Preprint Genome-wide association study reveals different T cell distributions in blood of individuals at high genetic risk of type 1 diabetes & LC,2024,Deecke+

[SNT Gatchaman]

Genome-wide association study reveals different T cell distributions in peripheral blood of healthy individuals at high genetic risk of type 1 diabetes and long COVID
Laura Deecke; Jan Homann; David Goldeck; Felix Luessi; Marijne Vandebergh; Olena Ohlei; Sarah Toepfer; Frauke Zipp; Ilja Demuth; Sarah L. Morgan; Lars Bertram; Graham Pawelec; Christina M. Lill

The immune system plays a crucial role in many human diseases. In this context, genome-wide association studies (GWAS) offer valuable insights to elucidate the role of immunity in health and disease. The present multi-omics study aimed to identify genetic determinants of immune cell type distributions in the blood of healthy individuals and to assess whether the distributions of these cells may play a role for autoimmune and COVID-19 disease risk.

To this end, the frequencies of different immune cells in 483 healthy individuals from the Berlin Aging Study II were quantified using flow cytometry, and GWAS was performed for 92 immune cell phenotypes. Additionally, we performed linear regression analyses of immune cell distributions using polygenic risk scores (PRS) based on prior GWAS for five autoimmune diseases as well as for COVID-19 infection and post-COVID syndrome ("long COVID").

We validated seven previously described immune loci and identified 13 novel loci showing genome-wide significant (α=5.00E-8) association with different immune cell phenotypes. The most significant novel signal was conferred by the SLC52A3 locus, encoding for a riboflavin transporter protein, which was associated with naïve CD57+ CD8+ T cells (p=4.13E-17) and colocalized with SLC52A3 expression.

Several novel loci contained immunologically plausible candidate genes, e.g., variants near TBATA and B3GAT1 representing genes associated with T cell phenotypes. The PRS of type 1 diabetes were significantly associated with CD8+ T cells at different differentiation states (p≤7.02E-4), and PRS of long COVID were associated with early-differentiated CD4+ T cells (p≤1.54E-4).

In conclusion, our extensive immune cell GWAS analyses highlight several novel genetic loci of likely relevance for immune system function. Furthermore, our PRS analyses point to a shared genetic basis between immune cell distributions in healthy adults and T1D (CD8+ T cells) as well as long COVID (CD4+ T cells).


Link | PDF (Preprint: MedRxiv)

 

[SNT Gatchaman]

The most significant novel immune cell locus was SLC52A3 that was associated with naïve CD57+ CD8+ T cells and showed colocalization with SLC52A3 expression. SLC52A3 encodes the "solute carrier family 52 member 3", a riboflavin transporter protein that is strongly expressed in the intestine and plays a role in intestinal absorption of riboflavin (vitamin B2). Our GWAS now further supports a role of riboflavin in the distribution of naïve CD57+ CD8+ T cells in peripheral blood. Interestingly, the population of naïve CD57+ CD8+ T cells is only a very small subset of CD8+ cells (<1%) and has rarely been studied specifically. Thus, independent replication of this genome-wide significant finding will be required.

A second finding from this arm of the study was that early-differentiated CD4+ T cells are likely involved in predisposition to long COVID, which is in agreement with previous, functional data. Our novel results now show that the genetic predisposition to TID and long COVID leads to different immune cell compositions of CD8+ and CD4+ T cells already in the pre-disease state.