Systemic Markers of Inflammation, Endothelial Dysfunction, and Age-Related Maculopathy RONALD KLEIN, MD, MPH, BARBARA E.K. KLEIN, MD, MPH, MICHAEL D. KNUDTSON, MS, TIEN YIN WONG, MD, PHD, ANOOP SHANKAR, MD, MPH, AND MICHAEL Y. TSAI, PHD ● PURPOSE: To examine the association of systemic markers of inflammatory disease and endothelial dysfunc- tion with age-related maculopathy (ARM). ● DESIGN: (1) Nested case-control analysis of prevalent ARM and (2) prospective analyses of incident ARM in a random sample of a population-based cohort. ● METHODS: Standardized protocols for blood collection, measurement of markers, administration of a question- naire, and gradings of stereoscopic color fundus photog- raphy to determine ARM were used. Standard univariate and multivariate analyses were performed. PARTICIPANTS: Included in the nested case-control study were 188 cases with moderate to advanced ARM and 195 controls matched for age, gender, and current smoking status at a baseline examination from 1988 to 1990, and living in Beaver Dam, Wisconsin. Included in the prospective analyses as a random sample of 321 persons were those who participated in a 5-year and/or 10-year follow-up. MAIN OUTCOME MEASURES: Prevalent and incident ARM. ● RESULTS: Serum C-reactive protein, amyloid A, inter- leukin-6, tumor necrosis factor-, intracellular adhesion molecule, E-selectin, folate, and Chlamydia pneumoniae IgG antibody were not associated with either prevalent or incident ARM. ● CONCLUSION: Contrary to other reports, we cannot confirm a strong or consistent relationship of markers of inflammation and endothelial dysfunction with ARM. (Am J Ophthalmol 2005;140:35– 44. © 2005 by Elsevier Inc. All rights reserved.) I NFLAMMATION HAS BEEN POSTULATED TO HAVE A ROLE in the pathogenesis of age-related maculopathy (ARM). 1–5 Hageman and associates 4 have shown that drusen contain protein associated with immune-mediated processes and inflammation. Additionally, chronic inflam- matory cells have been observed on the outer surface of the Bruch membrane in eyes with neovascular macular degen- eration. 3 These cells may cause atherogenesis and micro- vascular injury by direct release of long-acting oxidants, toxic oxygen compounds, and proteolytic enzymes that may also damage the Bruch membrane. 6,7 However, data from epidemiologic studies to date have not shown a consistent relationship between systemic inflammation or presence of inflammatory markers and ARM. 8 –19 Further- more, although a few clinical trials have suggested possible beneficial effects of intravitreal corticosteroids in reducing neovascular ARM progression for as long as 12 months, there have been no demonstrated protective effects of systemic anti-inflammatory drugs on the risk of ARM. 20 –24 Endothelial dysfunction, resulting from inflammation, hypertension, cigarette smoking, and other factors, has been postulated as being involved in the pathogenesis of ARM. 25 However, with the exception of data from a small case-control study that showed an association of one such marker, von Willebrand factor, with ARM, there have been no population-based data examining this relation. 25 The purpose of the present report is to examine whether markers of systemic inflammation and endothelial dysfunc- tion are associated with ARM in two samples of partici- pants in the population-based Beaver Dam Eye Study. METHODS ● STUDY POPULATION: We conducted a nested case- control study and a prospective analysis of a random sample of subjects in the Beaver Dam Eye Study cohort. The population and recruitment methods for the full cohort have been described in previous reports. 26 –34 In brief, at baseline, a private census of the population of Beaver Dam, Wisconsin, was performed from September Accepted for publication Jan 29, 2005. From the Department of Ophthalmology and Visual Sciences, Univer- sity of Wisconsin Medical School Madison, Madison, Wisconsin (R.K., B.E.K.K., M.D.K., A.S.); Department of Ophthalmology, University of Melbourne, East Melbourne, Australia (T.Y.W.); and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota (M.Y.T.). This study was supported by National Institutes of Health Bethesda, Maryland, grant no. EY06594 (R.K. and B.E.K.K.). Inquiries to Ronald Klein, MD, MPH, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 610 North Walnut Street, 460 WARF, Madison, WI 53726; fax: (608) 263-0279; e-mail: kleinr@epi.ophth.wisc.edu © 2005 BY ELSEVIER INC.ALL RIGHTS RESERVED. 0002-9394/05/$30.00 35.e1 doi:10.1016/j.ajo.2005.01.051