Multiple sclerosis (MS) is associated with extensive immunological alterations in adult patients. MS patients show changes in T cell composition, including increased CD4+/CD8+ ratios. However, it is unclear to which extent these changes in T cell composition are influenced by genetic risk for MS, and how this may precede a possible disease onset.
In the current study we investigate the association between polygenic risk scores (PRSs) for MS and T cell subsets in a large population-based pediatric sample, to provide new understanding about the link between genetic risk for MS and disease pathophysiology.
We included participants from the population-based Generation R study who had genetic- and immunological data available. Children were sampled for immunological data around the age of 6 years (IQR: 5.9-6.2). Linear regression analyses were used to analyze the impact of MS-PRSs on absolute T cell numbers (n=1,261) and CD4+ and CD8+ T cell fractions (n=675) adjusted for important child- (age and sex) and environmental confounding factors (serum vitamin D levels and cytomegalovirus positivity).
The MS-PRS showed a negative correlation with CD8+ T cell frequencies (β=-0.05, SE=0.015, ΔR2=0.020, p=2.88 × 10-4), which resulted in a positive association with CD4+/CD8+ ratios (β=0.07, SE=0.011, ΔR2=0.054, p=9.20 × 10-10). Interestingly, the latter was driven by 2 out of 196 genome-wide significant MS risk variants. Both from within the HLA class II region, risk variants rs3135388 and rs9271366 were positively associated with the CD4+/CD8+ ratio. No association was found with absolute total T cell numbers.
This study shows that higher genetic risk for MS is associated with T cell alterations at an early age. Our results show a possibility that MS genetics affect the T cell composition during childhood, which may contribute to increased risk of MS disease later in life.