Lymphocyte count polygenicity underlies dimethyl fumarate–associated lymphopenia in multiple sclerosis
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 TremlettPurpose:
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 (
Conclusion:
Common polygenic variation of lymphocyte counts was significantly associated with moderate lymphopenia during DMF treatment.