Specific Growth Factor Found to Increase Risk of MS

A recent meta-analysis confirmed a causal relationship between fibroblast growth factor (FGF) 23 and the risk of multiple sclerosis (MS), suggesting that some growth factors play an essential role in the risk of the disease.

The study, published in Frontiers in Immunology, leveraged a large sample of genetic data from several sources to clarify whether a causal relationship exists between MS and growth factors, including FGF23 as well as growth differentiation factor 15 (GDF15), insulin growth factor 1 (IGF1), insulin-like growth factor binding proteins 3 (IGFBP3), and vascular endothelial growth factor (VEGF).

MS affects about 2.8 million people worldwide and is diagnosed in 2.1 per 100,000 people annually. The etiology and mechanisms of the disease are not fully understood, and more studies are needed to improve understanding of its nasogenesis.

Growth factors are regulating cytokines that assist in cell proliferation, differentiation, and activation. Past research has suggested that growth factors act as risk factors for MS and play an important role in the initiation and progression of the disease.

Among the 5 growth factors included in the analysis, FGF23 is known to regulate various biological functions and is a critical player in vitamin D metabolism. GDF15 regulates inflammation and apoptosis in various diseases and is known to positively correlate with MS disability scores. VEGF contributes to the breakdown of the blood-brain barrier (BBB) and is detected in serum and central nervous tissue in patients with MS.

IGF1 protects the survival of neurons and glia cells, stimulates the regeneration of myelin, attenuates the damage of the BBB, and alleviates immune-mediated inflammation. IGF1 is also associated with susceptibility to MS. IGF1 is regulated by IGFBP3, which is the most abundant IGFBP in human serum and can directly inhibit cell growth. Decreased IGFBP3 levels and reduced bioavailability of IGF1 are commonly reported in the serum of patients with MS.

The investigators used data from genome-wide association studies to conduct a 2-sample Mendelian randomization (MR) analysis to understand the potential causal roles that these growth factors could play in MS risk. Genetic instruments and meta-analyses were used to examine the roles of the growth factors in patients of European ancestry:

• FGF23: 7 studies containing 16,624 patients (mean age range, 36.4-78.0 years; 54.5% women)
• GDF15: 4 community-based cohort of 5440 patients (mean age, 62.0 years; 53.0% women)
• IGF1: 451,993 patients (mean age, 56.5 years; 54.0% women)
• IGFBP3: 13 studies including 18,995 patients (57.6% women)
• VEGF: meta-analysis including 16,112 patients (mean age, 54.8 years; 54.0% women)

The primary MR analysis showed that circulating levels of FGF23 were inversely associated with risk of MS, with an odds ratio (OR) of 0.63 (95% CI, 0.49-0.82; P = .00047). Weighted median estimators identified that FGF23 was also associated with lower MS risk (OR, 0.67; 95% CI, 0.51-0.87; P = .0031).

“Our result also implied a potential therapeutic role of FGF23 for the treatment of MS….Further clinical trials are warranted to explore the potential therapeutic effects of FGF23 in MS patients,” wrote the investigators.

FGF23 was the sole growth factor examined in the analysis that was found to be associated with MS risk. Genetically predicted concentrations of GDF15 (OR, 0.96; 95% CI, 0.90-1.04; P = .33), IGF1 (OR, 1.06; 95% CI, 0.94-1.19; P = .35), IGFBP3 (OR, 1.01; 95% CI, 0.92-1.11; P = .77), and VEGF (OR, 0.99; 95% CI, 0.94-1.06; P = .84) demonstrated no causal relationship with MS.

The study had several limitations, including that MR analyses are not a replacement for randomized controlled trials and are subject to the presence of linkage disequilibrium, cryptic relatedness, genetic heterogeneity, pleiotropy, canalization, or covariable adjustment. Additionally, the genetic data used in the analysis were collected from only European populations, suggesting that generalizability to other populations is limited. Possible sex-specific differences were also not examined.

Reference

Lu H, Wu PF, Ma DL, Zhang W, Sun M. Growth factors and their roles in multiple sclerosis risk. Front Immunol. 2021;12:768682. doi:10.3389/fimmu.2021.768682