Hepcidin and Ferroportin Genetic Variants in MS susceptibility and progression (Donato Gemmati, ITALY)
Iron involvement and unbalancing are strongly suspected in multiple sclerosis (MS) etiopathogenesis, but their
roles are quite debated. Iron deposits encircle the veins in brain MS lesions, increasing local metal
concentrations in parenchymal as documented by MR and histochemics. Conversely, systemic iron overload is
not always observed. We explored in MS patients the role of two common single nucleotide polymorphisms
(SNPs) in the promoter of the genes of two strongly related iron homeostasis molecules: Hepcidin and
Ferroportin. By the DNA-pyrosequencing technique, we investigated in 414 MS cases (Relapse Remitting (RR),
n=273; Secondary Progressive (SP), n=103; Primary Progressive (PP), n=38), and in 414 matched healthy
controls, the following two SNPs: hepcidin (HEPC, -582AG) and ferroportin (FPN1, -8CG).
FPN1-8GG homozygotes were overrepresented in the whole population (OR=4.38; 95%CI, 1.89-10.1; P<0.0001).
Conversely, the HEPC -582GG homozygotes, were mainly represented in progressive courses (OR=4.4; 95%CI,
1.83-10.5; P=0.001). Moreover, the rate of -582GG homozygotes progressively increased as the MS clinical
phenotype worsened (P-trend=0.01). MS disability and severity scores (EDSS and MSSS) and progression index
(PI), all grew up comparing homozygotes versus the rest of genotypes: HEPC -582GG (EDSS, 4.24±2.87 vs
2.78±2.1; P=0.003; MSSS, 5.6±3.06 vs 3.79±2.6; P=0.001); FPN1-8GG (PI, 1.11±2.01 vs 0.6±1.31; P=0.01; MSSS,
5.08±2.98 vs 3.85±2.8; P=0.01). Finally, HEPC -582G-carriers had a significant higher chance to switch into
progressive form (HR=3.55; 1.83-6.84; log-rank P=0.00006), (see Figure). We conclude that iron gene variants,
in the presence of local iron overload, might be responsible for suboptimal iron handling. This might account
for the significant variability observed in the MS phenotypes, particularly affecting MS risk and progression with
potential application in clinical practice.
If you have a gene variant that is suboptimal for iron handling, does the technique tried by some pwMS of donating blood help? Or is this a matter of the iron getting into the brain, which is going to happen no matter what if you have CCSVI and diapedesis going on, and once the iron is in the brain, your genetic variant makes you less able to get it out efficiently? The research indicates that these iron genes are important and iron is a factor in MS if having genetic variants that don't handle iron well is linked to having more severe MS.