Heavy metals, organic solvents, and multiple sclerosis: An exploratory look at gene-environment interactions

<div><p>ABSTRACT</p><p>Exposure to heavy metals and organic solvents are potential etiologic factors for multiple sclerosis (MS), but their interaction with MS-associated genes is under-studied. The authors explored the relationship between environmental exposure to lead, mercury, and solvents and 58 single-nucleotide polymorphisms (SNPs) in MS-associated genes. Data from a population-based case-control study of 217 prevalent MS cases and 496 age-, race-, gender-, and geographically matched controls were used to fit conditional logistic regression models of the association between the chemical, gene, and MS, adjusting for education and ancestry. MS cases were more likely than controls to report lead (odds ratio [OR] = 2.03; 95% confidence interval [CI]: 1.07, 3.86) and mercury exposure (OR = 2.06; 95% CI: 1.08, 3.91). Findings of potential gene-environment interactions between SNPs in <i>TNF-</i>α, <i>TNF-</i>β, TCA-β, <i>VDR, MBP,</i> and <i>APOE</i>, and lead, mercury, or solvents should be considered cautiously due to limited sample size.</p></div

Group Differences by Bipolar Status and BDNF Val66Met Genotype.

<p>Group Differences by Bipolar Status and BDNF Val66Met Genotype.</p

Brain regions with larger volumes (ml) in healthy controls.

<p>Brain regions with larger volumes (ml) in healthy controls.</p

Variables with larger volumes (ml) in bipolar subjects.

<p>Variables with larger volumes (ml) in bipolar subjects.</p

The x-axis is in cM along with the location of genes on that chromosome

<p><b>Copyright information:</b></p><p>Taken from "Adjusting for covariates on a slippery slope: linkage analysis of change over time"</p><p>http://www.biomedcentral.com/1471-2156/4/s1/S50</p><p>BMC Genetics 2003;4(Suppl 1):S50-S50.</p><p>Published online 31 Dec 2003</p><p>PMCID:PMC1866487.</p><p></p> SOLAR curves are for the normalized SBP slopes. The SIBLINK curve shows the ASP LOD score for HBP

<i>SIX6</i> variants identified by sequencing POAG cases and controls.

<p>Coordinates are based on the Hg19 reference; MAF = minor allele frequency;</p><p>AA = amino acid; GERP = Genomic Evolutionary Rate Profiling.</p

OCT measurements from POAG cases homozygous for rs33912345.

<p>SD = standard deviation; OCT = optical coherence tomography.</p

<i>In vitro</i> luciferase assay results showing the effect of <i>SIX6</i> enhancer variants.

<p><i>SIX6</i> enhancer alleles were tested using a dual luciferase assay and the ratio of the experimental luciferase: control luciferase was calculated (DLR ratio). All vectors were co-transfected with NeuroD and E47. In this context, the <i>SIX6</i> enhancer is functioning to increase expression compared to the empty vector (pGL4.23), driven by a minimal promoter. Compared to the reference enhancer (Ref), one variant (Chr14:60974449_G) significantly increases the enhancer's activity.</p

<i>In vivo</i> zebrafish morpholino complementation assay showing the effect of <i>SIX6</i> nonsynonymous variants.

<p>Zebrafish embryos were microinjected with a translation blocking morpholino designed to target <i>six6a</i>. Total eye size (µm²) was measured 3 days post fertilization. Compared to the uninjected controls, morphants showed a significant reduction in eye size. Zebrafish were co-injected with the morpholino and a human <i>SIX6</i> allele (Glu93Gln, Glu129Lys, Asn141His, Leu205Arg, Thr212Met, or Ser242IIe). Results of each allele were compared to the <i>SIX6</i> non-risk allele (Ref). P-values are provided below the mean of each treatment.</p

Functional evaluation of <i>SIX6</i> variants on the volume of the optic nerve.

<p>Representative whole mount images of acetylated-tubulin expression in the heads of zebrafish embryos injected with a control or <i>six6a</i> morpholino, rescued by co-injection with human non-risk SIX6 transcript or a transcript containing the Leu205Arg hypomorphic variant (A). Acetylated-tubulin staining is restricted primarily to axon tracts and can be used to visualize the optic nerve. Relative to the control morphants, volumetric regions of interest (ROI) along the optic nerve in <i>six6a</i> morphants were reduced significantly. Co-injection of human variants revealed a hypomorphic (Leu205Arg, Asn141His) or benign (Glu93Gln) role of the variants on the optic nerve (B). Sample size for all injection paradigms ranged from 7–9 and p-values are plotted for each comparison (*** p<0.001; ** p<0.01). No significant changes in the volume of other axonal tracts in the head (marked by an asterisk) were detected. Standard error of the mean is shown and white scale bars = 20 um.</p