Growth Factors and Their Roles in Multiple Sclerosis Risk

Abstract

Background: Previous studies have suggested essential roles of growth factors on the risk of Multiple Sclerosis (MS), but it remains undefined whether the effects are causal.

Objective: We applied Mendelian randomization (MR) approaches to disentangle the causal relationship between genetically predicted circulating levels of growth factors and the risk of MS.

Methods: Genetic instrumental variables for fibroblast growth factor (FGF) 23, growth differentiation factor 15 (GDF15), insulin growth factor 1 (IGF1), insulin-like growth factor binding proteins 3 (IGFBP3) and vascular endothelial growth factor (VEGF) were obtained from up-to-date genome-wide association studies (GWAS). Summary-level statistics of MS were obtained from the International Multiple Sclerosis Genetics Consortium, incorporating 14,802 subjects with MS and 26,703 healthy controls of European ancestry. Inverse-variance weighted (IVW) MR was used as the primary method and multiple sensitivity analyses were employed in this study.

Results: Genetically predicted circulating levels of FGF23 were associated with risk of MS. The odds ratio (OR) of IVW was 0.63 (95% confidence interval [CI], 0.49-0.82; p < 0.001) per one standard deviation increase in circulating FGF23 levels. Weighted median estimators also suggested FGF23 associated with lower MS risk (OR = 0.67; 95% CI, 0.51-0.87; p = 0.003). While MR-Egger approach provided no evidence of horizontal pleiotropy (intercept = -0.003, p = 0.95). Results of IVW methods provided no evidence for causal roles of GDF1, IGF1, IGFBP3 and VEGF on MS risks, and additional sensitivity analyses confirmed the robustness of these null findings.

Conclusion: Our results implied a causal relationship between FGF23 and the risk of MS. Further studies are warranted to confirm FGF23 as a genetically valid target for MS.

Keywords: Mendelian randomization; fibroblast growth factor 23; genetic epidemiology; growth factors; multiple sclerosis.

Figure 1

The schematic diagram demonstrating concept of the MR design. Three key assumptions underlay standard selection procedure of instrumental SNPs. First, selected SNPs were robustly associated (p < 5 × 10^-8) with exposures of interest. Second, later-life confounders of the exposure-outcome link scarcely existed, given that genetic variants were inherited at gamete formation when randomized allocation of instrumental variant alleles among the large population were determined. Thirdly, the exclusion-restriction assumption, that instrumental SNPs affected the outcome only though the exposure, were examined by sensitivity analyses. FGF23, fibroblast growth factor 23; GDF15, growth differentiation factor 15; IGF1, insulin-like growth factor 1; IGFBP3, insulin-like growth factor-binding protein 3; VEGF, vascular endothelial growth factor; MS, multiple sclerosis; SNP, Single-nucleotide polymorphism.

Figure 2

The forest plot delineating causal estimates of growth factors on multiple sclerosis. CI, confidence interval; FGF23, fibroblast growth factor 23; GDF15, growth differentiation factor 15; IGF1, insulin-like growth factor 1; IGFBP3, insulin-like growth factor-binding protein 3; VEGF, vascular endothelial growth factor; MS, multiple sclerosis; SNP, Single-nucleotide polymorphism; OR, odds ratio.

Figure 3

The scatter plot (A) and leave-one-out plot (B) in the Mendelian randomization analysis of circulating FGF23 on the risk of MS. FGF23, fibroblast growth factor 23; IVW, inverse variance weighted; MS, multiple sclerosis; SNP, Single-nucleotide polymorphism.