Chronic low-grade inflammation, genetic susceptibility, and the risk of multiple sclerosis: a prospective cohort...

Immune dysregulation is central to multiple sclerosis (MS) pathogenesis, yet prospective evidence linking peripheral low-grade inflammation (LGI) to MS risk remains limited and inconsistent. We investigated the association of LGI with incident MS risk and MS-related brain structural measures in a large prospective cohort.

We analyzed data from 377,487 UK Biobank participants aged 40 to 69 years. A composite inflammation score (INFLA-score) was derived from C-reactive protein, white blood cell count, platelet count, and the neutrophil-to-lymphocyte ratio. Cox proportional hazards models assessed the association between LGI level and the incidence of multiple sclerosis (MS). Linear regression models evaluated the relationship between LGI level and the volume, cortical thickness, and surface area of six MS-related brain regions. Subgroup and interaction analyses were conducted.

Over a median follow-up of 13.8 years, 432 incident MS cases were documented, with a higher incidence density in women than in men (10.8 per 100,000 person-years vs 5.8 per 100,000 person-years). High-level LGI was associated with an increased risk of MS (HR = 1.38; 95% confidence interval [CI]: 1.10-1.72). This association was generally consistent across sex and polygenic risk score categories (all P for interaction > 0.05), but was stronger among individuals with higher socioeconomic deprivation (HR = 1.73; 95% CI: 1.27-2.35; P for interaction = 0.035) and those with hypertension (HR = 2.67; 95% CI: 1.63-4.35; P for interaction = 0.002). High-level LGI was negatively correlated with the volumes of the thalamus, superior temporal gyrus, lateral orbitofrontal cortex, putamen, caudate nucleus, and supramarginal gyrus (all P < 0.05). The association between LGI and lower brain volumes was generally more pronounced in males, while no significant interaction was observed between LGI and genetic risk on brain morphometry (all P for interaction > 0.05).

LGI is associated with an increased risk of MS and with adverse variations in brain morphometry in MS-related brain regions. These findings suggest that peripheral inflammation may serve as a potential marker for identifying individuals at elevated MS risk, warranting further investigation in interventional studies.