A Genetic Clue to Progressive MS: How a HIF1A Variant May Slow Smoldering Inflammation
Multiple sclerosis (MS) remains unpredictable—some individuals live decades with minimal disability, while others transition to secondary progressive MS (SP-MS) within years. Understanding why this progression happens is one of the central challenges in MS research. The study at hand takes a fresh approach by focusing on a biological feature that has recently emerged as a hallmark of progression: smoldering inflammation, the chronic, iron-driven inflammatory activity that persists at the edges of longstanding MS lesions. By examining genetic variants that regulate iron metabolism, the authors aimed to uncover whether inherited differences influence who progresses and who does not.
A Targeted Genetic Scan Leads to One Standout Gene
Instead of scanning the entire genome randomly, the researchers adopted a focused strategy. They selected 334 genes involved in iron-handling pathways—a logical choice, given the tight link between iron accumulation and chronic lesion activity—and then analyzed 23,019 genetic variants within these genes across two large cohorts from Italy and Sweden (totaling 2,817 patients). Their goal: compare long-term benign RR-MS cases to those who converted to SP-MS. One gene consistently emerged as the strongest signal: HIF1A (Hypoxia-Inducible Factor 1-alpha), a master regulator of hypoxia, iron metabolism, and immune cell activation. A variant called rs11621525 was associated with reduced risk of progressing to SP-MS when carrying the protective A allele.
Lower HIF1A Expression May Protect Against Progression
Gene expression analyses shed light on how this genetic variant exerts its effect. In treatment-naïve MS patients, those carrying the A allele showed significantly lower expression of HIF1A in immune cells. This is important because HIF1A is known to shape inflammatory and metabolic responses under stress conditions such as “virtual hypoxia,” a phenomenon implicated in MS lesion evolution. Reduced HIF1A activity may therefore temper chronic inflammatory processes that drive lesion expansion and axonal damage, suggesting a mechanism by which the protective allele influences disease trajectory.
MRI Evidence: Smaller Paramagnetic Rim Lesions
The study used iron-sensitive MRI to examine paramagnetic rim lesions (PRLs)—the clearest in-vivo marker of smoldering inflammation. PRLs appear as white-matter lesions surrounded by an iron-rich microglial rim, signaling chronic ongoing damage. Across Italian and Swedish imaging cohorts, individuals with the HIF1A protective allele had smaller PRL volumes, indicating milder chronic inflammatory activity. The MRI figures (page 27) visually demonstrate the contrast between lesions with and without rims, and the statistical analysis confirmed a significant association with genotype. This finding provides a compelling link between inherited biology and measurable chronic lesion behavior on MRI.
Pathology Confirms Reduced Smoldering Activity in the CNS
To deepen the biological picture, the authors analyzed post-mortem spinal cord tissue from progressive MS patients (159 samples). In carriers of the A allele, lesions displayed less microglia/macrophage activation (CD68+) and fewer acutely injured axons (BAPP+). Notably, even “normal-appearing” white matter showed reduced injury among these individuals, suggesting that the protective effect is not limited to visible lesions. The pathology images and quantitative plots (page 28) reinforce that this variant influences the very processes believed to drive slow, irreversible disability in MS.
Neurofilament Biomarkers Mirror the Genetic Effect
Neurofilament light chain (NFL) levels in blood and CSF are established biomarkers of axonal injury and predictors of future progression. Across multiple independent datasets, the protective HIF1A genotype was associated with lower plasma and CSF NFL levels, both during RR-MS and even at the earliest clinically isolated syndrome stage. These findings indicate a consistent reduction in subclinical neuroaxonal injury. The graphs on page 29 show clear downward shifts in NFL z-scores for A-allele carriers, providing further biomarker-level support for the gene’s protective role.
A Genetic Signal That May Predict Treatment Response
One of the study’s most intriguing insights is that the HIF1A variant not only shapes disease biology but may also influence treatment response, particularly to dimethyl fumarate (DMF). A-allele carriers experienced a greater reduction in plasma NFL after starting DMF, and they achieved higher rates of “No Evidence of Disease Activity” during follow-up—especially in treatment-naïve patients. Because DMF modulates oxidative and hypoxic stress pathways, the interaction with HIF1A biology is plausible and clinically relevant. These findings suggest a future in which genetic markers help guide therapy choices for MS patients.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Giordano, A., Stridh, P., Preziosa, P., Pisa, M., Sorosina, M., Mascia, E., ... & Esposito, F. (2024). Genetic variation in HIF1A is associated with smoldering inflammation and disease progression in Multiple Sclerosis. medRxiv, 2024-03.
