Rare Variants of Inflammasome Proteins and Regulatory Signals More Common in MS Patients, Study Finds

Jose Marques Lopes, PhD avatar

by Jose Marques Lopes, PhD |

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European ancestry, gene variants

Patients with multiple sclerosis (MS) have more genetic variants of genes that regulate the pro-inflammatory signals of protein complexes called inflammasomes, according to new research.

The findings support the importance of inflammasomes, which play an important role in the innate immune system, in the development of MS.

The study, “Multiple Sclerosis patients carry an increased burden of exceedingly rare genetic variants in the inflammasome regulatory genes,” was published in the journal Nature Scientific Reports.

More than 200 genetic variants, mainly implicated in the immune system, have been associated with an increased MS risk. However, prior large genetic studies have failed to identify rarer variants. Investigations of changes with small-to-moderate effects on disease risk also are needed, the researchers said.

Studying rare genetic variants and their links to MS could be facilitated if they are aggregated over a gene or a biological pathway, meaning that researchers can focus and analyze detail on a smaller portion of DNA sequences.

Using an approach called “next generation sequencing,” researchers from Slovenia, Croatia, and Serbia previously reported rare variants of the NLRP1 gene implicated in development of MS in families with multiple affected members. NLRP1 protein is one of the three proteins that form inflammasomes.

As the name suggests, inflammasomes are important pro-inflammatory elements that, once activated, promote the production of two very powerful signaling molecules called IL-1beta and IL-18. Inflammasomes also have been shown to contribute for MS progression by promoting the loss of myelin protective layer of nerve fibers, and the breakdown of the blood-brain barrier that protects the brain.

Given the important role of inflammasomes, researchers hypothesized that rare variants that could impair inflammasome function also could contribute to increased risk for MS.

The team focused on rare protein-altering variants that were aggregated over 62 key genes for NLRP1/NLRP3 inflammasome regulation. Their frequency was evaluated among 86 MS patients from independent families who had two or more first-degree relatives with MS. They also analyzed these genes in samples collected from 89 patients with sporadic MS (without family history of the disease), and 144 individuals without the disease.

They identified 300 rare protein-altering variants within inflammasome regulatory genes. Their frequency was significantly higher in MS patients, regardless of family history, compared with people without MS.

A detailed analysis revealed increasingly common variants among MS patients, which was most pronounced for rarer variants with greater predicted damaging effect. Seventeen variants found in patients with familial history of the disease were considered MS enriched, as they were overrepresented in the MS groups. The 10 rarest variants were found exclusively in these MS patients.

Variants more frequent in MS patients were found in inflammasome genes NLRP1/3 and CASP1, in genes that encode protein involved in inflammasome inactivation like MEFV and RIPK2, and genes involved in the response to infections, including POLR3A, DHX58, IFIH1, TYK2, and PTPRC.

“We have discovered a significantly increased burden of rare protein-altering variants within the genes involved in inflammasome regulation among the patients with MS,” the researchers wrote.

“The increased burden was most pronounced for the exceedingly rare variants with concomitantly high predicted [disease-associated effect] which were present in several genes and pathways with already established links to MS or its risk factors,” they said.

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