Diabetes
Neutrophil-to-lymphocyte ratio and immune cell proportion differences in at-risk children with and without type 1 diabetes Kirk Hohsfield* Kirk Hohsfield Patrick M. Carry Alex Romero Lauren A. Vanderlinden Marian Rewers Katerina Kechris Jill M. Norris Randi K. Johnson
Introduction:
Risk factors for type 1 diabetes (T1D) likely differ before and after the appearance of islet autoimmunity (IA), a critical stage of disease progression marked by the advent of autoantibodies. We investigated the neutrophil-to-lymphocyte ratio (NLR), a systemic inflammation biomarker, and immune cell proportions as risk factors for T1D in The Environmental Determinants of Diabetes in the Young (TEDDY) prospective cohort study.
Methods:
Using plasma DNA methylation (Illumina EPIC array) measured in a matched, nested case-control design, immune cell (B, CD4T, CD8T, monocyte, natural killer, and neutrophil) proportions were estimated via the Houseman method. We tested for differences in NLR and cell type proportions between T1D cases and controls using conditional logistic regression (NLR) and linear mixed effects models (cell types), adjusting for age, sex, and matching strata. Each cell type was modeled as a log ratio with neutrophils to account for the compositional data and exponentiated to be a mean difference cell proportion ratio (CPR). Analyses focused on two critical time points in the natural history of T1D: just before (pre-IA: 60 case-control pairs) and just after (post-IA: 76 case-control pairs) IA seropositivity.
Results:
No differences in NLR or cell proportions were identified pre-IA (P>0.05). However, both the NLR and cell-specific proportions differed post-IA. A one-unit increase in NLR led to an 86% decrease in T1D odds (OR: 0.14, 95% CI: 0.03, 0.77). Compared to controls, T1D cases had increased NK (CPR: 1.40, 95% CI: 1.02, 1.92), CD8T (CPR: 1.21, 95% CI: 1.02, 1.44), and CD4T (CPR: 1.16, 95% CI: 1.01, 1.33) cell proportion ratios post-IA.
Conclusions:
We identified expansion of key lymphocyte populations distinguishing T1D cases from controls post-IA, including NK, CD8T, and CD4T cells. Environmental factors or inflammatory triggers driving these immune cell changes may give clues to the etiology of T1D and should be investigated further.