Multiple sclerosis risk variants influence the peripheral B-cell compartment early in life in the general population

Casper L. de Mol, Marvin M. van Luijn, Karim L. Kreft, Kirsten I.M. Looman, Menno C. van Zelm, Tonya White, Henriette A. Moll, Joost Smolders, Rinze F. Neuteboom*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Background and purpose: Multiple sclerosis (MS) is associated with abnormal B-cell function, and MS genetic risk alleles affect multiple genes that are expressed in B cells. However, how these genetic variants impact the B-cell compartment in early childhood is unclear. In the current study, we aim to assess whether polygenic risk scores (PRSs) for MS are associated with changes in the blood B-cell compartment in children from the general population. Methods: Six-year-old children from the population-based Generation R Study were included. Genotype data were used to calculate MS-PRSs and B-cell subset-enriched MS-PRSs, established by designating risk loci based on expression and function. Analyses of variance were performed to examine the effect of MS-PRSs on total B-cell numbers (n = 1261) as well as naive and memory subsets (n = 675). Results: After correction for multiple testing, no significant associations were observed between MS-PRSs and total B-cell numbers and frequencies of subsets therein. A naive B-cell-MS-PRS (n = 26 variants) was significantly associated with lower relative, but not absolute, naive B-cell numbers (p = 1.03 × 10−4 and p = 0.82, respectively), and higher frequencies and absolute numbers of CD27+ memory B cells (p = 8.83 × 10−4 and p = 4.89 × 10−3, respectively). These associations remained significant after adjustment for Epstein–Barr virus seropositivity and the HLA-DRB1*15:01 genotype. Conclusions: The composition of the blood B-cell compartment is associated with specific naive B-cell-associated MS risk variants during childhood, possibly contributing to MS pathophysiology later in life. Cell subset-specific PRSs may offer a more sensitive tool to define the impact of genetic risk on the immune system in diseases such as MS.

Original languageEnglish
Pages (from-to)434-442
Number of pages9
JournalEuropean Journal of Neurology
Issue number2
Early online date28 Sept 2022
Publication statusPublished - Feb 2023

Bibliographical note

Funding Information:
This study was sponsored by the Dutch MS Research Foundation. The Generation R Study is made possible by continuous support from the Erasmus MC, Rotterdam, the Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the NWO, and the Ministry of Health, Welfare, and Sport.

Publisher Copyright:
© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.


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