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Table 1. 
Inflammatory Factors and the Prevalence of Emphysema and Gout by Age at Baseline in the Beaver Dam Eye Study*
Inflammatory Factors and the Prevalence of Emphysema and Gout by Age at Baseline in the Beaver Dam Eye Study*
Table 2. 
The 10-Year Incidence and Progression of Age-Related Maculopathy by Age in the Beaver Dam Eye Study*
The 10-Year Incidence and Progression of Age-Related Maculopathy by Age in the Beaver Dam Eye Study*
Table 3. 
The Relationship of Gout, Emphysema, Serum Albumin Level, and White Blood Cell Count to the 10-Year Incidence of Early Age-Related Maculopathy in the Beaver Dam Eye Study*
The Relationship of Gout, Emphysema, Serum Albumin Level, and White Blood Cell Count to the 10-Year Incidence of Early Age-Related Maculopathy in the Beaver Dam Eye Study*
Table 4. 
The Relationship of Gout, Emphysema, Serum Albumin Level, and White Blood Cell Count to the 10-Year Incidence of Late Age-Related Maculopathy and Progression of Age-Related Maculopathy*
The Relationship of Gout, Emphysema, Serum Albumin Level, and White Blood Cell Count to the 10-Year Incidence of Late Age-Related Maculopathy and Progression of Age-Related Maculopathy*
1.
Ross  R Atherosclerosis. N Engl J Med. 1999;340115- 126Article
2.
Akiyama  HBarger  SBarnum  S  et al.  Inflammation and Alzheimer's disease. Neurobiol Aging. 2000;21383- 421Article
3.
Pickup  JCCrook  MA Is type II diabetes mellitus a disease of the innate immune system? Diabetologia. 1998;411241- 1248Article
4.
Sarks  SHPenfold  PLKillingsworth  MCvan Driel  D Patterns in macular degeneration. In:Ryan  SJDawson  AKLittle  HLeds.Retinal Diseases. New York, NY Grune & Stratton1985;87- 93
5.
Penfold  PLKillingsworth  MCSarks  SH Senile macular degeneration. Invest Ophthalmol Vis Sci. 1986;27364- 371
6.
Penfold  PLMadigan  MCGillies  MCProvis  JM Immunological and aetiological aspects of macular degeneration. Prog Retin Eye Res. 2001;20385- 414Article
7.
Hageman  GSLuthert  PJChong  NHV  et al.  An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res. 2001;20705- 732Article
8.
Ernst  EHammerschmidt  DEBagge  UMatrai  ADormandy  JA Leukocytes and the risk of ischemic diseases. JAMA. 1987;2572318- 2324Article
9.
Kannel  WBAnderson  KWilson  PW White blood cell count and cardiovascular disease: insights from the Framingham Study. JAMA. 1992;2671253- 1256Article
10.
The Eye Disease Case-Control Study Group, Risk factors for neovascularage-related macular degeneration. Arch Ophthalmol. 1992;1101701- 1708Article
11.
Klein  RKlein  BEKFranke  T The relationship of cardiovascular disease and its risk factors to age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1993;100406- 414Article
12.
Smith  WMitchell  PLeeder  SRWang  JJ Plasma fibrinogen, other cardiovascular risk factors, and age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol. 1998;116583- 587Article
13.
Klein  R Epidemiology. In:Berger  JWFine  SLMaguire  MGeds.Age-Related Macular Degeneration. St Louis, Mo Mosby1999;31- 56
14.
Klein  RClegg  LCooper  LS  et al.  Prevalence of age-related maculopathy in the Atherosclerosis Risk in Communities Study. Arch Ophthalmol. 1999;1171203- 1210Article
15.
 Risk factors associated with age-related macular degeneration: a case-control study in the age-related eye disease study: age-related eye disease study report number 3: Age-Related Eye Disease Study Research Group. Ophthalmology. 2000;1072224- 2232Article
16.
Klein  RKlein  BEKJensen  SC  et al.  Age-related maculopathy in a multiracial United States population: the National Health and Nutrition Examination Survey III. Ophthalmology. 1999;1061056- 1065Article
17.
Klein  RKlein  BEMarino  EK  et al.  Early age-related maculopathy in the cardiovascular health study. Ophthalmology. 2003;11025- 33Article
18.
Klein  RKlein  BEKJensen  SC The relation of cardiovascular disease and its risk factors to the 5-year incidence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1997;1041804- 1812Article
19.
Snow  KKSeddon  JM Do age-related macular degeneration and cardiovascular disease share common antecedents? Ophthalmic Epidemiol. 1999;6125- 143Article
20.
Blumenkranz  MSRussell  SRRobey  MGKott-Blumenkranz  RPenneys  N Risk factors in age-related maculopathy complicated by choroidal neovascularization. Ophthalmology. 1986;93552- 558Article
21.
Klein  RKlein  BEKJensen  SC  et al.  Medication use and the 5-year incidence of early age-related maculopathy: the Beaver Dam Eye Study. Arch Ophthalmol. 2001;1191354- 1359Article
22.
Christen  WGGlynn  RJAjani  UA  et al.  Age-related maculopathy in a randomized trial of low-dose aspirin among US physicians. Arch Ophthalmol. 2001;1191143- 1149Article
23.
Gilles  MCLuo  WChua  W  et al.  The efficacy of a single intravitreal injection of triamcinolone for neovascular age-related macular degeneration [abstract]. Invest Ophthalmol Vis Sci. 2001;42S522
24.
Klein  RKlein  BELinton  KLDe Mets  DL The Beaver Dam Eye Study: visual acuity. Ophthalmology. 1991;981310- 1315Article
25.
Klein  RKlein  BEKLee  KE Changes in visual acuity in a population: the Beaver Dam Eye Study. Ophthalmology. 1996;1031169- 1178Article
26.
Klein  RKlein  BELee  KECruickshanks  KJChappell  RJ Changes in visual acuity in a population over a 10-year period: the Beaver Dam Eye Study. Ophthalmology. 2001;1081757- 1766Article
27.
Klein  RKlein  BEK Beaver Dam Eye Study: Manual of Operations.  Springfield, Va US Dept of Commerce1991;NTIS Accession No. PB 91-149823
28.
Klein  RKlein  BEK Beaver Dam Eye Study II: Manual of Operations.  Springfield, Va US Dept of Commerce1995;NTIS Accession No. PB 95-273827
29.
Klein  RDavis  MDMagli  YL  et al.  The Wisconsin Age-Related Maculopathy Grading System. Ophthalmology. 1991;981128- 1134Article
30.
Klein  RDavis  MDMagli  YL  et al.  Wisconsin Age-Related Maculopathy Grading System.  Madison Dept of Ophthalmology, University of Wisconsin School of Medicine1991;NTIS Accession No. PB 91-184267/AS
31.
Klein  RKlein  BEKLinton  KLP Prevalence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1992;99933- 943Article
32.
Klein  RKlein  BEKJensen  SCMeuer  SM The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1997;1047- 21Article
33.
Kaplan  ELMeier  P Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53457- 481Article
34.
Hosmer  DW  JrLemeshow  S Applied Logistic Regression.  New York, NY John Wiley & Sons1989;238- 245
35.
Doweiko  JPNompleggi  DJ The role of albumin in human physiology and pathophysiology. JPEN J Parenter Enteral Nutr. 1991;15476- 483Article
36.
Finkelstein  RFraser  RSGhezzo  HCosio  MG Alveolar inflammation and its relation to emphysema in smokers. Am J Respir Crit Care Med. 1995;1521666- 1672Article
37.
Stanescu  DSanna  AVeriter  C  et al.  Airways obstruction, chronic expectoration, and rapid decline of FEV1 in smokers are associated with increased levels of sputum neutrophils. Thorax. 1996;51267- 271Article
38.
Barnes  PJ Chronic obstructive pulmonary disease. N Engl J Med. 2000;343269- 280Article
39.
Roseff  RWohlgethan  JRSipe  JDCanoso  JJ The acute phase response in gout. J Rheumatol. 1987;14974- 977
40.
Schols  AMCreutzberg  ECBuurman  WACampfield  LASaris  WHWouters  EF Plasma leptin is related to proinflammatory status and dietary intake in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;1601220- 1226Article
41.
Ghezzi  PDinarello  CABianchi  MRosandich  ERepine  JEWhite  CW Hypoxia increases production of interleukin-1 and tumor necrosis factor by human mononuclear cells. Cytokine. 1991;3189- 194Article
42.
Hachicha  MNaccache  PHMcColl  SR Inflammatory microcrystals differentially regulate the secretion of macrophage inflammatory protein 1 and interleukin 8 by human neutrophils: a possible mechanism of neutrophil recruitment to sites of inflammation in synovitis. J Exp Med. 1995;1822019- 2025Article
43.
Klein  RKlein  BEKMoss  SE Age-related eye disease and survival: the Beaver Dam Eye Study. Arch Ophthalmol. 1995;113333- 339Article
Epidemiology
May 2003

Association of Emphysema, Gout, and Inflammatory Markers With Long-term Incidence of Age-Related Maculopathy

Author Affiliations

From the Department of Ophthalmology and Visual Sciences (Drs R. Klein, B. Klein, and Cruickshanks and Ms Tomany) and Department of Population Health Sciences (Dr Cruickshanks), University of Wisconsin Medical School, Madison. The authors have no relevant financial interest in this article.

Arch Ophthalmol. 2003;121(5):674-678. doi:10.1001/archopht.121.5.674
Abstract

Objective  To examine the relationship of 2 diseases associated with systemic inflammatory response, emphysema and gout, and selected markers of systemic inflammation with the 10-year incidence of age-related maculopathy.

Design  Population-based cohort study.

Participants  We included persons aged 43 to 86 years at baseline examination from 1988 to 1990 living in Beaver Dam, Wis, of whom 3684 subjects participated in a 5-year follow-up examination and 2764 participated in a 10-year follow-up.

Methods  Standardized protocols for physical examination, blood collection, administration of a questionnaire, and stereoscopic color fundus photography to determine the presence of age-related maculopathy. Standard univariate and multivariate analyses were performed.

Main Outcome Measures  Incidence and progression of age-related maculopathy.

Results  While controlling for age, sex, and other factors (history of heavy drinking or smoking, systolic blood pressure, and vitamin use), a higher white blood cell count at baseline was associated with the 10-year incidence ofdrusen 125 µm or greater in diameter (risk ratio [RR] per 106/µL= 1.10; 95% confidence interval [CI], 1.03-1.17), retinal pigment epithelial depigmentation (RR = 2.08; 95% CI, 1.01-1.16), and progression of age-related maculopathy (RR = 1.09; 95% CI, 1.03-1.15). A lower serum albumin level was associated with the incidence of exudative macular degeneration (RR per grams per deciliter = 0.31; 95% CI, 0.13-0.76). A history of emphysema at baseline was associated with the incidence of retinal pigment epithelial depigmentation(RR = 2.84; 95% CI, 1.40-5.78), increased retinal pigment (RR = 2.20; 95% CI, 1.11-4.35), and exudative macular degeneration (RR = 5.12; 95% CI, 1.63-16.06); a history of gout was associated with the incidence of pure geographic atrophy(RR = 3.48; 95% CI, 1.27-9.53).

Conclusions  These findings indicate modest relationships between both increased white blood cell count and emphysema and the increased 10-year incidence of lesions defining early and late age-related maculopathy. Further investigation of these relationships in other studies is needed.

INFLAMMATION HAS been hypothesized to be a pathogenetic mechanism in several age-related conditions such as atherosclerosis, 1 Alzheimer disease, 2 and diabetes.3 It has also been hypothesized that inflammation plays a role in the pathogenesis of age-related maculopathy (ARM).47 Hageman et al7 have shown that drusen contain proteins associated with immune-mediated processes and inflammation. In addition, chronic inflammatory cells have been observed on the outer surface of Bruch's membrane in eyes with neovascular macular degeneration.6 The presence of these cells may cause atherogenesis and microvascular injury by direct release of long-acting oxidants, toxic oxygen compounds, and proteolytic enzymes that may also damage Bruch's membrane.8,9

Epidemiological studies to date have not shown a consistent association of systemic inflammatory disease and its markers with ARM.1020 Furthermore, there has been no demonstrated protective effect of anti-inflammatory drugs on the incidence of ARM.2123 We examined whether 2 diseases associated with inflammatory response, emphysema and gout, and markers of systemic inflammation (eg, white blood cell count, platelet count, and serum albumin level) were related to the incidence and progression of ARM in the large population-based Beaver Dam Eye Study.24

METHODS
STUDY POPULATION

Methods used to identify and describe the population have appeared in previous reports.2432 In brief, a private census of the population of Beaver Dam, Wis, was performed from September 15, 1987, to May 4, 1988, to identify all residents in the city or township of Beaver Dam who were aged 43 to 84 years. The tenets of the Declaration of Helsinki were followed, the approval of the institutional review board was granted, and informed consent was obtained from each subject. Of the 5924 eligible individuals, 4926 participated in the baseline examination between March 1, 1988, and September 14, 1990.24 Ninety-nine percent of the population was white. Of those subjects who were still alive at follow-up, 3684 (81.1%) participated in the 5-year follow-up examinations from March 1, 1993, through June 14, 1995. Comparisons between participants and nonparticipants at the time of the baseline and 5-year follow-up examinations have appeared elsewhere.25

Prior to the start of the 10-year follow-up examinations on March 1, 1998, 350 (9.5%) of the participants from the 5-year examination had died. Of the 3334 surviving subjects in the baseline and second examination, 2764(82.9%) participated in the second follow-up examination between March 1, 1998, and June 9, 2000. One participant could not be located, 42 (1.3%) permitted an interview only, 38 (1.1%) had moved out of the area and did not participate, 337 (10.1%) refused to participate, and 152 (4.6%) died prior to being examined. The mean and median times between the baseline and 10-year follow-up examinations were 10.1 years and 10.0 years, respectively, and the SD was 0.4 years.

Comparisons between participants and nonparticipants at the 10-year follow-up have been presented elsewhere.26 Subjects who died before their scheduled examination for the 10-year follow-up (n = 502) were older at baseline than those who participated (69.1 years vs 58.7 years; P<.001). Subjects who were alive but did not participate in the 10-year follow-up (n = 418) were also older at baseline than those who did (61.1 years vs 58.7 years; P<.001). After adjusting for age, those who were alive during the study period and did not participate were more likely to have fewer years of education, a lower income, poorer visual acuity, a history of cardiovascular disease, a history of never drinking alcohol, more pack-years smoked, a higher serum cholesterol level, higher systolic and diastolic blood pressures, and a higher white blood cell count than participants; they were also more likely to be retired at baseline. After adjusting for age and sex, participants with early ARM at baseline were as likely to participate as those without ARM (data not shown). While controlling for age, there were no differences in participation at the follow-up examinations for men and women with a history of emphysema or gout and early ARM compared with those who had a history of these conditions without early ARM (data not shown).

PROCEDURES

Similar procedures were used at both the baseline and follow-up examinations and are described in detail elsewhere.28,29 Informed consent was obtained from each participant. The examinations at baseline and follow-up included measuring weight, height, pulse rate, and blood pressure(using a random-zero sphygmomanometer following the Hypertension Detection and Follow-up Program protocol).27 We administered a standardized questionnaire that included specific questions regarding history of gout, emphysema, cigarette smoking, and vitamin use. Casual blood specimens were obtained. White blood cell and platelet counts were determined using a Coulter counter method. Serum albumin and uric acid levels were determined by Technicon, Inc (RA 1000 Analyzer; Bayer Diagnostics, Tarrytown, NY). We obtained stereoscopic 30° color fundus photographs centered on the optic disc (Diabetic Retinopathy Study [DRS] standard field 1) and macula (DRS standard field 2) and nonstereoscopic color fundus photographs temporal to but including the fovea of each eye.27 For purposes of this article, the 2663 people (3570 at the first 2 examinations) with at least 1 eye free of confounding lesions (eg, retinal detachment or non–age-related chorioretinal scarring) at all 3 examinations (right eye: n = 2592 [3475 at the first 2 examinations]; left eye: n = 2600 [3501 at the first 2 examinations]; both eyes: n = 2529 [3406 at the first 2 examinations]) are included in the analyses.2932

The Wisconsin Age-Related Maculopathy Grading System29,30 was used to assess the presence and severity of lesions associated with ARM. Grading procedures, lesion descriptions, and detailed definitions for the presence and severity of specific lesions as well as the 5-year incidence have appeared elsewhere.2932Incidence implies the appearance of a lesion at follow-up that was absent at baseline and that could be graded at both the baseline and follow-up examinations. Progression implies the presence of a lesion at baseline with a worsening at follow-up.

Incidence was determined for maximum size and type of each specific drusen class, increased retinal pigment, retinal pigment epithelial (RPE) depigmentation, pigmentary abnormalities (defined as RPE depigmentation or increased retinal pigment), signs of exudative macular degeneration, and pure geographic atrophy. For example, if none of the subfields had soft indistinct drusen at baseline and these drusen were present in 1 or more subfields at the 5- or 10-year follow-up examination, the eye would be considered to have"incident" soft indistinct drusen.

Early ARM was defined as the presence of either soft indistinct drusen or any type of drusen associated with RPE depigmentation or increased retinal pigment. Late ARM was defined as either exudative macular degeneration or pure geographic atrophy.

A 6-level severity scale for ARM was defined as follows:

  • Level 10: no drusen of any type, or hard drusen or small soft drusen (<125 µm in diameter) only, regardless of area of involvement, and no pigmentary abnormalities (increased retinal pigment or RPE depigmentation).

  • Level 20: hard drusen or small soft drusen (<125 µm in diameter) regardless of area of involvement, with increased retinal pigment but no RPE depigmentation, or soft drusen (≥125 µm in diameter) with drusen area smaller than 196 350 µm2 (equivalent to a circle with a diameter of 500 µm) and no pigmentary abnormalities.

  • Level 30: soft drusen (≥125 µm in diameter) with drusen area smaller than 196 350 µm2 and RPE depigmentation, or soft drusen (≥125 µm in diameter) with drusen area of 196 350µm2 or greater and with or without increased retinal pigment but no RPE depigmentation.

  • Level 40: soft drusen (≥125 µm in diameter) with drusen area of 196 350 µm2 or greater and RPE depigmentation with or without increased retinal pigment.

  • Level 50: pure geographic atrophy without exudative macular degeneration.

  • Level 60: exudative macular degeneration with or without geographic atrophy.

For participants, progression was defined as an increase in maculopathy severity in either eye by 2 or more steps from levels 10 through 30 and 1 or more steps from level 40 or 50 from baseline to either the 5-year or 10-year follow-up examination.

Age was defined as the age at the time of baseline examination. People were defined as having a history of emphysema or gout if at baseline they responded affirmatively to questions regarding the presence of these conditions. Subjects were classified as nonsmokers if they had smoked fewer than 100 cigarettes in their lifetime, as ex-smokers if they had smoked more than this number of cigarettes in their lifetime but had stopped smoking before the baseline examination, and as current smokers if they had not stopped smoking. A current heavy drinker was defined as a person consuming 4 or more servings of alcoholic beverages daily; a former heavy drinker, as someone who had consumed 4 or more servings daily in the past but not the previous year; and a nonheavy drinker, as a person who had never consumed 4 or more servings daily on a regular basis. Participants were classified as current vitamin users if they took at least 1 vitamin per week within a month prior to the baseline examination, past vitamin users if they had ever regularly taken vitamins at least once per week but not within the last month, and as never using vitamins if they had never regularly taken vitamins at least once a week.

STATISTICAL METHODS

For these analyses, we examined the associations of white blood cell count, serum albumin level, serum uric acid level, platelet count, and history of emphysema and gout at baseline with the incidence of each of the specific maculopathy lesions, incidence of 2 end points of disease severity (early and late ARM), and progression of ARM. White blood cell count, serum albumin level, serum uric acid level, and platelet count were treated as continuous variables. To analyze the data, we used SAS statistical software (SAS Institute Inc, Cary, NC). The analytical approaches used allowed subjects who were right-censored(not seen after the 5-year examination because of death or nonparticipation) to contribute information to the estimates. Cumulative events were estimated using the Kaplan-Meier (product limit) survival approach.33 Multivariate risk ratios and 95% confidence intervals were calculated from the discrete linear logistic model.34 All risk factors of interest that were continuous were treated as such in the analyses. Age- and sex-adjusted models were constructed by outcome for each of the potential risk factors. Final models were then built according to outcome for each risk factor by adding vitamin use, systolic blood pressure, and history of smoking or heavy drinking into the model. Tests of trend were done treating categorical risk factors as continuous variables in the discrete linear logistic model and computing the χ2 statistic for the parameter estimate. In these models, smoking status, heavy drinking status, and vitamin use were each assessed using 2 indicator variables.

RESULTS

The mean serum uric acid level increased with age, whereas the serum albumin level and platelet count decreased with age (Table 1). There was no relationship between white blood cell count and age, but the prevalence of emphysema and gout increased with age (Table 1). The 10-year incidence and progression of ARM, soft indistinct drusen, drusen size 125 µm or greater in diameter, RPE depigmentation, increased retinal pigment, exudative macular degeneration, and geographic atrophy increased with age (Table 2).

While controlling first for age and sex (data not shown) and then for age, sex, a history of heavy drinking, smoking status, systolic blood pressure, and vitamin use at baseline, we found that a higher white blood cell count at baseline was associated with an increased 10-year incidence of large retinal drusen, RPE depigmentation, and progression of ARM; that a lower serum albumin level was associated with an increased incidence of exudative macular degeneration; that a history of emphysema at baseline was associated with a higher incidence of RPE depigmentation, increased retinal pigment, and exudative macular degeneration; and that a history of gout was associated with a higher incidence of pure geographic atrophy (Table 3 and Table 4). The fully adjusted models were similar to those adjusted only for age and sex. Higher platelet count and higher serum uric acid level were not statistically significantly associated with ARM (data not shown).

COMMENT

In Beaver Dam, while controlling for age, cigarette smoking, and other risk factors, a higher white blood cell count was related to an increased 10-year risk of developing large drusen, pigmentary abnormalities, and progression of ARM. In addition, another sign associated with systemic inflammation, lower serum albumin level, was related to the 10-year incidence of exudative macular degeneration.35 Furthermore, in Beaver Dam a history of emphysema, independent of smoking and age, was associated with the incidence of pigmentary abnormalities and exudative macular degeneration, and gout was associated with the incidence of geographic atrophy. The local destructive pathologic process in gout and emphysema is thought to be inflammation.3640 These conditions may be associated with systemic inflammation caused by the release of cytokines, such as interleukin 1 and interleukin 8, and by increased circulating levels of tumor necrosis factor α and the increased release of this hormone from circulating cells.38,41,42 These factors have been hypothesized to play a role in the pathogenesis of exudative macular degeneration.7 However, it is possible that the associations reported in this article may be due in part to noninflammatory processes, such as low oxygen tension in persons with emphysema, rather than inflammatory disease.

Epidemiological data, most of which are cross-sectional, have not been consistent regarding the association of white blood cell count and other inflammatory factors with ARM.1020 In a small case-control study, 21 an association was found between higher white blood cell count and exudative macular degeneration, but no association was found in the Cardiovascular Health Study17 (CHS), National Health and Nutrition Examination Survey III16 (NHANES III), or Atherosclerosis Risk in Communities Study.14 Another marker of systemic inflammation, high plasma fibrinogen level, was found to be associated with prevalent late but not early ARM in the Blue Mountains Eye Study12 and with exudative macular degeneration in the NHANES III. However, the plasma fibrinogen level was not associated with ARM in the Rotterdam Study, 13 CHS, or Eye Disease Case-Control Study.10 Furthermore, the CHS showed no association of C-reactive protein, another marker of systemic inflammation, with ARM.

There are several strengths to this study including its high participation rate, length of follow-up, and use of standardized protocols to measure ARM end points. However, any conclusions or explanations in this article regarding associations or lack of them must be made with caution for several reasons. First, the concomitant low frequency of certain risk factors (eg, emphysema) and of the incidence of some lesions (eg, pure geographic atrophy), evident in the large 95% confidence intervals around the estimated risk ratios, limits our ability to detect (or reject) meaningful relationships. For example, in Beaver Dam, with 3470 participants, 71 of whom had a history of emphysema at baseline and 23 of whom had an incidence of pure geographic atrophy by the 10-year examination, we would be able to detect an odds ratio of about 8.2 with a power of 0.80 (α = .05) for this association. Second, some findings (eg, gout and the incidence of geographic atrophy) of potential biological significance may be entirely due to chance given the large number of associations examined. Third, it is possible that no relationship was found between some risk factors and ARM because subjects with these factors who developed this disease did not live to participate in the follow-up examination. However, nonparticipation as a result of death is unlikely to bias our findings because ARM was not shown to be associated with mortality.43

In summary, the 10-year incidence data from Beaver Dam show a modest association of 2 diseases, gout and pulmonary emphysema, and 2 signs of inflammation, higher white blood cell count and lower serum albumin level, with the 10-year incidence of ARM independent of smoking and other risk factors. Further prospective study is needed that will examine the associations of inflammatory disease and markers of acute and chronic inflammation, such as interleukins and C-reactive protein, with ARM.

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Article Information

Submitted for publication June 21, 2002; final revision received September 18, 2002; accepted January 22, 2003.

This study was supported by grant EY06594 (Drs R. Klein and B. Klein) from the National Institutes of Health, Bethesda, Md, and in part by Research to Prevent Blindness (Dr R. Klein, Senior Scientific Investigator Award), New York, NY.

We thank the Beaver Dam Scientific Advisory Board (Mae Gordon, PhD, Lee Jampol, MD, Mary Frances Cotch, PhD, Natalie Kurinij, PhD, Daniel Seigel, PhD, and Robert Wallace, MD) and George Davis, MD, Alan Ehrhardt, MD, and Thomas Castillo, MD, for their contributions.

Corresponding author: Ronald Klein, MD, MPH, Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison, 610 N Walnut St, 450 WARF, Madison, WI 53726-2397 (e-mail: kleinr@epi.ophth.wisc.edu).

References
1.
Ross  R Atherosclerosis. N Engl J Med. 1999;340115- 126Article
2.
Akiyama  HBarger  SBarnum  S  et al.  Inflammation and Alzheimer's disease. Neurobiol Aging. 2000;21383- 421Article
3.
Pickup  JCCrook  MA Is type II diabetes mellitus a disease of the innate immune system? Diabetologia. 1998;411241- 1248Article
4.
Sarks  SHPenfold  PLKillingsworth  MCvan Driel  D Patterns in macular degeneration. In:Ryan  SJDawson  AKLittle  HLeds.Retinal Diseases. New York, NY Grune & Stratton1985;87- 93
5.
Penfold  PLKillingsworth  MCSarks  SH Senile macular degeneration. Invest Ophthalmol Vis Sci. 1986;27364- 371
6.
Penfold  PLMadigan  MCGillies  MCProvis  JM Immunological and aetiological aspects of macular degeneration. Prog Retin Eye Res. 2001;20385- 414Article
7.
Hageman  GSLuthert  PJChong  NHV  et al.  An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res. 2001;20705- 732Article
8.
Ernst  EHammerschmidt  DEBagge  UMatrai  ADormandy  JA Leukocytes and the risk of ischemic diseases. JAMA. 1987;2572318- 2324Article
9.
Kannel  WBAnderson  KWilson  PW White blood cell count and cardiovascular disease: insights from the Framingham Study. JAMA. 1992;2671253- 1256Article
10.
The Eye Disease Case-Control Study Group, Risk factors for neovascularage-related macular degeneration. Arch Ophthalmol. 1992;1101701- 1708Article
11.
Klein  RKlein  BEKFranke  T The relationship of cardiovascular disease and its risk factors to age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1993;100406- 414Article
12.
Smith  WMitchell  PLeeder  SRWang  JJ Plasma fibrinogen, other cardiovascular risk factors, and age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol. 1998;116583- 587Article
13.
Klein  R Epidemiology. In:Berger  JWFine  SLMaguire  MGeds.Age-Related Macular Degeneration. St Louis, Mo Mosby1999;31- 56
14.
Klein  RClegg  LCooper  LS  et al.  Prevalence of age-related maculopathy in the Atherosclerosis Risk in Communities Study. Arch Ophthalmol. 1999;1171203- 1210Article
15.
 Risk factors associated with age-related macular degeneration: a case-control study in the age-related eye disease study: age-related eye disease study report number 3: Age-Related Eye Disease Study Research Group. Ophthalmology. 2000;1072224- 2232Article
16.
Klein  RKlein  BEKJensen  SC  et al.  Age-related maculopathy in a multiracial United States population: the National Health and Nutrition Examination Survey III. Ophthalmology. 1999;1061056- 1065Article
17.
Klein  RKlein  BEMarino  EK  et al.  Early age-related maculopathy in the cardiovascular health study. Ophthalmology. 2003;11025- 33Article
18.
Klein  RKlein  BEKJensen  SC The relation of cardiovascular disease and its risk factors to the 5-year incidence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1997;1041804- 1812Article
19.
Snow  KKSeddon  JM Do age-related macular degeneration and cardiovascular disease share common antecedents? Ophthalmic Epidemiol. 1999;6125- 143Article
20.
Blumenkranz  MSRussell  SRRobey  MGKott-Blumenkranz  RPenneys  N Risk factors in age-related maculopathy complicated by choroidal neovascularization. Ophthalmology. 1986;93552- 558Article
21.
Klein  RKlein  BEKJensen  SC  et al.  Medication use and the 5-year incidence of early age-related maculopathy: the Beaver Dam Eye Study. Arch Ophthalmol. 2001;1191354- 1359Article
22.
Christen  WGGlynn  RJAjani  UA  et al.  Age-related maculopathy in a randomized trial of low-dose aspirin among US physicians. Arch Ophthalmol. 2001;1191143- 1149Article
23.
Gilles  MCLuo  WChua  W  et al.  The efficacy of a single intravitreal injection of triamcinolone for neovascular age-related macular degeneration [abstract]. Invest Ophthalmol Vis Sci. 2001;42S522
24.
Klein  RKlein  BELinton  KLDe Mets  DL The Beaver Dam Eye Study: visual acuity. Ophthalmology. 1991;981310- 1315Article
25.
Klein  RKlein  BEKLee  KE Changes in visual acuity in a population: the Beaver Dam Eye Study. Ophthalmology. 1996;1031169- 1178Article
26.
Klein  RKlein  BELee  KECruickshanks  KJChappell  RJ Changes in visual acuity in a population over a 10-year period: the Beaver Dam Eye Study. Ophthalmology. 2001;1081757- 1766Article
27.
Klein  RKlein  BEK Beaver Dam Eye Study: Manual of Operations.  Springfield, Va US Dept of Commerce1991;NTIS Accession No. PB 91-149823
28.
Klein  RKlein  BEK Beaver Dam Eye Study II: Manual of Operations.  Springfield, Va US Dept of Commerce1995;NTIS Accession No. PB 95-273827
29.
Klein  RDavis  MDMagli  YL  et al.  The Wisconsin Age-Related Maculopathy Grading System. Ophthalmology. 1991;981128- 1134Article
30.
Klein  RDavis  MDMagli  YL  et al.  Wisconsin Age-Related Maculopathy Grading System.  Madison Dept of Ophthalmology, University of Wisconsin School of Medicine1991;NTIS Accession No. PB 91-184267/AS
31.
Klein  RKlein  BEKLinton  KLP Prevalence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1992;99933- 943Article
32.
Klein  RKlein  BEKJensen  SCMeuer  SM The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1997;1047- 21Article
33.
Kaplan  ELMeier  P Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53457- 481Article
34.
Hosmer  DW  JrLemeshow  S Applied Logistic Regression.  New York, NY John Wiley & Sons1989;238- 245
35.
Doweiko  JPNompleggi  DJ The role of albumin in human physiology and pathophysiology. JPEN J Parenter Enteral Nutr. 1991;15476- 483Article
36.
Finkelstein  RFraser  RSGhezzo  HCosio  MG Alveolar inflammation and its relation to emphysema in smokers. Am J Respir Crit Care Med. 1995;1521666- 1672Article
37.
Stanescu  DSanna  AVeriter  C  et al.  Airways obstruction, chronic expectoration, and rapid decline of FEV1 in smokers are associated with increased levels of sputum neutrophils. Thorax. 1996;51267- 271Article
38.
Barnes  PJ Chronic obstructive pulmonary disease. N Engl J Med. 2000;343269- 280Article
39.
Roseff  RWohlgethan  JRSipe  JDCanoso  JJ The acute phase response in gout. J Rheumatol. 1987;14974- 977
40.
Schols  AMCreutzberg  ECBuurman  WACampfield  LASaris  WHWouters  EF Plasma leptin is related to proinflammatory status and dietary intake in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;1601220- 1226Article
41.
Ghezzi  PDinarello  CABianchi  MRosandich  ERepine  JEWhite  CW Hypoxia increases production of interleukin-1 and tumor necrosis factor by human mononuclear cells. Cytokine. 1991;3189- 194Article
42.
Hachicha  MNaccache  PHMcColl  SR Inflammatory microcrystals differentially regulate the secretion of macrophage inflammatory protein 1 and interleukin 8 by human neutrophils: a possible mechanism of neutrophil recruitment to sites of inflammation in synovitis. J Exp Med. 1995;1822019- 2025Article
43.
Klein  RKlein  BEKMoss  SE Age-related eye disease and survival: the Beaver Dam Eye Study. Arch Ophthalmol. 1995;113333- 339Article
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