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Lymphocyte count polygenicity underlies dimethyl fumarate-associated lymphopenia in multiple sclerosis
Kaarina Kowalec1, Ali Manouchehrinia2, Elaine Kingwell3
1College of Pharmacy, University of Manitoba, Winnipeg, MB, Canada; Department of Biochemistry & Medical Genetics, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada; Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
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.
