Abstract Details

Title Genetic Variants in Iron Metabolism impact Disease Progression in MS through HIF1A

Topic Multiple Sclerosis

Presentation(s) S9 - MS Biomarkers, Immunology, and Basic Science (4:30 PM-4:42 PM)

Poster/Presentation
Number 006

Background Iron enrichment is a core feature of chronic active lesions, a key marker of progressive MS, and can be detected by magnetic resonance imaging. In parallel, the molecular profile of the lesion-associated microglia supports the relevance of genes involved in iron metabolism. However, it is still unclear their role in disease progression.

Objective We investigated the impact of Single Nucleotide Polymorphisms (SNPs) in genes implicated in iron metabolism on the risk of developing progressive MS.

Design/Methods We performed an association analysis on 37,794 SNPs in 319 genes involved in iron metabolism, comparing benign relapsing-remitting (RR) versus secondary progressive (SP) patients in a discovery Italian cohort from San Raffaele Hospital (OSR). Significant results were investigated in a nationwide replication cohort from Sweden (SWE). Benign RR-MS was defined as a confirmed RR course of at least 20 years and EDSS<=3.5. In the SP group, patients with confirmed conversion to SP within 20 years from onset and EDSS=>4.0 were included.

Results After quality controls, 2,817 patients were studied. We found a significant association involving SNPs in the Hypoxia-Inducible-Factor-1-alfa (HIF1A) gene in the discovery cohort (n=755; lead-SNP=rs11621525; p=3.30E-06, OR_SP=0.57), that was replicated in the SWE cohort (n=2,062; lead-SNP=rs1951795; p=0.0079, OR_SP=0.79). Previous evidence has shown that rs11621525_A down-regulates HIF1A expression in whole blood in healthy subjects. We replicated this effect in peripheral blood mononuclear cells from 78 RR-MS patients (p=0.034). We also studied the neurofilament (NFL) levels, a recognized marker of ongoing axonal injury and chronic white matter inflammation. RR-MS patients who were carriers of the A allele showed lower NFL, both in plasma (n=117;p=0.0026) and in cerebrospinal fluid (n=77;p=0.051).

Conclusions Genetic variants in HIF1A are associated with risk of progressive MS course and impact NFL levels. HIF1A is a fundamental regulator of iron metabolism, response to hypoxia and immune processes, therefore representing a promising candidate for further investigation.

Authors/Disclosures
Antonino Giordano (San Raffaele Scientific Institute) PRESENTER	Mr. Giordano has nothing to disclose.
	No disclosure on file
Melissa Sorosina	No disclosure on file
Elisabetta Mascia	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Pernilla Stridh (Karolinska Institutet)	No disclosure on file
Klementy Shchetynsky (Karolinska Institutet)	No disclosure on file
Maria Needhamsen	No disclosure on file
Fredrik L. Piehl, MD, PhD (Neuroimmunology Unit, Dept Clinical Neuroscience, Karolinska Institutet)	Dr. Piehl has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Parexel/Chugai. The institution of Dr. Piehl has received research support from UCB. The institution of Dr. Piehl has received research support from Merck KGaA. Dr. Piehl has received personal compensation in the range of $10,000-$49,999 for serving as a member scientific advisory board with Swedish Medical products Agency.
	No disclosure on file
Jan A. Hillert, MD (Karolinska Institute, Neurology R54)	Dr. Hillert has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Hillert has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Celgene. Dr. Hillert has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Dr. Hillert has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Hillert has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sandoz. Dr. Hillert has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. The institution of Dr. Hillert has received research support from Biogen. The institution of Dr. Hillert has received research support from Celgene. The institution of Dr. Hillert has received research support from Merck. The institution of Dr. Hillert has received research support from Novartis. The institution of Dr. Hillert has received research support from Sanofi. The institution of Dr. Hillert has received research support from Roche.
Tomas Olsson, MD, PhD (Karolinska Institutet)	Prof. Olsson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Prof. Olsson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Prof. Olsson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Prof. Olsson has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. The institution of Prof. Olsson has received research support from Biogen. The institution of Prof. Olsson has received research support from Novartis. The institution of Prof. Olsson has received research support from Sanofi. The institution of Prof. Olsson has received research support from Merck.
Ingrid Kockum	No disclosure on file
Maja Jagodic (Karolinska Institutet)	No disclosure on file
Massimo Filippi, MD, FAAN (Ospedale San Raffaele, Neuroimaging Research Unit)	Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi;. Dr. Filippi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi- Genzyme, Takeda. Dr. Filippi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla.
Federica Esposito	Federica Esposito has received personal compensation in the range of $0-$499 for serving as a Consultant for Merck. Federica Esposito has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Federica Esposito has received personal compensation in the range of $0-$499 for serving as a Consultant for Novartis. Federica Esposito has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Federica Esposito has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. The institution of Federica Esposito has received research support from Italian MS Society. The institution of Federica Esposito has received research support from Italian Ministry of Health. The institution of Federica Esposito has received research support from ERA Net. The institution of Federica Esposito has received research support from European Commission. Federica Esposito has received intellectual property interests from a discovery or technology relating to health care.