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Candidate Gene Testing in Clinical Cohort Studies with Multiplexed Genotyping and Mass Spectrometry
Published on: June 21, 2018
T cell composition and polygenic multiple sclerosis risk: A population-based study in children
Casper L de Mol1,2, Kirsten I M Looman2,3, Marvin M van Luijn4
1Department of Neurology, MS Center ErasMS, Erasmus University Medical Center, Rotterdam, the Netherlands.
Insights
Multiple sclerosis (MS) genetic risk influences T cell composition in children. A higher MS polygenic risk score (PRS) was linked to fewer CD8+ T cells, suggesting early immune system alterations.
Area of Science:
- Immunology
- Genetics
- Pediatrics
Background:
- Multiple sclerosis (MS) is characterized by altered T cell function and composition.
- Genetic risk variants for MS commonly impact immune system proteins.
- The extent to which genetic factors influence T cell composition before MS onset remains unclear.
Purpose of the Study:
- To investigate the association between a multiple sclerosis polygenic risk score (PRS) and T cell composition in a general childhood population.
- To determine if genetic risk factors for MS are detectable in T cell composition during childhood.
Main Methods:
- Utilized data from the population-based Generation R study, including genotyped children with immunophenotyped T cells at age 6.
- Employed analyses of variance to assess the impact of MS-PRS on T cell numbers, CD4+, and CD8+ T cell lineages and subsets.
- Constructed T-cell-specific PRSs based on functional pathway data.
Main Results:
- A significant negative correlation was found between the MS-PRS and CD8+ T cell frequencies (p = 2.92 × 10⁻³).
- This correlated with a positive association with CD4+/CD8+ T cell ratios (p = 8.27 × 10⁻⁹).
- The primary drivers of these associations were the MS risk variants HLA-DRB1*15:01 and an HLA-B risk variant.
Conclusions:
- Multiple sclerosis-associated genetic variants demonstrably impact T cell composition in childhood within the general population.
- These findings suggest that genetic predispositions to MS can manifest as altered immune cell profiles early in life.
Background And Purpose:
Patients with multiple sclerosis (MS) have altered T cell function and composition. Common genetic risk variants for MS affect proteins that function in the immune system. It is currently unclear to what extent T cell composition is affected by genetic risk factors for MS, and how this may precede a possible disease onset. Here, we aim to assess whether an MS polygenic risk score (PRS) is associated with an altered T cell composition in a large cohort of children from the general population.
Methods:
We included genotyped participants from the population-based Generation R study in whom immunophenotyping of blood T cells was performed at the age of 6 years. Analyses of variance were used to determine the impact of MS-PRSs on total T cell numbers (n = 1261), CD4+ and CD8+ lineages, and subsets therein (n= 675). In addition, T-cell-specific PRSs were constructed based on functional pathway data.
Results:
The MS-PRS negatively correlated with CD8+ T cell frequencies (p = 2.92 × 10-3 ), which resulted in a positive association with CD4+ /CD8+ T cell ratios (p = 8.27 × 10-9 ). These associations were mainly driven by two of 195 genome-wide significant MS risk variants: the main genetic risk variant for MS, HLA-DRB1*15:01 and an HLA-B risk variant. We observed no significant associations for the T-cell-specific PRSs.
Conclusions:
Our results suggest that MS-associated genetic variants affect T cell composition during childhood in the general population.
