High Levels of Plasma C-Reactive Protein and Future Risk of Age-Related Cataract DEBRA A. SCHAUMBERG, OD, MPH, PAUL M. RIDKER, MD, MPH, ROBERT J. GLYNN, PhD, WILLIAM G. CHRISTEN, ScD, M. REZA DANA, MD, MPH, AND CHARLES H. HENNEKENS, MD, DrPH PURPOSE: Chronic intraocular inflammation, with or without systemic inflammation, is associated with increased risk of cataract. Whether systemic inflammation alone is associated with cataract is unknown. This study examined the association between plasma C-reactive protein (CRP), a marker of systemic inflammation, and risk of cataract. METHODS: In the Physicians’ Health Study, we recently analyzed plasma CRP levels in baseline blood specimens from 543 men who later developed cardiovascular disease, and 543 who did not. These data provided a cost-efficient means to explore whether baseline plasma CRP is associated with future risk of age-related cataract. After excluding 252 men with prior diagnosis of cataract or missing data, we followed the remaining 834 men defined by baseline CRP level for 11 years for incident cataract. We used proportional hazards regression models, stratified by cardiovascular disease status. RESULTS: Baseline CRP was significantly higher among men who later developed cataract than levels among those who remained free of cataract, P = 0.02 (median 1.53 versus 1.23 mg/L). In a multivariable model adjusted for cardiovascular disease, randomized aspirin and beta carotene assignments, age, diabetes, cigarette smoking, alcohol consumption, body mass index, exercise, and parental history of myocardial infarction, the levels of CRP remained significantly associated with development of cataract (P = 0.001); but the association was less significant in a model using log CRP levels (P = 0.038). In exploratory analyses of a threshold effect, the excess risk was significant only among men with levels at or above the 97.5th centile (6.17 mg/L); compared to those with lower levels, the relative risk in these men was 3.00 (95% confidence interval, 1.53 to 5.91; P = 0.002). Relative risks associated with CRP levels at or above versus below the 85th, 90th, and 95th percentiles were not significant (relative risks 1.29, 1.50, and 1.77, respectively). CONCLUSIONS: Overall, our results suggest that elevated levels of CRP are associated with future risk of cataract in these apparently healthy men. This early report raises the possibility that systemic inflammation may play a role in the pathogenesis of age-related cataract. Ann Epidemiol 1999;9:166–171.  1999 Elsevier Science Inc. All rights reserved. KEY WORDS: C-Reactive Protein, Physicians’ Health Study, Cataract, Risk-Factor, Epidemiology, Inflammation. have demonstrated age (2), diabetes (3), cigarette smoking INTRODUCTION (4), alcohol consumption (5), and body mass index (BMI) Worldwide, age-related cataract is the leading cause of (6) to be risk factors for cataract. In clinical studies, patients blindness and visual impairment and a major public health with chronic intraocular inflammation, as well as those with burden (1). Biological mechanisms underlying the patho- systemic inflammatory and immune-mediated conditions genesis of cataract remain unclear. Epidemiologic studies such as juvenile rheumatoid arthritis (7), sarcoidosis (8), and atopy (9, 10) have increased risk of cataract formation despite sometimes minimal intraocular inflammation. Whe- ther lower levels of chronic systemic inflammation in other- From the Divisions of Preventive Medicine (D.A.S., P.M.R., R.J.G., W.G.C., C.H.H.), Cardiovascular Disease (P.M.R.), and Ophthalmology wise apparently healthy individuals are associated with age- (M.R.D.), Brigham and Women’s Hospital, the Department of Ambulatory related cataract is not known. Care and Prevention (C.H.H.), Massachusetts Eye and Ear Infirmary and C-reactive protein (CRP) is a major acute phase reactant the Schepens Eye Research Institute (M.R.D.), Harvard Medical School; and the Departments of Epidemiology (D.A.S., C.H.H.), and Biostatistics in humans (11), usually present at very low levels, but rising (R.J.G.), Harvard School of Public Health, Boston, MA. several hundred-fold or more during acute episodes of illness. Address reprint requests to: Debra A. Schaumberg, Division of Preven- Normally, the acute phase response lasts only a few days; tive Medicine, 900 Commonwealth Avenue East, Boston, MA 02215. Received May 19, 1998; revised July 20, 1998; accepted August 6, 1998. however, in cases of chronic or recurring inflammation,  1999 Elsevier Science Inc. All rights reserved. 1047-2797/99/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S1047-2797(98)00049-0