BDNF Risk Variant Linked to Brain Inflammation in RRMS Patients

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that is nowadays representing one of the main causes of disability in young people. The clinical course of MS is highly variable and reflects the complex pathogenesis characterized by inflammation and neurodegeneration already detectable in the initial stages of the disease.

Pro-inflammatory cytokines and chemokines released by autoreactive lymphocytes and activated resident immune cells drive neuroinflammation and the formation of demyelinating white matter lesions. Gray matter involvement in MS is not merely a consequence of chronic axonal damage; it has been proposed that inflammation may play a causal role, a process defined as inflammatory neurodegeneration.

Image: Applied Biosystems 7900HT Sequence Detection System is designed for automated, high-throughput detection of fluorescent PCR-related chemistries (Photo courtesy of Grizzly Analytical)

Neurologists at the Neuromed Research Institute (Pozzilli, Italy) and their colleagues explored whether the Brain Derived Neurotrophic Factor (BDNF) Val66Met polymorphism could influence the inflammatory response in MS. They analyzed the associations between this SNP and the CSF levels of a large set of pro-inflammatory and anti-inflammatory molecules in a group of relapsing–remitting (RR)-MS patients at the time of diagnosis. A group of 218 consecutive RR-MS Italian patients from Central and Southern Italy were enrolled in a study and 71.1% of whom were female, with a median age of 34 years. These patients had been diagnosed a median of three months earlier.

Genotyping for BDNF SNP Val66Met was performed on all enrolled patients. Genomic DNA was isolated from peripheral blood leukocytes according to standard procedures using the QIAamp DNA Blood Mini Kit, (QIAGEN LLC, Germantown, MD, USA). The BDNF region containing the Val66Met polymorphism was analyzed with a TaqMan Validate SNP Genotyping Assay using the ABI-Prism 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA, USA). In 210 MS patients, the CSF concentrations of inflammatory cytokines were analyzed using a Bio-Plex multiplex cytokine assay (Bio-Rad Laboratories, Hercules, CA, USA).

The scientists reported that among the patients, 12 had two copies of Val66Met (5.5%) and 70 had one copy (32.1%). The remaining 136 people had no copies of this variant (62.4%). Using a machine-learning algorithm that examined the levels of 27 inflammatory molecules, the team found that a combination of several molecules, including TNF, IL-8, and MCP-1, was significantly higher in people with either one or two copies of the variant (called Met carriers). Specifically, median TNF levels in Met carriers was 2.8 pg/mL compared with 1.95 pg/mL for non-carriers. IL-8 levels were a median of 23.8 pg/mL for Met carriers and 19.4 pg/mL for non-carriers, while MCP-1 levels rose from a median of 120.8 pg/mL in non-carriers to 139.4 pg/mL in carriers.

The authors concluded that for the first time an association between the BDNF Val66Met polymorphism and central inflammation in MS patients at the time of diagnosis. The findings suggest a role for this polymorphism in both inflammatory and neurodegenerative processes and may contribute to explaining its complex influence on the MS course. The study was originally published on February 10, 2022 in the journal Genes.

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