RANTES (CCL5) in Patients With Geographic Atrophy Age-Related Macular Degeneration.

Purpose: A previous study from our research group showed significantly lower levels of RANTES (Regulated upon Activation, Normal T Cell Expressed and Secreted) in patients with intermediate age-related macular degeneration (AMD) compared to control patients with no AMD. The primary aim of this study was to assess levels of RANTES in a cohort of patients with a more advanced form of the disease, geographic atrophy (GA), in comparison with controls. Methods: The study was conducted on a cohort of patients with GA recruited into a Colorado AMD registry. Cases and controls were defined with multimodal imaging. Plasma levels of the chemokine RANTES were measured using a multiplex assay. A nonparametric (rank-based) regression model was fit to RANTES with a sex by AMD category interaction. Results: The plasma levels of RANTES were significantly higher in the control group in comparison to the GA AMD group (median [interquartile range]): 10,204 [5799-19,554] pg/mL vs. 5435 [3420-9177] pg/mL, respectively, P < 0.01). When moderated by sex, there was no statistical difference between the male and female GA AMD or the male and female controls. Conclusions: We found lower level of RANTES in patients with GA AMD compared with controls. This finding is consistent with the findings from our previous intermediate AMD study. However, in contrast to the results of our previous research, when moderated by sex there was no statistical difference between male and female GA patients. Translational Relevance: The biomarker RANTES is significantly lower in GA AMD patients compared to controls.

Sex Differences in RANTES (CCL5) in Patients With Intermediate Age-Related Macular Degeneration (AMD) and Controls With no AMD.

PURPOSE: To determine if there are sex differences in levels of regulated upon activation, normal T cell expressed and secreted (RANTES) in patients with intermediate age-related macular degeneration (iAMD) and in controls with no AMD. METHODS: Patients with iAMD and controls defined by multi-modal imaging were recruited into a Colorado AMD registry. Plasma levels of the chemokine RANTES were measured using a multiplex assay. A nonparametric (rank-based) regression model was fit to RANTES with a sex by AMD category interaction. RESULTS: The plasma level of RANTES was significantly higher in the control group in comparison with the iAMD group. When moderated by sex, RANTES was significantly lower (P = 0.005) in males (median, 4525.6 pg/mL; interquartile range, 2589-7861 pg/mL) compared with females (median, 6686 pg/mL; interquartile range, 3485-12488 pg/mL) within the iAMD cohort. No significant difference was found in levels of RANTES between males and females in the control group. CONCLUSIONS: We found that levels of RANTES were moderated by sex in cases with iAMD with lower levels in males compared with females. The findings illustrate the importance of including sex as a biological variable in AMD research. There is a need for further studies of RANTES, stratified by sex, in the advanced phenotypes of AMD. TRANSLATIONAL RELEVANCE: The biomarker RANTES identified in the plasma of patients with iAMD reflects systemic alterations when stratified by sex.

Association of Systemic Inflammatory Factors with Progression to Advanced Age-related Macular Degeneration.

PURPOSE: Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly. The role of systemic inflammation in AMD remains unclear specifically in patients with intermediate AMD (iAMD). We sought to determine whether systemic inflammation was associated with future iAMD progression. METHODS: Combinations of 27 circulating inflammatory markers including complement factors, cytokines, chemokines, and high-sensitivity C-reactive protein (hsCRP) were evaluated in iAMD patients recruited into a Colorado AMD registry. Systemic inflammatory markers were combined using principal component analysis. Risk factors for AMD progression were evaluated using Cox regression models. RESULTS: This study included 99 subjects with iAMD, 21 of which progressed to advanced AMD. Two principal components (PCs) were identified that contributed to the risk of progression to advanced AMD, after adjusting for age and bilateral reticular pseudodrusen. The strongest associated PC was explained largely by the pro-inflammatory cytokine TNFα and the anti-inflammatory IL1ra antagonist of IL1. The additional PC was largely explained by IL6, IL8, C3 and factor D in the positive direction and CRP, MCP1, factor B and factor I in the negative direction. CONCLUSION: When evaluated through multivariate analyses, combinations of biomarkers distinguished patients who did and did not progress to future advanced AMD. Increased risk could result from different combinations of analyte levels indicating a complex relationship rather than a simple increase in a few markers. This suggests that studying systemic inflammation in iAMD can provide insights into early pathologic events and potentially identify patients at highest risk for the development of severe AMD.

Plasma C-C Chemokine Concentrations in Intermediate Age-Related Macular Degeneration.

Purpose: To determine the relationship between plasma concentrations of the C-C chemokines CCL2, CCL3, CCL4, and CCL5 and intermediate age-related macular degeneration (iAMD) patients compared with control inidividuals to further define the inflammatory pathways associated with age-related macular degeneration. Methods: The concentrations of CCL2, CCL3, CCL4, and CCL5 were measured using multiplex assays in plasma collected from 210 patients with iAMD and 102 control individuals with no macular degeneration as defined by multi-modal imaging. Non-inflammatory data included in the analysis were: age, sex, family history of AMD, history of smoking, body mass index, presence of reticular pseudo-drusen and cardiovascular disease. Median concentrations as well as a cutoff value for each chemokine were compared between the two groups. Results: The median concentrations of CCL2 and CCL4 did not differ between control and iAMD groups, however, CCL2 was elevated in iAMD when a cutoff comparison was used (p < 0.05). Median CCL3 and CCL5 concentrations were significantly decreased in the macular degeneration group compared with controls (p < 0.001) as well as when a cutoff value comparison was used. CCL3 and CCL5 were negatively correlated in cases and positively correlated in controls. Conclusions: Plasma CCL3 and CCL5 concentrations were significantly decreased and CCL2 concentrations were increased in patients with iAMD compared with controls, suggesting a role for C-C chemokines in the systemic inflammatory processes associated with disease development.