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

IF 5

Multiple sclerosis (Houndmills, Basingstoke, England) Pub Date : 2026-10-01 Epub Date: 2026-08-17 DOI:10.1177/13524585261471335

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

{"title":"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","doi":"10.1177/13524585261471335","DOIUrl":null,"url":null,"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 × 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.","PeriodicalId":520714,"journal":{"name":"Multiple sclerosis (Houndmills, Basingstoke, England)","volume":" ","pages":"1292-1301"},"PeriodicalIF":5.0000,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672884/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Multiple sclerosis (Houndmills, Basingstoke, England)","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1177/13524585261471335","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/8/17 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}

引用次数: 0

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 × 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.

查看原文本刊更多论文

淋巴细胞计数多基因性是多发性硬化症中富马酸二甲酯相关淋巴细胞减少的基础。

目的：每20名使用富马酸二甲酯（DMF）的患者中就有1人会出现严重的淋巴细胞减少症，DMF是一种用于多发性硬化症（MS）的常用疾病改善疗法。我们的目的是确定与dmf相关的淋巴细胞减少症相关的遗传变异。方法：采用病例对照设计，我们纳入了DMF期间2级（绝对淋巴细胞计数9/L）或3级（9/L）淋巴细胞减少的病例。对照组淋巴细胞计数正常，且DMF暴露时间大于或等于1年。我们生成了淋巴细胞计数的多基因评分，并在两个队列中评估了其预测dmf相关淋巴细胞减少的能力，并对协变量进行了调整。我们还进行了全基因组关联研究（GWAS）和基于基因的分析。发现：发现队列包括238名来自加拿大/澳大利亚的欧洲遗传血统的PwMS （n = 72例2级，34例3级），复制队列包括156名来自瑞典的PwMS （n = 34例2级，14例3级）。淋巴细胞计数的多基因评分越高，预示2级淋巴细胞减少的风险越低（风险比= 0.43,95%可信区间：0.25-0.73）。GWAS鉴定出一个与DMF期间最小淋巴细胞计数相关的位点（rs17087205, β = -0.63, SE = 0.11, p = 3.89e-8），但没有重复（β = -0.04, p = 0.47）。结论：DMF治疗期间淋巴细胞计数常见多基因变异与中度淋巴细胞减少显著相关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Multiple sclerosis (Houndmills, Basingstoke, England)

自引率

0.00%

发文量