Genetic Variants in Iron Metabolism impact Disease Progression in MS through HIF1A
Antonino Giordano1, Silvia Santoro1, Melissa Sorosina1, Elisabetta Mascia1, Ferdinando Clarelli1, Miryam Cannizzaro1, Laura Ferrè1, Thomas Moridi2, Pernilla Stridh2, Klementy Shchetynsky2, Maria Needhamsen2, Fredrik Piehl2, Lars Alfredsson2, Jan Hillert2, Tomas Olsson2, Ingrid Kockum2, Maja Jagodic2, Massimo Filippi1, Federica Esposito1
1IRCCS San Raffaele Hospital, Milan, Italy, 2Karolinska Institutet, Stockholm, Sweden
Objective:
We investigated the impact of Single Nucleotide Polymorphisms (SNPs) in genes implicated in iron metabolism on the risk of developing progressive MS.
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.
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.