Polygenic Lymphocyte Score Predicts Lymphopenia Risk in Patients With MS Treated With Dimethyl Fumarate

Common genetic variation associated with lymphocyte counts was linked to the risk of developing moderate lymphopenia among people with multiple sclerosis (MS) treated with dimethyl fumarate (DMF), according to findings from a case-control study recently published in the Multiple Sclerosis Journal. Investigators reported that a higher polygenic score for lymphocyte counts was associated with a significantly lower risk of grade 2 lymphopenia, with the association remaining after adjustment for baseline lymphocyte counts and other clinical and genetic factors.¹

Lead author Kaarina Kowalec, PhD, associate professor at the College of Pharmacy at the University of Manitoba Rady Faculty of Health Sciences in Canada, and colleagues, sought to address the limited ability of clinical and demographic factors to predict which patients will develop DMF-associated lymphopenia. Rather than focusing on individual genetic variants, the study evaluated the cumulative contribution of common genetic variation associated with lymphocyte counts, with the goal of determining whether inherited susceptibility to lower lymphocyte levels could help identify patients at greater risk of treatment-related lymphopenia.

"The association observed for grade 2 lymphopenia should be interpreted as reflecting susceptibility to DMF-related lymphocyte decline more broadly," Kowalec et al wrote.¹ "Grade 2 represents a clinically actionable window: it was common enough to permit well-powered analysis and occurs early enough that intervention remains possible, before the severe immunosuppression and opportunistic infection risk associated with grade 3."

Polygenic Variation Associated With DMF-Related Lymphopenia

The case-control study included 394 adults with relapsing-onset MS and documented exposure to DMF across discovery and replication cohorts from Canada, Australia, and Sweden. All participants had a normal absolute lymphocyte count (ALC) before starting DMF.¹

The discovery cohort consisted of 238 individuals of European genetic ancestry from Canada and Australia, including 106 patients who developed either grade 2 or grade 3 lymphopenia and 116 DMF-tolerant controls. The replication cohort included 156 individuals from Sweden, including 34 patients with grade 2 lymphopenia and 14 with grade 3 lymphopenia, along with 122 DMF-tolerant controls.

Grade 2 lymphopenia was defined as an ALC below 0.8 × 10^9/L on at least 1 laboratory test during DMF exposure, whereas grade 3 lymphopenia was defined as an ALC below 0.5 × 10^9/L. Prolonged lymphopenia was defined as at least 2 measurements meeting the respective threshold at least 6 months apart. DMF-tolerant controls had received treatment for at least 1 year and had all available on-treatment lymphocyte counts within the normal laboratory reference range.

To assess the contribution of inherited variation, investigators generated a polygenic score for lymphocyte counts using summary-level GWAS data from the Pan-UK Biobank, which included 407,277 individuals of European ancestry with measured lymphocyte counts. The score represented the cumulative genetic liability for lymphocyte counts and was standardized to a mean of 0 and standard deviation of 1.

Investigators then evaluated whether the score predicted the development of lymphopenia during DMF treatment. Serial ALC measurements were aligned according to time since DMF initiation, and interval-censored Cox proportional hazards models were used to examine time to first occurrence of grade 2 or grade 3 lymphopenia.

The primary models adjusted for age at DMF initiation, sex, and the first 5 genetic ancestry principal components. Additional models incorporated baseline lymphocyte count to determine whether genetic susceptibility remained associated with treatment-related lymphopenia beyond an individual's pretreatment lymphocyte level.

In the discovery cohort, higher polygenic scores were significantly associated with a lower risk of grade 2 lymphopenia. Each 1-standard-deviation increase in the score was associated with a 57% reduction in the risk of developing grade 2 lymphopenia (adjusted HR, 0.43; 95% CI, 0.25-0.73; P = .002). A categorical analysis comparing patients in the highest 20% of polygenic score values with those in the lower 80% produced a similar direction of effect, although the association did not reach statistical significance (adjusted HR, 0.58; 95% CI, 0.33-1.02).

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The association remained after baseline ALC was added to the model. In this analysis, each standard-deviation increase in the polygenic score was associated with a lower risk of grade 2 lymphopenia (adjusted HR, 0.48; 95% CI, 0.27-0.87; P = .016). Baseline lymphocytecount itself was inversely associated with the risk of developing lymphopenia, with lower pretreatment counts associated with greater risk.

Investigators did not observe a statistically significant association between the polygenic score and grade 3 lymphopenia in the discovery cohort. The authors noted that the smaller number of severe lymphopenia events limited the statistical power for this analysis.

Findings from the independent Swedish cohort were directionally consistent with the discovery results. The study was limited in its ability to assess grade 3 lymphopenia in Sweden because of the small number of events, with the model failing to converge for that outcome.

GWAS Identifies Nonreplicated Variant

In a separate genome-wide analysis, investigators examined individual genetic variants associated with the lowest ALC recorded during DMF treatment. The discovery GWAS identified 1 genome-wide significant locus on chromosome 9, involving variant rs17087205. The variant was associated with the minimum lymphocyte count during treatment (β = −0.63; standard error, 0.11; P = 3.89 × 10^−8).¹

However, the association was not replicated in the Swedish cohort, where the effect was substantially smaller and did not reach statistical significance (β = −0.05; P = .62). Investigators therefore noted that the finding would require replication in an additional cohort before it could be considered for potential clinical application. No genome-wide significant variants were identified for grade 2 or grade 3 lymphopenia or for prolonged grade 2 or grade 3 lymphopenia.

Gene-based analyses of 18,051 genes also failed to identify associations that survived Bonferroni or false discovery rate correction. The top-ranked genes included PRKAG3, LPL, SCN9A, LILRB2, and SLC28A3, although the investigators characterized these findings as exploratory because of the relatively small GWAS sample size. Similarly, no pathway enrichment findings survived global false discovery rate correction.

Investigators also evaluated a variant previously associated with DMF-related lymphopenia in an earlier study of patients enrolled in the DEFINE and CONFIRM phase 3 trials. Although its effect was in the same direction in the current discovery cohort, the association did not reach statistical significance. Together, these findings led the investigators to emphasize the potential importance of polygenic susceptibility rather than a single genetic variant in determining an individual's risk of lymphopenia during DMF treatment.

Potential for Pretreatment Risk Stratification

The findings raise the possibility that genetic information could eventually complement conventional laboratory monitoring to identify patients at greater risk for DMF-associated lymphopenia. Since the polygenic score is derived from germline genetic information, investigators noted that it could theoretically be calculated before DMF initiation. Patients with greater genetic susceptibility to lower lymphocyte counts could potentially undergo more intensive monitoring or earlier clinical review, while treatment selection or dosing strategies could also be investigated in future studies.¹

The authors emphasized, however, that the findings are not yet ready for clinical implementation. The study included only participants of European genetic ancestry, and substantially larger cohorts will be needed to determine whether the association extends to other populations.

The study also did not consistently account for other factors potentially associated with DMF-related lymphopenia, including body mass index and smoking status. Future research may need to determine whether these factors independently contribute to lymphopenia risk or interact with genetic susceptibility.

The investigators further suggested that the underlying genetic susceptibility to lower lymphocyte counts could have relevance beyond DMF, particularly for other therapies associated with lymphopenia. Ocrelizumab (Ocrevus; Genentech) was identified as one potential area for future investigation.

"Ultimately, the findings from this study could improve the treatment of MS by identifying who is most likely to have a potentially serious reduction in lymphocytes before they occur and thus enhance the health of people with MS," Kowalec et al concluded.¹ The authors added that the broader findings support a potential pharmacogenetic framework in which polygenic variation underlying a biological trait may influence an individual's susceptibility to drug-related disruption of that same trait.

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REFERENCES
1. Kowalec K,Manouchehrinia A,Kingwell E, et al. Lymphocyte count polygenicity underlies dimethyl fumarate–associated lymphopenia in multiple sclerosis. Multiple Sclerosis Journal. 2026;0(0). doi:10.1177/13524585261471335