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Smoking status and nonlinear associations of cerebrospinal fluid GDF11 and IGF2 with Subjective sleep quality: a cross-sectional study using generalized additive models

Year: 2026

Type: article

Abstract: Cigarette smoking is consistently associated with poorer sleep, yet the central biochemical correlates of this relationship remain insufficiently characterized in humans. Growth differentiation factor 11 (GDF11) and insulin-like growth factor 2 (IGF2) are candidate biomarkers of vascular and neurotrophic signaling, but their associations with sleep quality in smokers and non-smokers are unclear. In this cross-sectional study, 191 male participants (87 smokers and 104 non-smokers) undergoing anterior cruciate ligament reconstruction were enrolled. Preoperative cerebrospinal fluid (CSF) concentrations of GDF11 and IGF2 were measured by enzyme-linked immunosorbent assay, and sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Linear regression and overall generalized additive models (GAMs) were fitted first; smoking-stratified GAM and two-piecewise linear regression analyses were then conducted as exploratory secondary analyses. No formal biomarker × smoking interaction test was performed. Smokers had poorer PSQI scores, lower CSF GDF11 levels, and higher CSF IGF2 levels than non-smokers. Based on source-data reanalysis, the unadjusted mean differences (non-smokers minus smokers) were − 1.48 points for PSQI (95% CI, -2.19 to -0.77), 192.62 pg/mL for GDF11 (95% CI, 166.56 to 218.68), and − 1.68 ng/mL for IGF2 (95% CI, -3.10 to -0.26). Adjusted group differences remained significant for PSQI and GDF11 but not for IGF2 (p = 0.059). In separate fully adjusted linear models, GDF11 was not statistically significant, whereas the association for IGF2 was borderline (B = 0.068; 95% CI, -0.001 to 0.137; p = 0.055). Overall GAMs identified nonlinear associations of both biomarkers with PSQI scores. Exploratory smoking-stratified analyses suggested different curve shapes and sample-derived inflection points across groups. CSF GDF11 and IGF2 showed nonlinear associations with subjective sleep quality, and exploratory smoking-stratified analyses suggested possible heterogeneity in curve shape. Because no formal interaction test was performed, these subgroup patterns should not be interpreted as definitive effect modification. The sample-derived inflection points also require validation in independent cohorts. Linear regression showed no significant biomarker-PSQI associations. GAMs identified nonlinear biomarker-sleep associations. Smoking-stratified GAM curves showed different estimated shapes. Exploratory analyses suggested a threshold-like GDF11 pattern in non-smokers. Exploratory analyses suggested a threshold-like IGF2 pattern in smokers.

Source: BMC Psychology

DOI: 10.1186/s40359-026-05578-z