Exome sequencing study in patients with multiple sclerosis reveals variants associated with disease course

Abstract

BackgroundIt remains unclear whether disease course in multiple sclerosis (MS) is influenced by genetic polymorphisms. Here, we aimed to identify genetic variants associated with benign and aggressive disease courses in MS patients.MethodsMS patients were classified into benign and aggressive phenotypes according to clinical criteria. We performed exome sequencing in a discovery cohort, which included 20 MS patients, 10 with benign and 10 with aggressive disease course, and genotyping in 2 independent validation cohorts. The first validation cohort encompassed 194 MS patients, 107 with benign and 87 with aggressive phenotypes. The second validation cohort comprised 257 patients, of whom 224 patients had benign phenotypes and 33 aggressive disease courses. Brain immunohistochemistries were performed using disease course associated genes antibodies.ResultsBy means of single-nucleotide polymorphism (SNP) detection and comparison of allele frequencies between patients with benign and aggressive phenotypes, a total of 16 SNPs were selected for validation from the exome sequencing data in the discovery cohort. Meta-analysis of genotyping results in two validation cohorts revealed two polymorphisms, rs28469012 and rs10894768, significantly associated with disease course. SNP rs28469012 is located in CPXM2 (carboxypeptidase X, M14 family, member 2) and was associated with aggressive disease course (uncorrected p value < 0.05). SNP rs10894768, which is positioned in IGSF9B (immunoglobulin superfamily member 9B) was associated with benign phenotype (uncorrected p value < 0.05). In addition, a trend for association with benign phenotype was observed for a third SNP, rs10423927, in NLRP9 (NLR family pyrin domain containing 9). Brain immunohistochemistries in chronic active lesions from MS patients revealed expression of IGSF9B in astrocytes and macrophages/microglial cells, and expression of CPXM2 and NLRP9 restricted to brain macrophages/microglia.ConclusionsGenetic variants located in CPXM2, IGSF9B, and NLRP9 have the potential to modulate disease course in MS patients and may be used as disease activity biomarkers to identify patients with divergent disease courses. Altogether, the reported results from this study support the influence of genetic factors in MS disease course and may help to better understand the complex molecular mechanisms underlying disease pathogenesis.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1307-1) contains supplementary material, which is available to authorized users.

Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

“…In addition, the study of multi-incident MS families have nominated pathogenic mutations in NLRP1 , and purinergic receptors P2RX4 / P2RX7 which initiate inflammasome formation by modifying intracellular calcium and potassium concentrations [10, 11]. Rare missense variants in NLRP5 and NLRP9 have also been found to correlate with disease course and severity in MS patients [8, 56].…”

“…The activation of the inflammasome has been proposed as a mechanism of autoimmunity in MS patients [156], a hypothesis that is supported by rare variants in inflammasome components NLRP1 , NLRP3 , NLRP5 and NLRP9 which were identified in MS families, or found to correlate with disease course and severity [8, 11, 54, 56]. In this study we describe two missense substitutions in NLRP12 , a NOD-like receptor family member that negatively regulates inflammation and NF-κB signaling, while promoting T-cell activation and differentiation [53].…”

Mutations in NLRP5 and NLRP9 Are Associated with Litter Size in Small Tail Han Sheep

“…Previous studies found that several variants in NLRP9 may influence the disease course in multiple sclerosis patients, as determined by an exome sequencing study [19], and may be associated with familial late-onset Alzheimer's disease, as determined by a genome-wide association study [20]. However, little has been found regarding its effects on litter size.…”

Parâmetros Clínicos, Biológicos E Moleculares Na Resposta Ao Tratamento Com Interferon-Beta Em Pacientes Com Esclerose Múltipla

“…Não representando apenas risco à EM, os genes HLA também podem estar envolvidos na proteção, como é o caso do gene HLA-A201 (BOQUETT et al, 2018;MOHAJER et al, 2018). Recentemente, estudo demonstrou que o sequenciamento do exoma de pacientes com esclerose múltipla revelou variantes associadas com o curso da doença (GIL-VAREA et al, 2018).…”