Lymphocyte count polygenicity underlies dimethyl fumarate-associated lymphopenia in multiple sclerosis.

Authors

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

Published in

Multiple sclerosis (Houndmills, Basingstoke, England). Pages 13524585261471335. Aug 17, 2026. Epub Aug 17, 2026.

Abstract

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.
Using a case-control design, we included cases that had either grade 2 (absolute lymphocyte count <0.8 × 10⁹/L) or 3 (<0.5 × 10⁹/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.
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).
Common polygenic variation of lymphocyte counts was significantly associated with moderate lymphopenia during DMF treatment.

PMID:
42608789
Bibliographic data and abstract were imported from PubMed on 18 Aug 2026.

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