Exploratory Analysis of Sex-Related Immune Gene Expression in Patients With Severe Periodontitis

Background Biological sex influences immune function and inflammatory regulation, but its molecular role in periodontal disease remains insufficiently understood. This pilot study investigated sex-dependent differences in immune gene expression in patients with severe periodontitis. Methods Ten systemically healthy, non-smoking adults (five men and five women) with stage III/IV periodontitis were examined. Total RNA was extracted from saliva and analyzed using the nCounter ® Human Inflammation Panel (NanoString, Bruker Spatial Biology, USA). Results Among 249 immune-related genes analyzed, two showed notable preliminary trends of sex-associated differences: AREG was upregulated in males (log 2 FC = −0.67, d = −1.73, p = 0.03), and NOD2 was elevated in females (log 2 FC = 1.00, d = 1.36, p = 0.03), although these did not remain statistically significant after FDR correction. Conclusion These exploratory results suggest hypothesis-generating trends regarding sex-dependent differences in epithelial repair and innate immunity, highlighting AREG and NOD2 as candidate transcripts for further investigation. These initial findings may serve as a foundation for future, larger-scale multicenter studies with sex-stratified designs integrating transcriptomic, hormonal, and epigenetic analyses to clarify how biological sex influences molecular pathways involved in periodontal inflammation.