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American Journal of Epidemiology Advance Access originally published online on November 16, 2006
American Journal of Epidemiology 2007 165(4):375-382; doi:10.1093/aje/kwk022
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American Journal of Epidemiology Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.

ORIGINAL CONTRIBUTIONS

Association between Circulating White Blood Cell Count and Long-Term Incidence of Age-related Macular Degeneration

The Blue Mountains Eye Study

Anoop Shankar1, Paul Mitchell2, Elena Rochtchina2, Jennifer Tan2 and Jie Jin Wang2

1 Department of Community, Occupational, and Family Medicine, National University of Singapore, Republic of Singapore
2 Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia

Correspondence to Dr. Anoop Shankar, Department of Community, Occupational, and Family Medicine, National University of Singapore, Republic of Singapore 117597 (e-mail: ashankar{at}nus.edu.sg).

Received for publication March 3, 2006. Accepted for publication July 12, 2006.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Inflammatory processes are implicated in the development and progression of age-related macular degeneration (AMD). However, there are limited data on longitudinal associations between systemic markers of inflammation and AMD. The authors examined the prospective relation between the circulating white blood cell (WBC) count and early and late AMD in a population-based cohort of 3,654 participants, aged 49–97 years, in the Blue Mountains region, Australia. The main outcome of interest was the 10-year incidence of early and late AMD among individuals free from corresponding disease at the baseline (1992–1994). An elevated baseline WBC count was associated with early AMD incidence, independent of smoking and other major confounders. The multivariable relative risk comparing tertile 3 of WBC count (>6.7 x 109 cells/liter) with tertile 1 (≤5.5 x 109 cells/liter) was 1.85 (95% confidence interval: 1.33, 2.58). The association between WBC count and early AMD was present consistently in analyses of different early AMD lesions, including incident pigmentary abnormalities and soft indistinct/reticular drusen. Moreover, this association persisted in subgroup analyses by gender and smoking. An elevated WBC count at baseline was not consistently associated with late AMD incidence. This study provides population-based evidence supporting a longitudinal association between the circulating WBC count, a widely available marker of inflammation, and incidence of early AMD.

aged; Australia; inflammation; leukocyte count; macular degeneration

Abbreviations: AMD, age-related macular degeneration; CI, confidence interval; RR, relative risk; WBC, white blood cell


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Age-related macular degeneration (AMD) is a leading cause of blindness in elderly populations in the Western world (1). As the etiology of age-related maculopathy is largely unknown and treatment options are limited, identifying risk factors and preventive strategies is important to decrease the impact and burden of blindness from this condition.

Inflammation is hypothesized to be one of the pathogenetic mechanisms in several age-related conditions, including atherosclerosis (2), Alzheimer's disease (3), diabetes (4), and also AMD (5–8). However, data from epidemiologic studies on the association between circulating white blood cell (WBC) count and other markers of inflammation and AMD have been inconsistent (9–17). In this context, we examined the association between WBC count and 10-year incidence of AMD in a general population sample of older Australians.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population
The Blue Mountains Eye Study is a population-based cohort study of age-related eye diseases and other health outcomes in an urban Australian population. Study details were described previously (18). After a door-to-door census of residents living in two postcodes in the Blue Mountains region, west of Sydney, Australia, persons born before January 1, 1943 (age range: 49–97 years), were invited to attend a detailed examination at a local hospital. A baseline cohort examination (Blue Mountains Eye Study I) was performed on 3,654 of 4,433 (82.4 percent) eligible persons between 1992 and 1994 (19); 2,335 individuals (75 percent of survivors) were reexamined after 5 years (Blue Mountains Eye Study II: 1997–1999) and 1,952 (76 percent of survivors) after 10 years (Blue Mountains Eye Study III: 2002–2004). The cohort was 98 percent White, reflecting the community studied. This study followed the recommendations of the Declaration of Helsinki and was approved by the Western Sydney Area Human Ethics Committee. Written, informed consent was obtained from all participants.

Of the 3,654 baseline participants, 771 (21.1 percent) had died within 10 years and had no follow-up information available, and 429 (11.7 percent) were either lost to follow-up or had no retinal photographs available at both the 5- and 10-year follow-up time points for this study purpose, leaving 2,454 (67.2 percent) who had been examined at either or both the 5- and 10-year examinations and had retinal photographs available for the assessment of AMD lesions. The mean baseline WBC count was higher among individuals who were excluded from the analysis because of death or loss to follow-up, compared with those who were included (6.8 x 109 cells/liter vs. 6.3 x 109 cells/liter, p < 0.001). Of these 2,454 participants, 770 (31.4 percent) were seen only at the 5-year examinations, 126 (5.1 percent) were seen only at the 10-year examinations, and 1,558 (63.5 percent) were seen at both time points. We further excluded 181 individuals with missing WBC count information and those with a WBC count below 2 x 109 cells/liter or above 12 x 109 cells/liter. For the corresponding incident AMD analysis, we excluded those with prevalent early or late AMD among the remaining 2,273 individuals. The prevalence of any early AMD was 7.2 percent at the baseline, 13.3 percent at the 5-year, and 18.3 percent at the 10-year examinations, respectively. Similarly, the prevalence of any late AMD was 1.9 percent at the baseline, 3.2 percent at the 5-year, and 4.7 percent at the 10-year examinations, respectively.

Definition of "age-related macular degeneration"
Comprehensive eye examinations after pupil dilatation, including 30° stereoscopic retinal photographs of the macula and other retinal fields of both eyes (19) using a Zeiss model FF3 fundus camera (Carl Zeiss, Oberkochen, Germany), were performed on participants at the baseline, 5-year, and 10-year follow-up examinations. Grading for early and late AMD lesions was according to the Wisconsin Age-related Maculopathy Grading System (20) and was followed by a side-by-side grading of baseline and 5-year, as well as baseline and 10-year, photographs, when lesions were identified at either examination. Assessments of both intergrader and intragrader reliability showed good agreement for identifying AMD lesions (19).

Late AMD lesions were defined to include geographic atrophy of 175-µm diameter or more at the macula (regardless of foveal involvement) or neovascular AMD, as described in the International AMD Classification (21). For the analysis on incident neovascular AMD, cases of neovascular AMD at baseline were excluded, but cases with geographic atrophy at baseline were not excluded, as we considered that neovascular AMD could rarely still develop in eyes with geographic atrophy. For the analyses of incident geographic atrophy, we excluded both those with geographic atrophy at baseline and those with neovascular AMD at either the baseline or the follow-up examinations.

Early AMD was defined as absent late-stage AMD lesions and the presence of either 1) large (>125-µm diameter), indistinct soft or reticular drusen or 2) both large, distinct soft drusen and retinal pigmentary abnormalities (hyperpigmentation or hypopigmentation) (21) within the area of the superimposed grading grid (20). Incident early AMD was defined as the appearance at follow-up of either indistinct soft or reticular drusen or the co-presence of distinct soft drusen and retinal pigmentary abnormalities in either eye of persons in whom no late or early AMD was present at baseline and also no late AMD at the follow-up examinations. Definitions of incident AMD lesions closely followed the definitions developed by Klein et al. (20) for the Beaver Dam Eye Study, modified to use fewer categories for drusen size (19).

Exposure measurement
The baseline examination included measuring weight, height, pulse rate, and systolic and diastolic blood pressures by a trained observer and administering a standardized questionnaire that collected information regarding participants' demographic characteristics, cigarette smoking, alcohol intake, physical activity, medical histories, and medications taken, including aspirin. Fasting blood specimens were drawn from 3,222 baseline participants (88 percent) and then delivered by courier within the same day to Westmead Hospital, Sydney, for hematology and clinical biochemistry assessment. The WBC count was determined using Coulter Counter methods (Beckman Coulter, Inc., Fullerton, California). Reliability coefficients, based on blind replicate control data, ranged from 0.96 to 1.00. Hematocrit and fasting plasma glucose were measured by spun microhematocrit and hexokinase methods, respectively.

Age was defined as the age at the baseline examination. Education was categorized into beyond high school, high school, and below high school. Body mass index was calculated (weight (kg)/height (m)2). Diabetes status was categorized by use of American Diabetes Association criteria as follows: diabetes (diagnosis of diabetes by a physician and use of diabetic medications or fasting glucose levels of at least 7.0 mmol/liter (126 mg/dl)); fasting hyperglycemia (fasting glucose levels of 6.1 mmol/liter (110 mg/dl) or above but less than 7.0 mmol/liter (126 mg/dl)); and normoglycemia (fasting glucose levels of below 6.1 mmol/liter (110 mg/dl)). Cigarette smoking was categorized into current (currently a smoker or had given up smoking less than 12 months before the baseline examination), former (positively answered to the question, "Have you ever smoked regularly before?", and had given up smoking for at least 12 months before the study examination), and never smoker. Alcohol intake was categorized into heavy (≥3 drinks/day), moderate (<3 drinks/day), and never drinking. Physical inactivity (yes, no) was categorized as answering negatively to the question, "Have you participated in any recreational exercise/walk in the last 2 weeks?". Weekly aspirin intake was categorized into 3 times/week or more, and less than 3 times/week or none, by combining information on aspirin intake frequency in the questionnaire to get adequate sample size in each category.

Statistical analysis
We examined the association of baseline WBC count with the 10-year incidence of both early and late AMD. We categorized baseline WBC count into tertiles. We also analyzed WBC count as a continuous variable (per standard deviation increase). Cumulative incidence was estimated as (1 – Kaplan-Meier estimate) and expressed as percentage. The multivariable relative risk and 95 percent confidence intervals were calculated from the discrete logistic failure time model (22). Several factors were considered as potential confounders, including age (years), sex (male, female), smoking (current, former, never), education (beyond high school, high school, below high school), body mass index (kg/m2), alcohol consumption (heavy, moderate, never), physical inactivity (yes, no), weekly aspirin use (≥3 times per week, none/<3 times per week), diabetes/fasting hyperglycemia status (present, absent), total cholesterol (mg/dl), high density lipoprotein cholesterol (mg/dl), and triglyceride level (mg/dl). Our final multivariable model included age (years), sex (male, female), smoking (current, former, never), and previously reported to be associated with incident AMD in our cohort (23). Other factors assessed were not associated with AMD in our cohort. We tested the trend in hazard ratios across tertiles by modeling an ordinal variable corresponding to the median value for each WBC count tertile. To examine the consistency of association between WBC count and AMD, we performed stratified analysis by gender and smoking status. All analyses used SAS, version 9.1, software (SAS, Inc., Cary, North Carolina).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Selected baseline characteristics of the cohort by tertiles of WBC count are presented in table 1. The mean age of study participants was 64 years and increased with increasing WBC count tertile. The proportions of males and current smokers also increased with increasing WBC count categories.


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  		TABLE 1. Baseline characteristics in 1992–1994 for the whole cohort and by tertiles of white blood cell count, Blue Mountains Eye Study

 
Overall, there was a clear, positive association between increasing tertiles of WBC count and incident early AMD, as shown in table 2. The 10-year cumulative incidence of early AMD, pigmentary abnormality, and soft indistinct/reticular drusen increased with increasing WBC count tertiles. The multivariable relative risk comparing individuals in the highest tertile (>6.7 x 109 cells/liter) with those in the lowest WBC count tertile (≤5.5 x 109 cells/liter) ranged from 1.4 to 1.9 for early AMD, pigmentary abnormality, and soft indistinct/reticular drusen. Corresponding models for assessing trend across WBC count tertiles were also statistically significant. When the WBC count was analyzed as a continuous variable, the multivariable relative risk of early AMD associated with a 1-standard deviation (1.6 x 109 cells/liter) increase in WBC count was 1.36 (95 percent confidence interval (CI): 1.16, 1.61); results were similar and statistically significant for pigmentary abnormality and soft indistinct/reticular drusen. The multivariable relative risk of early AMD comparing tertile 3 with tertiles 1 and 2 of the WBC count was 1.60 (95 percent CI: 1.22, 2.11).


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  		TABLE 2. Relation between tertiles of white blood cell count and 10-year incident early age-related macular degeneration, Blue Mountains Eye Study, from 1992–1994 to 2002–2004

 
Table 3 presents the association between increasing tertiles of WBC count and incident late AMD. The 10-year cumulative incidence of any late AMD and geographic atrophy increased with increasing WBC count tertiles. The multivariable relative risk comparing individuals in the highest tertile (>6.7 x 109 cells/liter) with those in the lowest WBC count tertile (≤5.5 x 109 cells/liter) suggested a positive association with any late AMD (relative risk (RR) = 1.82, 95 percent CI: 0.96, 3.44) and geographic atrophy (RR = 2.39, 95 percent CI: 0.98, 5.79), but failed to reach statistical significance ({alpha} = 0.05), probably because of small numbers with the outcomes. The ptrend across increasing tertiles of WBC count was 0.06 for any late AMD and 0.04 for geographic atrophy, supporting a borderline dose-response relation. There was no clear association between increasing tertiles of WBC count and incident neovascular AMD.


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  		TABLE 3. Relation between tertiles of white blood cell count and 10-year incident late age-related macular degeneration, Blue Mountains Eye Study, from 1992–1994 to 2002–2004

 
Table 4 presents the association between increasing tertiles of WBC count and early AMD stratified by gender and smoking status. The relative risk of early AMD comparing the highest with the lowest tertile of WBC count was higher among males (RR = 3.0) compared with females (RR = 1.5). Within smoking categories, the relative risk of early AMD comparing the highest with the lowest tertile of WBC count was relatively similar among current (RR = 1.9), former (RR = 2.2), and never (RR = 1.6) smokers. However, the relative risk estimates among current smokers failed to reach conventional levels of statistical significance ({alpha} = 0.05).


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  		TABLE 4. Relation between tertiles of white blood cell count and 10-year incident early age-related macular degeneration, by gender and smoking, Blue Mountains Eye Study, from 1992–1994 to 2002–2004

 
Table 5 presents the association between increasing tertiles of WBC count and any late AMD stratified by gender and smoking status. The relative risk of any late AMD comparing the highest with the lowest tertile of WBC count was higher among males (RR = 5.5) than among females (RR = 1.2). Within smoking categories, the relative risk of any late AMD comparing the highest with the lowest tertile of WBC count was statistically significant among former smokers (RR = 3.3); there was no clear association among current (RR = 0.9) and never (RR = 0.9) smokers.


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  		TABLE 5. Relation between tertiles of white blood cell count and incident any late age-related macular degeneration, by gender and smoking, Blue Mountains Eye Study, from 1992–1994 to 2002–2004

 
In a subsidiary analysis, we additionally adjusted for plasma fibrinogen levels (continuous variable, per g/liter increase) in the multivariable model in tables 2 and 3; the results were essentially similar for both early and late AMD analyses. For example, for incident early AMD, compared with WBC count tertile 1 (referent), the relative risk was 1.32 (95 percent CI: 0.93, 1.87) for tertile 2 and 1.86 (95 percent CI: 1.32, 2.60) for tertile 3.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In the Blue Mountains cohort of older Australians, we found that a higher WBC count was associated with incident early AMD, independent of age, sex, and smoking status. The relative risk of incident early AMD increased in a dose-dependent manner with increasing WBC count tertiles. The association between WBC count and incident early AMD was consistently present in analyses of different early AMD component lesions, including pigmentary abnormality and soft indistinct/reticular drusen. In our study, a WBC count above 6.7 x 109 cells/liter (highest tertile) predicted incident AMD among older Australians. The same level of WBC count has recently been found to be independently predictive of cardiovascular events and all-cause mortality in the large Women's Health Initiative Observational Study (24). The WBC count is a stable, well-standardized, and inexpensive marker that reflects systemic inflammation. Results from our study further extend recent evidence from Seddon et al. (17) linking C-reactive protein, a highly specific marker of inflammation, and AMD to the more widely available measure of WBC count.

Several lines of recent evidence suggest that the association between WBC count and early AMD is plausible, including the role of immune mechanisms in subretinal neovascularization (5, 8), drusen formation (6, 25), supportive animal models (26), the role of inflammatory cells in a number of retinal vasculopathies (27, 28), and the use of antiinflammatory agents to effectively intervene in AMD (29, 30). Chronic inflammatory cells, including macrophage leukocytes, have been observed in excised neovascular membranes from patients with AMD (7). Ultrastructural studies on subretinal neovascularization associated with AMD suggest that activated white blood cells are involved in the promotion of neovascular proliferation and exudation from new vessels (8).

In the current study, the magnitude of association between WBC count and early AMD, the independence of this association from traditional risk factors, including smoking, evidence of dose-response trend, and the consistency within subgroup analysis by early AMD component lesions suggest that these findings are less likely to be due to chance. Confounding by smoking is a concern in the association between WBC count and AMD, as smoking is associated with AMD (23) and elevations in WBC count (31). In our study, WBC count was associated with early AMD even after adjusting for smoking status (table 2), and in subgroup analyses, the association was also present among never smokers (table 4), suggesting that the observed association between WBC count and early AMD is not fully explained by smoking. Results from previous cross-sectional and case-control studies have been largely inconsistent, with some supporting (11, 15, 17) and others not agreeing with (10, 12–14, 16) our results. However, our findings are consistent with results from the only previous longitudinal data, the Beaver Dam Eye Study (9), which used a similar study design and protocols, suggesting comparability to follow-up results from other general population samples.

In the current study, in contrast to the findings for early AMD, there was no consistent association between WBC count and late AMD outcomes. It is possible that activated leukocytes and inflammatory mediators are more important in the early, initiating stages of AMD development than in progression to late AMD. This is analogous to the role of leukocytes and inflammatory processes in atherosclerosis initiation (2). Retinal pigment epithelium uses the same receptor-ligand pairings, including intercellular adhesion molecule 1 and leukocyte function-associated antigen 1, in controlling leukocyte traffic into the retina as the vascular endothelium (5). Increased levels of circulating leukocytes and soluble intercellular adhesion molecule 1 in the serum are, in turn, associated with retinal vasculitis and dysfunction of the blood-retinal barrier, suggesting a role in the development of early AMD (32). As a corollary, one potential explanation for the inconsistent findings in some previous cross-sectional or case-control studies could be the admixture of early and late AMD cases, if they have different associations with inflammation. However, future longitudinal studies with a larger number of late AMD outcomes are required before a lack of association between WBC count and late AMD can be concluded.

The main advantages of our study include its stable general population sample base, longitudinal follow-up for up to 10 years, and the use of standardized protocols for exposure and outcome assessment. Several study limitations also need to be considered while interpreting our findings. We do not have enough late AMD outcomes to confirm or rule out an association with WBC count. C-reactive protein, a more specific marker of inflammation, was not available to make a simultaneous comparison with WBC count. Differential participation rates at the baseline may have biased our results. It is possible that our results are biased by selective survival of the cohort. However, as WBC count has been shown to be related to decreased survival (24, 33), selective survival is likely to underestimate our findings. Selective survival could be an explanation for the lack of observed association between WBC count and late AMD in the current study. Short-term inflammation related to an acute condition at baseline could misclassify the WBC count, causing temporary elevations. Such exposure (WBC count) misclassification is likely to be nondifferential and to underestimate the true association, and it is a potential explanation for the lack of observed association between the WBC count and late AMD in the current study.

Several research groups recently reported that genetic variation in a regulator of the alternative complement pathway (complement factor H gene) accounts for a significant attributable risk of AMD (34–41), perhaps around 50 percent (35, 36, 39). Hageman et al. (34) also expand upon a hypothesis concerning the role in AMD of complement activation by an infectious agent or atypical activator. This is supported by previous studies suggesting that complement activation is involved in the formation of drusen (6, 25). They propose that genetic variation in a regulator of the alternate complement pathway, when combined with a triggering event, such as infection, underlies a major proportion of AMD in the human population (34). Our finding of an association between elevated WBC count and incident AMD supports the hypothesis proposed by Hageman et al. (34), summarized by Bok (42), that AMD, similar to other age-related conditions, such as Alzheimer's disease (3) and atherosclerosis (2), could involve a major inflammatory component.

In conclusion, results from this study appear to support the hypothesis of an association between higher WBC count and incident early AMD. These data provide important new epidemiologic evidence of an essential link between inflammation and AMD development and suggest that local inflammatory processes that have long been known to be associated with drusen development (5, 6, 8, 25) may be reflected in the systemic inflammatory marker of higher WBC count. Our findings support recent data implicating variations in the complement factor H gene in the pathogenesis of AMD (25, 34–42). Results from our study also support the recent use of antiinflammatory agents in the treatment of AMD (29, 30). Finally, recent observational data suggest that patients on long-term antiinflammatory treatment for other diseases appear to have significantly lower lifetime prevalence of AMD (43), suggesting a preventive effect for antiinflammatory treatment. Based on our results, individuals in the highest tertile of WBC count (>6.7 per 109 cells/liter) in the general population may be a good target group for future AMD prevention trials to evaluate antiinflammatory agents.


   ACKNOWLEDGMENTS
 
Supported in part by the Australian National Health and Medical Research Council, Canberra, Australia (project grants 974159 and 211069).

The funding agencies had no role in the research presented in the paper, and the researchers were fully independent in pursuing this research.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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