Abstract
OBJECTIVES: The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) is an innovative measure for assessing cardiovascular disease risk, primarily associated with lipid profiles. Lipid metabolism disorders have been reported to be associated with age-related macular degeneration (AMD), yet the relationship between NHHR and AMD has not been previously explored. This study primarily aims to investigate the potential association between NHHR and the prevalence of AMD. METHODS: A comprehensive cross-sectional stratified survey using the National Health and Nutrition Examination Survey (NHANES) dataset of the US was conducted, including 4,017 participants aged 40 years and older, from 2005 to 2008. The NHHR was calculated as [Total Cholesterol (TC) - High-Density Lipoprotein Cholesterol (HDL-C)]/HDL-C. Data on AMD were derived from retinal photography. Logistic regression, stratified analysis, RCS curve, ROC/AUC, and subgroup interaction analysis were used to explore the relationship between NHHR and AMD. Meanwhile, patients who visited the People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine (PHFT, China) between November 2021 and September 2025 were recruited retrospectively. All participants who met the study inclusion criteria were screened from the hospital-wide integrated informatics platform for clinical research. Finally, the clinical data of 96 eligible participants of PHFT were included in this study for conducting external validation analysis. RESULTS: The cross-sectional study from NHANES included 4,017 participants, of whom 3,678 (91.56%) had no AMD and 339 (8.44%) exhibited AMD. The external validation study from PHFT consisted of 48 patients with AMD and 48 non-AMD participants. Both studies indicated that compared with the non-AMD group, the AMD group had a significantly lower NHHR (p < 0.01). In the fully adjusted Model, when NHHR was stratified into tertiles, the results showed that for each one-unit increase in NHHR, the risk of AMD in individuals in the highest tertile was reduced by 33.1 and 76.8%, respectively. The results of the RCS curve and threshold effect analyses from the two studies confirmed a negative correlation trend between the two variables (p < 0.05). The subgroup and interaction analysis, based on data from the NHANES, shows consistent associations between NHHR and AMD across various subgroups. CONCLUSION: Our preliminary research indicates that NHHR might be a reliable independent indicator of the risk of developing AMD. In the future, large-scale sample studies and more prospective research are still needed to confirm our findings.