Iron-related gene variants and brain iron in multiple sclerosis and healthy individuals

Neuroimage Clin. 2017 Nov 8;17:530-540. doi: 10.1016/j.nicl.2017.11.003. eCollection 2018.

Abstract

Brain iron homeostasis is known to be disturbed in multiple sclerosis (MS), yet little is known about the association of common gene variants linked to iron regulation and pathological tissue changes in the brain. In this study, we investigated the association of genetic determinants linked to iron regulation with deep gray matter (GM) magnetic susceptibility in both healthy controls (HC) and MS patients. Four hundred (400) patients with MS and 150 age- and sex-matched HCs were enrolled and obtained 3 T MRI examination. Three (3) single nucleotide polymorphisms (SNPs) associated with iron regulation were genotyped: two SNPs in the human hereditary hemochromatosis protein gene HFE: rs1800562 (C282Y mutation) and rs1799945 (H63D mutation), as well as the rs1049296 SNP in the transferrin gene (C2 mutation). The effects of disease and genetic status were studied using quantitative susceptibility mapping (QSM) voxel-based analysis (VBA) and region-of-interest (ROI) analysis of the deep GM. The general linear model framework was used to compare groups. Analyses were corrected for age and sex, and adjusted for false discovery rate. We found moderate increases in susceptibility in the right putamen of participants with the C282Y (+ 6.1 ppb) and H63D (+ 6.9 ppb) gene variants vs. non-carriers, as well as a decrease in thalamic susceptibility of progressive MS patients with the C282Y mutation (left: - 5.3 ppb, right: - 6.7 ppb, p < 0.05). Female MS patients had lower susceptibility in the caudate (- 6.0 ppb) and putamen (left: - 3.9 ppb, right: - 4.6 ppb) than men, but only when they had a wild-type allele (p < 0.05). Iron-gene linked increases in putamen susceptibility (in HC and relapsing remitting MS) and decreases in thalamus susceptibility (in progressive MS), coupled with apparent sex interactions, indicate that brain iron in healthy and disease states may be influenced by genetic factors.

Keywords: EDSS, Expanded Disability Status Scale; FDR, false discovery rate; FWE, family-wise error rate; GLM, general linear model; GM, gray matter; GRE, gradient recalled echo; HC, healthy control; HFE, human hemochromatosis gene; Iron; Iron related genes; MS, multiple sclerosis; MSSS, multiple sclerosis severity scale; Multiple sclerosis; QSM; QSM, quantitative susceptibility mapping; Quantitative susceptibility mapping; ROI, region of interest; RRMS, relapsing-remitting multiple sclerosis; SNP, single nucleotide polymorphism; T1w, T1-weighted; TF, transferrin; TFCE, threshold-free cluster enhancement; VBA, voxel-based analysis; ppb, parts per billion.

MeSH terms

  • Adult
  • Aged
  • Brain / metabolism
  • Brain Chemistry / genetics*
  • Female
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • Gray Matter / metabolism
  • Hemochromatosis Protein / genetics*
  • Humans
  • Image Interpretation, Computer-Assisted
  • Iron / metabolism*
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / metabolism
  • Polymorphism, Single Nucleotide
  • Transferrin / genetics*

Substances

  • HFE protein, human
  • Hemochromatosis Protein
  • Transferrin
  • Iron