Multiple Sclerosis patients carry an increased burden of exceedingly rare genetic variants in the inflammasome regulatory genes

Lovro Vidmar,Smiljana Ristič,Ales Maver,Jelena Drulović,Ivana Novaković,Saša Šega,Juraj Sepčić,Borut Peterlin

doi:10.1038/s41598-019-45598-x

Lovro Vidmar, Smiljana Ristič + Show 6 more

Open Access

https://doi.org/10.1038/s41598-019-45598-x

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Abstract

The role of rare genetic variation and the innate immune system in the etiology of multiple sclerosis (MS) is being increasingly recognized. Recently, we described several rare variants in the NLRP1 gene, presumably conveying an increased risk for familial MS. In the present study we aimed to assess rare genetic variation in the inflammasome regulatory network. We performed whole exome sequencing of 319 probands, comprising patients with familial MS, sporadic MS and control subjects. 62 genes involved in the NLRP1/NLRP3 inflammasome regulation were screened for potentially pathogenic rare genetic variation. Aggregate mutational burden was analyzed, considering the variants’ predicted pathogenicity and frequency in the general population. We demonstrate an increased (p = 0.00004) variant burden among MS patients which was most pronounced for the exceedingly rare variants with high predicted pathogenicity. These variants were found in inflammasome genes (NLRP1/3, CASP1), genes mediating inflammasome inactivation via auto and mitophagy (RIPK2, MEFV), and genes involved in response to infection with DNA viruses (POLR3A, DHX58, IFIH1) and to type-1 interferons (TYK2, PTPRC). In conclusion, we present new evidence supporting the importance of rare genetic variation in the inflammasome signaling pathway and its regulation via autophagy and interferon-β to the etiology of MS.

Highlights

Multiple sclerosis (MS) is a debilitating neurological disease affecting young adults
In a separate analysis performed to identify a subset of variants with the most likely functional significance, all variants were annotated with Combined Annotation–Dependent Depletion (CADD) scores and minor allele frequency (MAF) obtained from the Genome Aggregation Database (gnomAD) database
To assess if this finding was specific for the investigated set of inflammasome regulatory genes (Table 1), the observed trends were compared to 100,000 random gene sets of the same size in a Monte Carlo simulation

Summary

Introduction

Multiple sclerosis (MS) is a debilitating neurological disease affecting young adults. Enabled by the generation sequencing (NGS) technology, we have recently reported several rare variants in the NLRP1 gene, presumably conveying an increased risk for MS in families with multiple affected members[7]. NLR Family Pyrin Domain Containing 1 (NLRP1) functions as the pattern recognition receptor (PRR) within the multi-protein signaling assemblies called inflammasomes, which lay at the forefront of the innate immune system. Their importance extends beyond infectious disease, as deregulated inflammasome activity has been associated with inflammatory[8], autoimmune[9] and neurological[10] diseases, including MS11–14. The burden of these variants can be evaluated for an association with the disease as a set[25], instead of testing the effects of individual variants, as is commonly done in GWA studies

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