Genetic Study of Severe Prolonged Lymphopenia in Multiple Sclerosis Patients Treated With Dimethyl Fumarate
In delayed-release dimethyl fumarate (DMF)-treated patients, absolute lymphocyte count (ALC) often declines in the first year and stabilizes thereafter; early declines have been associated with development of severe prolonged lymphopenia (SPL). Prolonged moderate or severe lymphopenia is a known ris...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-11-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2019.01039/full |
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| author | Dipen Sangurdekar Chao Sun Helen McLaughlin Katherine Ayling-Rouse Normand E. Allaire Michelle A. Penny Paola G. Bronson |
| author_facet | Dipen Sangurdekar Chao Sun Helen McLaughlin Katherine Ayling-Rouse Normand E. Allaire Michelle A. Penny Paola G. Bronson |
| author_sort | Dipen Sangurdekar |
| collection | DOAJ |
| description | In delayed-release dimethyl fumarate (DMF)-treated patients, absolute lymphocyte count (ALC) often declines in the first year and stabilizes thereafter; early declines have been associated with development of severe prolonged lymphopenia (SPL). Prolonged moderate or severe lymphopenia is a known risk factor for progressive multifocal leukoencephalopathy (PML); DMF-associated PML is very rare. It is unknown whether genetic predictors of SPL secondary to DMF treatment exist. We aimed to identify genetic predictors of reduced white blood cell (WBC) counts in DMF-treated multiple sclerosis (MS) patients. Genotyping (N = 1,258) and blood transcriptional profiling (N = 1,133) were performed on MS patients from DEFINE/CONFIRM. ALCs were categorized as: SPL, < 500 cells/µL for ≥6 months; moderate prolonged lymphopenia (MPL), < 800 cells/µL for ≥6 months, excluding SPL; mildly reduced lymphocytes, < 910 cells/µL at any point, excluding SPL and MPL; no lymphopenia, ≥910 cells/µL. Genome-wide association, HLA, and cross-sectional gene expression studies were performed. No common variants, HLA alleles, or expression profiles clinically useful for predicting SPL or MPL were identified. There was no overlap between genetic peaks and genetic loci known to be associated with WBC. Gene expression profiles were not associated with lymphopenia status. A classification model including gene expression features was not more predictive of lymphopenia status than standard covariates. There were no genetic predictors of SPL (or MPL) secondary to DMF treatment. Our results support ALC monitoring during DMF treatment as the most effective way to identify patients at risk of SPL. |
| first_indexed | 2024-04-14T05:36:46Z |
| format | Article |
| id | doaj.art-90588c16f2dc479da5489a748b9085f0 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-04-14T05:36:46Z |
| publishDate | 2019-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-90588c16f2dc479da5489a748b9085f02022-12-22T02:09:36ZengFrontiers Media S.A.Frontiers in Genetics1664-80212019-11-011010.3389/fgene.2019.01039468627Genetic Study of Severe Prolonged Lymphopenia in Multiple Sclerosis Patients Treated With Dimethyl FumarateDipen Sangurdekar0Chao Sun1Helen McLaughlin2Katherine Ayling-Rouse3Normand E. Allaire4Michelle A. Penny5Paola G. Bronson6Translational Genome Sciences, Translational Biology, Biogen, Cambridge, MA, United StatesTranslational Genome Sciences, Translational Biology, Biogen, Cambridge, MA, United StatesHuman Target Validation Core, Translational Biology, Biogen, Cambridge, MA, United StatesEnvision Pharma Group, Horsham, United KingdomTranslational Genome Sciences, Translational Biology, Biogen, Cambridge, MA, United StatesTranslational Genome Sciences, Translational Biology, Biogen, Cambridge, MA, United StatesHuman Target Validation Core, Translational Biology, Biogen, Cambridge, MA, United StatesIn delayed-release dimethyl fumarate (DMF)-treated patients, absolute lymphocyte count (ALC) often declines in the first year and stabilizes thereafter; early declines have been associated with development of severe prolonged lymphopenia (SPL). Prolonged moderate or severe lymphopenia is a known risk factor for progressive multifocal leukoencephalopathy (PML); DMF-associated PML is very rare. It is unknown whether genetic predictors of SPL secondary to DMF treatment exist. We aimed to identify genetic predictors of reduced white blood cell (WBC) counts in DMF-treated multiple sclerosis (MS) patients. Genotyping (N = 1,258) and blood transcriptional profiling (N = 1,133) were performed on MS patients from DEFINE/CONFIRM. ALCs were categorized as: SPL, < 500 cells/µL for ≥6 months; moderate prolonged lymphopenia (MPL), < 800 cells/µL for ≥6 months, excluding SPL; mildly reduced lymphocytes, < 910 cells/µL at any point, excluding SPL and MPL; no lymphopenia, ≥910 cells/µL. Genome-wide association, HLA, and cross-sectional gene expression studies were performed. No common variants, HLA alleles, or expression profiles clinically useful for predicting SPL or MPL were identified. There was no overlap between genetic peaks and genetic loci known to be associated with WBC. Gene expression profiles were not associated with lymphopenia status. A classification model including gene expression features was not more predictive of lymphopenia status than standard covariates. There were no genetic predictors of SPL (or MPL) secondary to DMF treatment. Our results support ALC monitoring during DMF treatment as the most effective way to identify patients at risk of SPL.https://www.frontiersin.org/article/10.3389/fgene.2019.01039/fullmultiple sclerosislymphopeniadimethyl fumaratepharmacogenomicstranscriptomics |
| spellingShingle | Dipen Sangurdekar Chao Sun Helen McLaughlin Katherine Ayling-Rouse Normand E. Allaire Michelle A. Penny Paola G. Bronson Genetic Study of Severe Prolonged Lymphopenia in Multiple Sclerosis Patients Treated With Dimethyl Fumarate Frontiers in Genetics multiple sclerosis lymphopenia dimethyl fumarate pharmacogenomics transcriptomics |
| title | Genetic Study of Severe Prolonged Lymphopenia in Multiple Sclerosis Patients Treated With Dimethyl Fumarate |
| title_full | Genetic Study of Severe Prolonged Lymphopenia in Multiple Sclerosis Patients Treated With Dimethyl Fumarate |
| title_fullStr | Genetic Study of Severe Prolonged Lymphopenia in Multiple Sclerosis Patients Treated With Dimethyl Fumarate |
| title_full_unstemmed | Genetic Study of Severe Prolonged Lymphopenia in Multiple Sclerosis Patients Treated With Dimethyl Fumarate |
| title_short | Genetic Study of Severe Prolonged Lymphopenia in Multiple Sclerosis Patients Treated With Dimethyl Fumarate |
| title_sort | genetic study of severe prolonged lymphopenia in multiple sclerosis patients treated with dimethyl fumarate |
| topic | multiple sclerosis lymphopenia dimethyl fumarate pharmacogenomics transcriptomics |
| url | https://www.frontiersin.org/article/10.3389/fgene.2019.01039/full |
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