Lymphocyte count polygenicity underlies dimethyl fumarate–associated lymphopenia in multiple sclerosis
Year: 2026
Type: article
Study design: Observational Study
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.
Source: Multiple Sclerosis Journal
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
Institutions: Karolinska Institutet, University of Manitoba, University College London, University of British Columbia, Dalhousie University, University of Saskatchewan, University of Toronto, The Alfred Hospital, Alfred Health, Monash University, John Hunter Hospital, Hunter Medical Research Institute, University of Newcastle Australia, Health Sciences Centre, Children's Hospital Research Institute of Manitoba, CancerCare Manitoba, McGill University Health Centre, Research Institute of the McGill University Health Centre, Karolinska University Hospital, BC Children's Hospital Research Institute, Djavad Mowafaghian Centre for Brain Health
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,400
OpenAlex ID: W7203699948