UBC Faculty Research and Publications

Exome sequencing study in patients with multiple sclerosis reveals variants associated with disease course Gil-Varea, Elia; Urcelay, Elena; Vilariño-Güell, Carles; Costa, Carme; Midaglia, Luciana; Matesanz, Fuencisla; Rodríguez-Antigüedad, Alfredo; Oksenberg, Jorge; Espino-Paisan, Laura; Dessa Sadovnick, A.; Saiz, Albert; Villar, Luisa M; García-Merino, Juan A; Ramió-Torrentà, Lluís; Triviño, Juan C; Quintana, Ester; Robles, René; Sánchez-López, Antonio; Arroyo, Rafael; Alvarez-Cermeño, Jose C; Vidal-Jordana, Angela; Malhotra, Sunny; Fissolo, Nicolas; Montalban, Xavier; Comabella, Manuel


Background: It 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. Methods: MS 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. Results: By 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

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