Integrative Population‐Based Analysis of Homocysteine and Systemic Immunity‐Inflammation Index Reveals Gender‐ and Hormone‐Specific Patterns for Precision Biomarker Stratification

Background Homocysteine (Hcy) is a sulfur‐containing nonessential amino acid and an important intermediate in the metabolism of methionine. Elevated Hcy levels are an independent risk factor for chronic diseases and are often linked to inflammation. The systemic immunity‐inflammation index (SII) is a novel inflammatory biomarker reflecting immune‐inflammatory status. To our knowledge, this is the first study to explore the potential association between Hcy and SII, integrating metabolic and immune‐inflammatory dimensions, with a focus on gender‐ and hormone‐related differences. Methods This cross‐sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2006. A total of 17,824 U.S. adults were enrolled in the final analysis. Multivariate linear regression analysis was employed to investigate the relationship between Hcy and SII, adjusting for multiple covariates. To further explore gender differences, gender‐stratified analyses and interaction tests were conducted. Additionally, threshold effect analysis and smooth curve fitting were performed within different gender groups. Subgroup analyses were also conducted within the female sample to evaluate the consistency of the findings. Results Multivariate linear regression analysis revealed a significant positive correlation between Hcy and SII [2.91 (1.45, 4.36)]. Interaction tests and gender stratification analyses indicated marked differences in the association between Hcy and SII across genders ( p for interaction < 0.01). In men, Hcy was positively correlated with SII [5.76 (3.81, 7.72)], while this association was lost in women ( p = 0.338). Additional threshold effect analysis and smoothing curve fitting demonstrated distinctly nonlinear trends between sexes. Subgroup analyses of pre‐ and postmenopausal women and those using hormone replacement therapy (HRT) revealed a negative correlation between Hcy and SII in premenopausal women [−6.04 (−9.53, −2.55)], which shifted to a positive correlation postmenopause [5.74 (2.25, 9.24)]. Conclusion This study identified a significant association between Hcy levels and SII, highlighting the moderating role of gender and hormonal status in this relationship. These findings support an integrative framework linking metabolic and immune‐inflammatory processes and emphasize the importance of gender‐ and hormone‐specific stratification for precision biomarker interpretation.