Lymphocyte count polygenicity underlies dimethyl fumarate–associated lymphopenia in multiple sclerosis

Purpose: One in 20 people using dimethyl fumarate (DMF), a commonly used disease-modifying therapy for multiple sclerosis (MS), develops severe lymphopenia. We aimed to identify genetic variation associated with DMF-related lymphopenia. Methods: Using a case–control design, we included cases that had either grade 2 (absolute lymphocyte count <0.8 × 10 9 /L) or 3 (<0.5 × 10 9 /L) lymphopenia during DMF. Controls had normal lymphocyte counts and ⩾1 year of DMF exposure. We generated a polygenic score for lymphocyte counts and evaluated its ability to predict DMF-associated lymphopenia in two cohorts, with adjustment for covariates. We also conducted a genome-wide association study (GWAS) and gene-based analyses. Findings: The discovery cohort comprised 238 PwMS of European genetic ancestry from Canada/Australia ( n = 72 grade 2 cases, 34 grade 3 cases), and the replication cohort comprised 156 PwMS from Sweden ( n = 34 grade 2, 14 grade 3). A higher polygenic score for lymphocyte counts predicted reduced risk of grade 2 lymphopenia (hazard ratio = 0.43, 95% confidence interval: 0.25–0.73). The GWAS identified one locus associated with the minimum lymphocyte count during DMF (rs17087205, beta = −0.63, SE = 0.11, p = 3.89e–8) but did not replicate (beta = −0.04, p = 0.47). Conclusion: Common polygenic variation of lymphocyte counts was significantly associated with moderate lymphopenia during DMF treatment.

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Journal
Multiple Sclerosis Journal
Published
2026-08-17
DOI
https://doi.org/10.1177/13524585261471335
Primary Topic
Multiple Sclerosis Research Studies
Type
article
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article

Lymphocyte count polygenicity underlies dimethyl fumarate–associated lymphopenia in multiple sclerosis

R. Carruthers, Brianne Desrochers, Helen Tremlett, Pernilla Stridh et al.
Multiple Sclerosis Journal
Multiple Sclerosis Research Studies
article

Lymphocyte count polygenicity underlies dimethyl fumarate–associated lymphopenia in multiple sclerosis

R. Carruthers, Brianne Desrochers, Helen Tremlett, Pernilla Stridh, Britt I. Drögemöller, Annie J Kuan, Kira Groen, Elaine Kingwell, Michael C. Levin, Michael Zhong, Jan Hillert, Vicki E. Maltby, Ingrid Skelton Kockum, Kaarina Kowalec, Klementy Shchetynsky, Kristy Dever, Michael S. Kobor, Ali Manouchehrinia, Ruth Ann Marrie, Vilija Jokubaitis, Wenzhuo Luo, Daniel Luo, Katherine Knox, Dalia Rotstein, Charity Evans, Julie MacIsaac, Galen EB Wright, Jeannette Lechner-Scott, Tomas Olsson, Lars Alfredsson, Abdullah Al Maruf, Sasha Bernatsky
article en

Abstract

Purpose: One in 20 people using dimethyl fumarate (DMF), a commonly used disease-modifying therapy for multiple sclerosis (MS), develops severe lymphopenia. We aimed to identify genetic variation associated with DMF-related lymphopenia. Methods: Using a case–control design, we included cases that had either grade 2 (absolute lymphocyte count <0.8 × 10 9 /L) or 3 (<0.5 × 10 9 /L) lymphopenia during DMF. Controls had normal lymphocyte counts and ⩾1 year of DMF exposure. We generated a polygenic score for lymphocyte counts and evaluated its ability to predict DMF-associated lymphopenia in two cohorts, with adjustment for covariates. We also conducted a genome-wide association study (GWAS) and gene-based analyses. Findings: The discovery cohort comprised 238 PwMS of European genetic ancestry from Canada/Australia ( n = 72 grade 2 cases, 34 grade 3 cases), and the replication cohort comprised 156 PwMS from Sweden ( n = 34 grade 2, 14 grade 3). A higher polygenic score for lymphocyte counts predicted reduced risk of grade 2 lymphopenia (hazard ratio = 0.43, 95% confidence interval: 0.25–0.73). The GWAS identified one locus associated with the minimum lymphocyte count during DMF (rs17087205, beta = −0.63, SE = 0.11, p = 3.89e–8) but did not replicate (beta = −0.04, p = 0.47). Conclusion: Common polygenic variation of lymphocyte counts was significantly associated with moderate lymphopenia during DMF treatment.

Multiple Sclerosis Journal
Manitoba Health (CA), Karolinska University Hospital (SE), Vancouver Coastal Health (CA), University of British Columbia (CA), University of Toronto (CA), John Hunter Hospital (AU), McGill University Health Centre (CA), Karolinska Institutet (SE), University of Saskatchewan (CA), Hunter Medical Research Institute (AU), Children's Hospital Research Institute of Manitoba (CA), BC Children's Hospital (CA), Alfred Health (AU), University College London (GB), University of Manitoba (CA), Monash University (AU)
Good health and well-being
Openalex Percentile: Top 10%
Multiple Sclerosis Research Studies
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