Contributions
Abstract: P481
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Imaging
Background: The disturbance of brain iron levels among multiple sclerosis (MS) patients has been well documented in recent years. However, little is known about the association of MS related iron disturbance and genetic predisposition to iron overload. Important iron single nucleotide polymorphism (SNPs) include: rs1800562 (Cys282Tyr; hemochromatosis), rs1799945 (His63Asp; iron uptake dysregulation), and rs1049296 (transferrin C1/C2; iron transport disruption).
Objective: Investigate the association of iron-related SNPs with a novel iron sensitive imaging technique in MS and healthy controls (HCs). Associations with clinical measures of MS disease progression was also assessed.
Methods: The study included 261 relapsing remitting MS, 139 progressive MS, and 150 HCs. DNA was obtained from peripheral blood mononuclear cells. Participants underwent 3T MRI with quantitative susceptibility mapping (QSM) and genotyping for SNPs associated with iron regulating genes: rs1800562 (risk allele A), rs1799945 (risk allele G), and rs1049296 (risk allele T). Susceptibility was determined for the deep gray matter, with higher values representing increased iron content. Voxelwise associations with SNPs were investigated. Age adjusted regression analyses (α< .05) with main effects of disease, MS type, sex, SNPs and interaction effects between predictors were investigated.
Results: There were more rs1049296 T allele carriers among MS patients than HCs (29.8% v. 17.8%, p=.014). rs1799945 was significantly associated with putamen susceptibility (beta=.190, p< .05), regardless of study group. MS rs1800562 A allele carriers had reduced putamen susceptibility (p< .05). Additional interaction effects were found between men and women: male rs1800562 A allele carriers had higher hippocampal susceptibility; and male rs1049296 T allele carriers had lower putamen susceptibility (p< .05). Voxelwise analysis confirmed the increased susceptibility in the putamen of MS rs1800562 carriers. EDSS was significantly associated with rs1800562 allele status (p=.027), but only among progressive MS patients.
Discussion: The rs1800562 polymorphism, a SNP associated with hemochromatosis and iron regulation, appears to have MS-specific effects in its association with putamen iron concentration. Significant sex interactions highlight that iron-associated genes have diverging effects on brain susceptibility among men and women. Further research will have to corroborate these disease and sex effects.
Disclosure:
Jesper Hagemeier: nothing to disclose
Murali Ramanathan: received research funding from the National Multiple Sclerosis Society and the National Science Foundation. He receives royalty income from a self-published textbook.
Ferdinand Schweser: nothing to disclose.
Michael G Dwyer: received research grant support from Novartis and consultant fees from Claret Medical and EMD Serono.
Fuchun Lin: nothing to disclose
Niels Bergsland: nothing to disclose
Bianca Weinstock-Guttman: received honoraria as a speaker and as a consultant for Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis and Acorda. Dr Weinstock-Guttman received research funds from Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis, Acorda.
Robert Zivadinov: received personal compensation from Biogen Idec, Teva Pharmaceuticals, EMD Serono, Novartis, Claret Medical and Genzyme for speaking and consultant fees. Dr Zivadinov received financial support for research activities from Biogen Idec, Teva Pharmacuticals, EMD Serono, Novartis, Claret Medical and Genzyme. Dr Zivadinov serves on the editorial board of Journal of Alzheimer"s Disease, BMC Medicine, BMC Neurology, Veins and Lymphatics and Clinical CNS Drugs. He is Treasurer of the International Society for Neurovascular Disease.
Abstract: P481
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Imaging
Background: The disturbance of brain iron levels among multiple sclerosis (MS) patients has been well documented in recent years. However, little is known about the association of MS related iron disturbance and genetic predisposition to iron overload. Important iron single nucleotide polymorphism (SNPs) include: rs1800562 (Cys282Tyr; hemochromatosis), rs1799945 (His63Asp; iron uptake dysregulation), and rs1049296 (transferrin C1/C2; iron transport disruption).
Objective: Investigate the association of iron-related SNPs with a novel iron sensitive imaging technique in MS and healthy controls (HCs). Associations with clinical measures of MS disease progression was also assessed.
Methods: The study included 261 relapsing remitting MS, 139 progressive MS, and 150 HCs. DNA was obtained from peripheral blood mononuclear cells. Participants underwent 3T MRI with quantitative susceptibility mapping (QSM) and genotyping for SNPs associated with iron regulating genes: rs1800562 (risk allele A), rs1799945 (risk allele G), and rs1049296 (risk allele T). Susceptibility was determined for the deep gray matter, with higher values representing increased iron content. Voxelwise associations with SNPs were investigated. Age adjusted regression analyses (α< .05) with main effects of disease, MS type, sex, SNPs and interaction effects between predictors were investigated.
Results: There were more rs1049296 T allele carriers among MS patients than HCs (29.8% v. 17.8%, p=.014). rs1799945 was significantly associated with putamen susceptibility (beta=.190, p< .05), regardless of study group. MS rs1800562 A allele carriers had reduced putamen susceptibility (p< .05). Additional interaction effects were found between men and women: male rs1800562 A allele carriers had higher hippocampal susceptibility; and male rs1049296 T allele carriers had lower putamen susceptibility (p< .05). Voxelwise analysis confirmed the increased susceptibility in the putamen of MS rs1800562 carriers. EDSS was significantly associated with rs1800562 allele status (p=.027), but only among progressive MS patients.
Discussion: The rs1800562 polymorphism, a SNP associated with hemochromatosis and iron regulation, appears to have MS-specific effects in its association with putamen iron concentration. Significant sex interactions highlight that iron-associated genes have diverging effects on brain susceptibility among men and women. Further research will have to corroborate these disease and sex effects.
Disclosure:
Jesper Hagemeier: nothing to disclose
Murali Ramanathan: received research funding from the National Multiple Sclerosis Society and the National Science Foundation. He receives royalty income from a self-published textbook.
Ferdinand Schweser: nothing to disclose.
Michael G Dwyer: received research grant support from Novartis and consultant fees from Claret Medical and EMD Serono.
Fuchun Lin: nothing to disclose
Niels Bergsland: nothing to disclose
Bianca Weinstock-Guttman: received honoraria as a speaker and as a consultant for Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis and Acorda. Dr Weinstock-Guttman received research funds from Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme&Sanofi, Novartis, Acorda.
Robert Zivadinov: received personal compensation from Biogen Idec, Teva Pharmaceuticals, EMD Serono, Novartis, Claret Medical and Genzyme for speaking and consultant fees. Dr Zivadinov received financial support for research activities from Biogen Idec, Teva Pharmacuticals, EMD Serono, Novartis, Claret Medical and Genzyme. Dr Zivadinov serves on the editorial board of Journal of Alzheimer"s Disease, BMC Medicine, BMC Neurology, Veins and Lymphatics and Clinical CNS Drugs. He is Treasurer of the International Society for Neurovascular Disease.