Multiple sclerosis (Houndmills, Basingstoke, England) · 2026
Lymphocyte count polygenicity underlies dimethyl fumarate-associated lymphopenia in multiple sclerosis.
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Kowalec Kaarina, Manouchehrinia Ali, Kingwell Elaine, Carruthers Robert, Marrie Ruth Ann, Evans Charity, Rotstein Dalia, Kuan Annie J, Luo Wenzhuo, Luo Daniel, Desrochers Brianne, Jokubaitis Vilija G, Lechner-Scott Jeannette, Maltby Vicki E, Groen Kira, Wright Galen Eb, Drögemöller Britt I, Bernatsky Sasha, Levin Michael C, Knox Katherine, Maruf Abdullah Al, Zhong Michael, Alfredsson Lars, Hillert Jan, Kockum Ingrid, Olsson Tomas, Stridh Pernilla, Shchetynsky Klementy, Dever Kristy, MacIsaac Julie, Kobor Michael S, Tremlett Helen
Аннотация
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 × 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.
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.
METHODS: 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.
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.