assay . The association between rs74093865 and rank transformed IgG, IgM and IgA indices was tested using linear regression with adjustments made for sex, age, assay plate, time points of lumbar puncture and DNA sampling.
Results: rs74093865 was significantly associated with indices for IgG, IgM and IgA in patients with MS and CIS. In accordance with our previous findings, the A allele, which corresponds to the IGHC Gm21* allotype, correlated with higher IgG index (p=2E-13). Interestingly, lower IgM and IgA indices were seen in patients carrying the A allele of rs74093865 (p=3E-7 and p=5E-4 for IgM and IgA indices, respectively).
Conclusion: The results of this study confirm the association of a genetic variant located around the immunoglobulin heavy chain locus with intrathecal immunoglobulin synthesis. Interestingly the Gm21* allotype seems to be associated with higher intrathecal IgG synthesis and lower intrathecal IgA and IgM synthesis.
Disclosure: C. Gasperi: nothing to disclose.
A. Krysta: nothing to disclose.
G. Antony: nothing to disclose.
A. Bayas: Personal compensation from Merck Serono, Biogen, Bayer Vital, Novartis, TEVA, Roche and Sanofi/Genzyme and grants for congress trips and participation from Biogen, Novartis, Sanofi/Genzyme and Merck Serono.
R. Gold has nothing to disclose.
C. Heesen: nothing to disclose.
T. Kümpfel has received travel expenses and personal compensations from Bayer Healthcare, Teva Pharma, Merck-Serono, Novartis Pharma, Sanofi-Aventis/Genzyme and Biogen-Idec as well as grant support from Bayer-Schering AG and Novartis Pharma.
R.A. Linker received compensation for personal activities and/or research support from Bayer Health Care, Biogen, Genzyme/Sanofi, Merck, Novartis Pharma, Roche and TEVA Pharma. RAL holds an endowed professorship supported by Novartis Pharma.
F. Paul: nothing to disclose.
M. Stangel has received honoraria for scientific lectures or consultancy from Bayer Healthcare, Biogen, Baxter/Baxalta, CSL Behring, Euroimmune, Grifols, Merck-Serono, Novartis, Roche, Sanofi Genzyme, and Teva. His institution received research support from Biogen, Novartis, Sanofi Genzyme and Teva. He is on the editorial board of PLoS ONE and Multiple Sclerosis International.
B. Tackenberg received consultancy fees, speaker honoraria and research grants from Bayer, Biogen, CSL Behring, Grifols, Merck Serono, Novartis, Octapharma, Roche, Sanofi Genzyme, Teva.
F. Then Bergh: none related to this project.
H. Tumani: nothing to disclose.
C. Warnke: consultancy, grant support: Novartis, Bayer, Biogen, Teva.
F. Weber received honoraria from Genzyme, Novartis TEVA and Biogen for speaking or for serving on a scientific advisory board, a travel grant for the attention of a scientific meeting from Merck-Serono and Novartis and grant support from Merck-Serono, Novartis and from the Federal Ministry of Education and Research (BMBF, Projects Biobanking and Omics in ControlMS as part of the Competence Network Multiple Sclerosis).
W. Wick: nothing to disclose.
H. Wiendl: nothing to disclose.
U.K. Zettl: none related to this project.
U. Ziemann: nothing to disclose.
F. Zipp: nothing to disclose.
D. Buck has received compensation for activities with Bayer HealthCare, BiogenIdec, MerckSerono, and Novartis. She is supported by the Abirisk Consortium.
B. Hemmer has served on scientific advisory boards for Roche, Novartis, Bayer Schering, and Genentech; has received speaker honoraria from Biogen Idec and Roche; and has received research support from Chugai Pharmaceuticals. He holds part of a patent for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and genetic determinants of neutralizing antibodies to interferon-beta
Abstract: P960
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Genetics /Epigenetics and Pharmacogenetics
Introduction: Intrathecal synthesis of immunoglobulins can often be observed in patients with multiple sclerosis (MS) and clinically isolated syndrome (CIS) and the amount of intrathecal immunoglobulin synthesis in an individual patient remains relatively stable over time. We could previously show an association between the IgG index and genetic variants located around the immunoglobulin heavy chain locus (IGHC) on chromosome 14 using a genome wide association study (GWAS). The variants corresponded to different allotypes that code for structurally distinct immunoglobulin heavy chains. The aim of this study was to confirm the previously described association by genotyping the single nucleotide polymorphism (SNP) rs74093865, which is in strong linkage disequilibrium (r2 0.9) with the lead SNP rs10136766 from our previous study and to further investigate the effect of this genetic variant on intrathecal synthesis of IgA and IgM.
Methods: DNA samples from 785 MS or CIS patients with available data on intrathecal immunoglobulin synthesis, who were not part of our previous study, were obtained and genotyped for the rs74093865 using a TaqMan SNP genotyping assay . The association between rs74093865 and rank transformed IgG, IgM and IgA indices was tested using linear regression with adjustments made for sex, age, assay plate, time points of lumbar puncture and DNA sampling.
Results: rs74093865 was significantly associated with indices for IgG, IgM and IgA in patients with MS and CIS. In accordance with our previous findings, the A allele, which corresponds to the IGHC Gm21* allotype, correlated with higher IgG index (p=2E-13). Interestingly, lower IgM and IgA indices were seen in patients carrying the A allele of rs74093865 (p=3E-7 and p=5E-4 for IgM and IgA indices, respectively).
Conclusion: The results of this study confirm the association of a genetic variant located around the immunoglobulin heavy chain locus with intrathecal immunoglobulin synthesis. Interestingly the Gm21* allotype seems to be associated with higher intrathecal IgG synthesis and lower intrathecal IgA and IgM synthesis.
Disclosure: C. Gasperi: nothing to disclose.
A. Krysta: nothing to disclose.
G. Antony: nothing to disclose.
A. Bayas: Personal compensation from Merck Serono, Biogen, Bayer Vital, Novartis, TEVA, Roche and Sanofi/Genzyme and grants for congress trips and participation from Biogen, Novartis, Sanofi/Genzyme and Merck Serono.
R. Gold has nothing to disclose.
C. Heesen: nothing to disclose.
T. Kümpfel has received travel expenses and personal compensations from Bayer Healthcare, Teva Pharma, Merck-Serono, Novartis Pharma, Sanofi-Aventis/Genzyme and Biogen-Idec as well as grant support from Bayer-Schering AG and Novartis Pharma.
R.A. Linker received compensation for personal activities and/or research support from Bayer Health Care, Biogen, Genzyme/Sanofi, Merck, Novartis Pharma, Roche and TEVA Pharma. RAL holds an endowed professorship supported by Novartis Pharma.
F. Paul: nothing to disclose.
M. Stangel has received honoraria for scientific lectures or consultancy from Bayer Healthcare, Biogen, Baxter/Baxalta, CSL Behring, Euroimmune, Grifols, Merck-Serono, Novartis, Roche, Sanofi Genzyme, and Teva. His institution received research support from Biogen, Novartis, Sanofi Genzyme and Teva. He is on the editorial board of PLoS ONE and Multiple Sclerosis International.
B. Tackenberg received consultancy fees, speaker honoraria and research grants from Bayer, Biogen, CSL Behring, Grifols, Merck Serono, Novartis, Octapharma, Roche, Sanofi Genzyme, Teva.
F. Then Bergh: none related to this project.
H. Tumani: nothing to disclose.
C. Warnke: consultancy, grant support: Novartis, Bayer, Biogen, Teva.
F. Weber received honoraria from Genzyme, Novartis TEVA and Biogen for speaking or for serving on a scientific advisory board, a travel grant for the attention of a scientific meeting from Merck-Serono and Novartis and grant support from Merck-Serono, Novartis and from the Federal Ministry of Education and Research (BMBF, Projects Biobanking and Omics in ControlMS as part of the Competence Network Multiple Sclerosis).
W. Wick: nothing to disclose.
H. Wiendl: nothing to disclose.
U.K. Zettl: none related to this project.
U. Ziemann: nothing to disclose.
F. Zipp: nothing to disclose.
D. Buck has received compensation for activities with Bayer HealthCare, BiogenIdec, MerckSerono, and Novartis. She is supported by the Abirisk Consortium.
B. Hemmer has served on scientific advisory boards for Roche, Novartis, Bayer Schering, and Genentech; has received speaker honoraria from Biogen Idec and Roche; and has received research support from Chugai Pharmaceuticals. He holds part of a patent for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and genetic determinants of neutralizing antibodies to interferon-beta