Plasma Neuronal Growth Regulator 1 May Link Physical Activity to Reduced Risk of Type 2 Diabetes: A Proteome-Wide Study of ARIC Participants

Habitual physical activity (PA) impacts the plasma proteome and reduces the risk of developing type 2 diabetes (T2D).Using a large-scale proteome-wide approach in Atherosclerosis Risk in Communities study participants, we aimed to identify plasma proteins associated with PA and determine which of thesemay be causally related to lower T2D risk. PA was associated with 92 plasma proteins in discovery (P < 1.01 × 1025), and 40 remained significant in replication (P < 5.43 × 1024). Eighteen of these proteins were independently associated with incident T2D (P < 1.25 × 1023), including neuronal growth regulator 1 (NeGR1; hazard ratio per SD 0.85; P = 7.5× 10211). Two-sampleMendelian randomization (MR) inverse variance weighted analysis indicated that higher NeGR1 reduces T2D risk (odds ratio [OR] per SD 0.92; P = 0.03) and was consistent withMR-Egger, weighted median, and weightedmode sensitivity analyses. A stronger association was observed for the single cis-acting NeGR1 genetic variant (OR per SD 0.80; P = 6.3 × 1025). Coupled with previous evidence that low circulating NeGR1 levels promote adiposity, its association with PA and potential causal role in T2D shown here suggest that NeGR1may link PA exposure with metabolic outcomes. Further research is warranted to confirm our findings and examine the interplay of PA, NeGR1, adiposity, andmetabolic health.