Abstract
Background/aims
There is evidence that smoking is a risk factor for age related macular degeneration (AMD). However, not all studies have demonstrated this association and several key questions about the role of smoking in AMD have still to be determined. The aim of this study was to further investigate this relation for both choroidal neovascularisation (CNV) and geographic atrophy (GA).
Methods
To investigate the relation between smoking and the risk of developing age related macular degeneration (AMD) in white people, 435 cases with end stage AMD were compared with 280 controls. All subjects had graded stereoscopic colour fundus photography and AMD was defined as the presence of GA or CNV. Smoking history was assessed using multiple parameters in a detailed questionnaire.
Results
Comparison of current and former smokers with non‐smokers was consistent with smoking being a risk factor for AMD but did not reach statistical significance. There was a strong association between AMD and pack years of cigarette smoking (p = 0.002), the odds ratio increasing with the amount smoked; for subjects with more than 40 pack years of smoking the odds ratio was 2.75 (95% CI 1.22 to 6.20) compared with non‐smokers. Both types of AMD showed a similar relation; smoking more than 40 pack years of cigarettes was associated with an odds ratio of 3.43 (95% CI 1.28 to 9.20) for GA and 2.49 (95% CI 1.06 to 5.82) for CNV. Stopping smoking was associated with reduced odds of AMD and the risk in those who had not smoked for over 20 years was comparable to non‐smokers. The risk profile was similar for males and females. Passive smoking exposure was associated with an increased risk of AMD (OR 1.87; 95% CI 1.03 to 3.40) in non‐smokers.
Conclusions
The authors have demonstrated a strong association between the risk of both GA and CNV and pack years of cigarette smoking. This provides support for a causal relation between smoking and AMD. They also show an increased risk for AMD in non‐smokers exposed to passive smoking. Stopping smoking appears to reduce the risk of developing AMD.
Keywords: age related macular degeneration, smoking, case control
Age related macular degeneration (AMD) is the commonest cause of severe visual impairment in the Western world and is a significant public health problem.1,2,3,4,5,6 Studies have attempted to define avoidable risk factors in a bid to reduce the incidence of this devastating condition and smoking has been found to be a risk factor in a number of studies.7,8,9,10,11,12,13,14,15 However, this has not been a consistent finding, with other studies showing no association.16,17,18,19,20,21,22 Although this is partly the result of differing definitions of AMD, several key questions about the role of smoking in AMD have still to be determined and, in particular, whether the association holds for both forms of end stage disease—namely, geographic atrophy (GA) and choroidal neovascularisation (CNV). We designed a case‐control study to assess the relation between a variety of smoking behaviours and end stage AMD.
Methods
We conducted a case‐control study in the UK counties of Norfolk, Suffolk, Cambridgeshire, and Buckinghamshire from 2001 to 2003, and compared cases of choroidal neovascular membrane or geographic atrophy with spouse controls. Multicentre research ethics committee and local research ethics committee approvals were obtained for the study.
Case‐control selection
Patients with AMD were ascertained from hospital ophthalmic clinics, general practices, optometrists and charitable societies for people with visual impairment. Patients with a spouse willing to act as a control were prioritised for recruitment, but cases without a spouse were also accepted. It was not the aim to match cases to their own spouse. All study subjects were examined by an ophthalmologist (JCK) and completed a detailed questionnaire on smoking history. All subjects had colour, stereoscopic fundus photography of the macular region (field 2 of the modified Airlie House classification23) and photographs were graded according to the International Classification of Age‐related Maculopathy and Macular Degeneration.24 In this classification the term AMD is reserved for the late stages of the disease, CNV (which also includes pigment epithelial detachment, PED) and GA. Patients were accepted as cases if they were confirmed to have AMD in one or both eyes. Spouses with early changes of age related maculopathy were accepted as controls. Spouses found to have AMD were reclassified as cases. All subjects were selected to be white, over 50 years old, and were excluded if they had more than 6 dioptres of myopic refractive error. If pseudophakic or aphakic they were only included if a preoperative refraction was available. Cases and controls were also excluded if they had evidence of other inflammatory or retinovascular disease such as retinal vessel occlusion, diabetic retinopathy, or chorioretinitis that could contribute to the development or confound the diagnosis of maculopathy. Fundus photographs were graded at the reading centre, Moorfields Eye Hospital, London, UK, and underwent both a preliminary and final grading process blinded to their provisional status as cases or controls. Discrepancies between preliminary and final grading were adjudicated by a senior ophthalmologist (ACB). Discrepancies between photographic grading and clinical examination were decided by reference to the medical case records and any previous colour photographs or fluorescein angiography.
Smoking history
Smoking data were collected and status was assessed in the same manner for both cases and controls using a questionnaire modified from that used for the European Prospective Investigation of Cancer (EPIC) study.25 Smoking status was assessed as non‐smoker, former, or current smoker, with smokers defined as subjects smoking at least one cigarette per day for a year. The questionnaire included an assessment of the number of cigarettes smoked per day in each decade of life, use of other tobacco products, extent to which subjects inhaled, and exposure to passive smoking (only assessed in non‐smokers and defined as having lived in the same house as a smoker for at least 5 years). To calculate pack years of smoking, the average of number of cigarettes smoked per day was divided by 20 to give packs per day and multiplied by the total number of years of smoking.26 Smoking of other tobacco products was also assessed and converted into pack years by equating 1 g of loose tobacco to one cigarette; cigars were taken as equivalent to 5 g of tobacco and cigarillos/small cigars as 2 g.
Data analysis
Data were analysed using logistic regression models and odds ratios for categorical variables are presented in relation to a reference category. Age was fitted as a continuous variable. Comparisons with controls were made for all cases of AMD, all cases with CNV (including cases also having GA), and all cases with GA (including cases also having CNV). Data were analysed using SPSS version 11.0 software (SPSS Inc, Chicago, IL, USA).
Results
The study comprised 435 cases with end stage AMD and 280 spouse controls. Summary data are presented in table 1. Two hundred and sixty one cases had CNV as the only manifestation of AMD, 106 cases had GA only, and 68 had a mixed phenotype with both CNV and GA present in the same subject, either in different eyes or in the same eye. The number of females in the case and control groups was 235 (54.0%) and 164 (58.6%), respectively. The mean age of cases was 80.2 (SD 7.0) years and of controls was 75.6 (SD 7.6) years. Increasing age was associated with increasing odds of AMD, OR 1.09 for each additional year (95% CI 1.07 to 1.12, p<0.0001) so all analyses were adjusted for age. Sex was included as a parameter in all analyses and was not found to be a risk factor for AMD.
Table 1 Age, sex, disease status, and smoking data for cases and controls.
| Cases (n = 435): GA only (n = 106), CNV only (n = 261), mixed GA/CNV (n = 68) | Controls (n = 280) | |
|---|---|---|
| Mean age, years (SD) | ||
| All subjects | 80.2 (7.0) | 75.6 (7.6) |
| GA only | 81.2 (6.9) | |
| CNV only | 79.8 (7.1) | |
| Sex | ||
| Male | 200 (46.0%) | 116 (41.4%) |
| Female | 235 (54.0%) | 164 (58.6%) |
| Smoking status | ||
| Non‐smoker | 159 (36.6%) | 111 (39.6%) |
| Former | 243 (55.9%) | 152 (54.3%) |
| Current | 33 (7.6%) | 17 (6.1%) |
| Mean length of time of smoking (years) (SD) | ||
| Former | 32.5 (16.1) | 26.9 (14.4) |
| Current | 57.9 (9.8) | 54.8 (10.3) |
| Mean pack years of cigarette smoking (SD) | ||
| Former | 23.0 (18.2) | 16.0 (12.8) |
| Current | 37.3 (14.6) | 36.4 (16.7) |
| Categorical pack years of cigarette smoking | ||
| 0 | 159 (36.6%) | 111 (39.6%) |
| 0.1–20 | 123 (28.3%) | 106 (37.9%) |
| 20.1–40 | 100 (23.0%) | 49 (17.5%) |
| >40 | 53 (12.2%) | 14 (5.0%) |
| Categorical pack years of smoking other tobacco products | ||
| 0 | 324 (74.7%) | 220 (78.9%) |
| 0.1–20 | 99 (22.8%) | 51 (18.3%) |
| 20.1–40 | 8 (1.8%) | 4 (1.4%) |
| >40 | 3 (0.7%) (1 missing data) | 4 (1.4%) (1 missing data) |
| Inhaled (former and current smokers) | ||
| Not at all | 60 (21.8%) | 37 (21.9%) |
| A little | 134 (48.7%) | 87 (51.5%) |
| Deeply | 81 (29.5%) (1 missing data) | 45 (26.6%) |
| Years since quitting smoking | ||
| None (current smoker) | 33 (7.6%) | 17 (6.1%) |
| Less than 20 years | 72 (16.6%) | 36 (12.9%) |
| 20 years or more | 171 (39.3%) | 116 (41.4%) |
| Non‐smoker | 159 (36.6%) | 111 (39.6%) |
| Passive smoking exposure (non‐smokers) | ||
| No | 44 (27.8%) | 38 (34.5%) |
| Yes | 114 (72.2%) (1 missing data) | 72 (65.5%) (1 missing data) |
Comparison of current and former smokers with non‐smokers was consistent with smoking being a risk factor for AMD (table 2). For current smokers the data suggested an approximate doubling of risk for both CNV and GA. However, these analyses were not statistically significant.
Table 2 Comparison of cases with controls for smoking status*.
| Smoking status | Odds ratios (95% confidence interval) | ||
|---|---|---|---|
| All cases (n = 435) v controls (n = 280) | All cases with CNV (n = 329) v controls (n = 280) | All cases with GA (n = 174) v controls (n = 280) | |
| Non‐smoker† | 1.00 | 1.00 | 1.00 |
| Former smoker | 1.12 (0.79 to 1.60) | 1.04 (0.72 to 1.52) | 1.12 (0.71 to 1.77) |
| Current smoker | 1.89 (0.96 to 3.70) | 1.97 (0.98 to 3.98) | 2.15 (0.93 to 4.98) |
| p Value (two tailed) | 0.18 | 0.15 | 0.20 |
*The logistic regression model described included age, sex, smoking status.
†Denotes reference category.
In the logistic regression model in table 3, there was a strong association between pack years of cigarette smoking and the risk of AMD, GA, and CNV and the odds ratios increased with the amount smoked. For subjects who had smoked more than 40 pack years the odds ratio for AMD was 2.75 (95% CI 1.22 to 6.20, p = 0.01), for CNV 2.49 (95% CI 1.06 to 5.82, p = 0.04), and for GA 3.43 (95% CI 1.28 to 9.20, p = 0.01) compared to non‐smokers. There was no significant association between pack years of smoking other tobacco products and risk of AMD. Whether subjects inhaled did not affect the risk of AMD. An alternative model including duration of smoking instead of pack years was investigated but did not fit the data so well.
Table 3 Comparison of cases with controls by other smoking variables*.
| Odds ratios (95% confidence interval) | |||
|---|---|---|---|
| All cases (n = 431) v controls (n = 279) | All cases with CNV (n = 326) v controls (n = 279) | All cases with GA (n = 172) v controls (n = 279) | |
| Pack years of cigarette smoking | |||
| 0† | 1.00 | 1.00 | 1.00 |
| 0.1–20 | 0.84 (0.50 to 1.42) | 0.81 (0.47 to 1.40) | 0.79 (0.41 to 1.54) |
| 20.1–40 | 1.62 (0.86 to 3.05) | 1.51 (0.77 to 2.93) | 1.65 (0.74 to 3.67) |
| >40 | 2.75 (1.22 to 6.20) | 2.49 (1.06 to 5.82) | 3.43 (1.28 to 9.20) |
| p Value (two tailed) for pack years | 0.002 | 0.007 | 0.003 |
| Pack years of smoking other tobacco products | |||
| 0† | 1.00 | 1.00 | 1.00 |
| 0.1–20 | 1.34 (0.83 to 2.16) | (0.83 to 2.28) | 1.15 (0.62 to 2.10) |
| 20.1–40 | 0.82 (0.22 to 3.00) | 1.05 (0.28 to 3.96) | 1.21 (0.27 to 5.36) |
| >40 | 0.28 (0.06 to 1.37) | 0.13 (0.01 to 1.26) | 0.67 (0.14 to 3.35) |
| p Value (two tailed) for pack years of other tobacco smoked | 0.21 | 0.18 | 0.91 |
| Inhaled | |||
| Not at all† | 1.00 | 1.00 | 1.00 |
| A little | 1.01 (0.59 to 1.71) | 0.96 (0.55 to 1.70) | 1.09 (0.55 to 2.13) |
| Deeply | 1.00 (0.55 to 1.82) | 1.05 (0.56 to 1.98) | 0.86 (0.39 to 1.88) |
| p Value (two tailed) for inhaled | 1.00 | 0.95 | 0.76 |
*The logistic regression model included age, sex, pack years of cigarette smoking, pack years of smoking other tobacco products, and inhalation status.
†Denotes reference category.
For non‐smokers, passive smoking exposure was found to increase risk for AMD, with odds ratio of 1.87 (95% CI 1.03 to 3.40), p = 0.04 (table 4). The odds were similar for CNV and GA subgroups but did not reach statistical significance.
Table 4 Comparison of non‐smoking cases with non‐smoking controls for passive smoking*.
| Passive smoking exposure | Odds ratios (95% confidence interval) | ||
|---|---|---|---|
| All non‐smoking cases (n = 158) v non‐smoking controls (n = 110) | Cases with CNV (n = 124) v controls (n = 110) | Cases with GA (n = 61) v controls (n = 110) | |
| No† | 1.00 | 1.00 | 1.00 |
| Yes | 1.87 (1.03 to 3.40) | 1.81 (0.97 to 3.39) | 1.50 (0.69 to 3.27) |
| p Value (two tailed) | 0.04 | 0.06 | 0.30 |
*The logistic regression model included age and sex.
†Denotes reference category.
Stopping smoking was associated with reduced odds of both GA and CNV (table 5). In comparison to non‐smokers, the odds ratios for AMD, GA, and CNV were all highest in current smokers, somewhat lower in subjects who stopped smoking less than 20 years ago, and lower again in subjects who stopped smoking more than 20 years ago in whom the risk was not significantly different from non‐smokers.
Table 5 Comparison of cases with controls by years since quitting smoking*.
| Years since quitting smoking | Odds ratios (95% confidence interval) for AMD | |||
|---|---|---|---|---|
| All cases (n = 435) v controls (n = 280) | All cases with CNV (n = 329) v controls (n = 280) | All cases with GA (n = 174) v controls (n = 280) | ||
| Non‐smoker† | 1.00 | 1.00 | 1.00 | |
| More than 20 years | 0.91 (0.62 to 1.34) | 0.85 (0.57 to 1.28) | 0.92 (0.56 to 1.50) | |
| Less than 20 years | 1.74 (1.05 to 2.99) | 1.70 (1.00 to 2.89) | 1.83 (0.97 to 3.47) | |
| 0 years (current smoker) | 2.13 (1.08 to 4.22) | 2.00 (0.99 to 4.05) | 2.14 (0.92 to 4.97) | |
| p Value (two tailed) for years since quitting smoking | 0.01 | 0.02 | 0.05 | |
*The logistic regression model included age and sex.
†Denotes reference category.
Discussion
Of the many environmental factors investigated in relation to AMD, smoking is the one most consistently found to be associated with increased risk.9,10,27 Several case‐control and population based studies have reported odds ratios typically in the range 2–5. Other studies have failed to find any association and the parameter used to assess smoking exposure may be an important contributing factor. In common with our own findings, some studies have been unable to demonstrate a clear association between AMD and whether or not subjects have ever smoked.11,13,17,21 This emphasises the importance of looking at a variety of smoking parameters. McCarty et al11 argued that total length of time of smoking was the most significant factor for development of AMD rather than pack years or current or former smoking status. In our statistical modelling pack years of cigarettes proved to be a better fit to the data than number of years of smoking, and was the most significant risk factor for AMD. There was a dose‐response relation with the odds ratio increasing with the amount smoked and the highest risk being in those smoking more than 40 pack years. We did observe a trend, although not statistically significant, with smoking status (table 2). However, it is apparent from table 1 that there are additional differences in smoking behaviour that are not captured by smoking status alone. For former smokers the mean length of time of smoking and the total amount smoked are both higher in cases than controls. The same applies to current smokers. This is why pack years of smoking is a better measure of risk for AMD. It is clear from these data that the amount smoked is more important than whether or not someone has ever smoked. Previously, the majority of positive associations have been demonstrated for CNV, which largely reflects the limited number of studies investigating the specific effect on the two types of end stage disease. Even in the large population based studies28,29,30 the small numbers of cases of GA meant that in general it was not possible to show an increased risk specifically for this form of AMD. The results of this study clearly show an increased risk for GA as well as CNV.
The mean age of the control group was slightly younger than for the cases and, since age is a well established risk factor, we adjusted for this in the analyses. We found no difference in the risk profile between men and women. We found evidence that passive smoking (living with a smoker for 5 years or more) increases risk for AMD in non‐smokers. Passive smoking has been suggested to increase risk for AMD in one other study,15 which gave an odds ratio of 1.42 but did not reach statistical significance. No increased risk was demonstrated for exposure to other tobacco products. There is evidence that switching to non‐cigarette tobacco products such as pipes and cigars may attenuate some of the harmful effects of cigarette smoking and this was attributed to reduced total tobacco consumption.31 In the current study, since the majority (93%) of those using other tobacco products also smoked cigarettes, it is not possible to show a differential effect of other tobacco products. Whether or not smokers inhaled did not affect the risk of AMD but since the majority (80%) of smokers inhaled it would also be difficult to show this effect. Because of the multivariable nature of the model fitted, and the complex associations between different smoking variables, the null associations of smoking other tobacco products and inhalation with AMD cannot be reliably interpreted.
Stopping smoking was associated with reduced odds of AMD and the risk in those who had not smoked for over 20 years was comparable to non‐smokers. This is another reason why smoking should be discouraged and those who do smoke should be encouraged to stop. The benefits of giving up smoking applied to both CNV and GA.
The mechanisms of smoking as a risk factor for AMD are thought to be largely related to oxidative damage. Experimental evidence suggests that smoking impairs retinal pigment epithelium (RPE) function, resulting in a build up of waste products at the RPE/retinal interface.32 This leads to the formation of drusen and consequent damage to Bruch's membrane, allowing the in‐growth of new vessels. Some of the damage may also be mediated by the direct effect of nicotine, which both potentiates PDGF mediated upregulation of endothelial smooth muscle cell proliferation33 and activates pro‐inflammatory mediators.34 The development of GA following such oxidative damage is, similarly, thought to be related to the formation of drusen with subsequent atrophy of the adjacent RPE and photoreceptors. Complement mediated inflammation has also been proposed as an important mechanism in AMD and exciting new research has shown that a variant in the complement factor H (CFH) gene is associated with a higher risk for AMD.35,36,37,38,39 Plasma levels of CFH are known to be reduced in smokers.40
The strength of this study lies in the fact that we have been careful to choose a highly select case group with only the late forms of AMD confirmed by clinical assessment and photographic grading. Controls were examined, questioned, and photographed in exactly the same manner as the cases and similar exclusion criteria applied. Limitations of any study of environmental risk factors include the possibility that recall bias may confound the results. Subjects were fully informed of their involvement in a study of the causes of AMD and some may have been aware of suggestions of a possible link with smoking. It is our impression, however, that participants in this study were largely unaware of smoking as a risk factor for AMD. In addition, all the questions formed part of a larger health and lifestyle questionnaire and as such it would be difficult for a subject to discern specifically which questions may be leading to a possible link with AMD. We attempted to improve the accuracy of pack year estimation by collecting data on the number of cigarettes smoked in each decade of life.26 When analysing the results it was apparent that subjects smoked only modest amounts in their teens and during the post‐war years owing to cost limitations but tended to smoke much more heavily from their 30s onwards, emphasising the importance of ascertaining information about the amount smoked throughout life.
Conclusions
We have demonstrated a clear association between the risk of AMD and pack years of cigarette smoking. This provides strong support for a causal relation between smoking and AMD. We have shown that the risk applies to both CNV and GA. We also show an increased risk for AMD in non‐smokers exposed to passive smoking. Absence of an association with exposure to other types of tobacco products suggests that it is cigarettes in particular that confer increased risk. Stopping smoking appears to reduce the risk of both GA and CNV; this needs to be emphasised as a public health issue.
Acknowledgements
The following investigators also contributed to this work as part of the Genetic Factors in AMD Study: SS Bhattacharya, P Bishop, P Black, Z Butt, NE Day, C Edelsten, A Fitt, DW Flanagan, A Glenn, S Harding, C Jakeman, C Jones, RJ Lamb, A Lotery, V Moffat, C Moorman, A Nicholas, RJ Pushpanathan, E Redmond, T Rimmer. With special thanks to Tunde Peto for directing the fundus photograph grading and Kay‐Tee Khaw for advice on the patient questionnaire. We also appreciate the help of the clinic staff and medical photographers at the Addenbrooke's Centre for Clinical Investigation, Cambridge; Ipswich Hospital; Peterborough District Hospital; Moorfields Eye Hospital, London; Norfolk and Norwich University Hospital, Norwich; West Suffolk Hospital, Bury St Edmunds; Queen Elizabeth Hospital, King's Lynn; James Paget Hospital, Great Yarmouth; Stoke Mandeville Hospital, Aylesbury. Many thanks to all the patients and their families who participated in this study.
Abbreviations
AMD - age related macular degeneration
CFH - complement factor H
CNV - choroidal neovascularisation
GA - geographic atrophy
PED - pigment epithelial detachment
RPE - retinal pigment epithelium
Footnotes
This work was supported by a programme grant from the Medical Research Council.
The authors declare no competing interests in the preparation and submission of this manuscript.
Multicentre research ethics committee, Trent, UK and local research ethics committee approvals from each of the participating units detailed above were obtained for the study.
References
- 1.Evans J, Wormald R. Is the incidence of registrable age‐related macular degeneration increasing? Br J Ophthalmol 1996809–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Evans J R. Causes of blindness and partial sight in England and Wales 1990–1991. Studies on Medical and Population Subjects. 1995;57
- 3.Hawkins B S, Bird A, Klein R.et al Epidemiology of age‐related macular degeneration. Mol Vis 1999526. [PubMed] [Google Scholar]
- 4.Buch H, Vinding T, Nielsen N V. Prevalence and causes of visual impairment according to World Health Organization and United States criteria in an aged, urban Scandinavian population: the Copenhagen City Eye Study. Ophthalmology 20011082347–2357. [DOI] [PubMed] [Google Scholar]
- 5.Klaver C C, Wolfs R C, Vingerling J R.et al Age‐specific prevalence and causes of blindness and visual impairment in an older population: the Rotterdam Study. Arch Ophthalmol 1998116653–658. [DOI] [PubMed] [Google Scholar]
- 6.McCarty C A, Nanjan M B, Taylor H R. Vision impairment predicts 5 year mortality. Br J Ophthalmol 200185322–326. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.The Eye Disease Case‐Control Study Group Risk factors for neovascular age‐related macular degeneration. Arch Ophthalmol 19921101701–1708. [DOI] [PubMed] [Google Scholar]
- 8.Age‐Related Eye Disease Study Research Group 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, Ophthalmology 20001072224–2232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Klein R, Klein B E, Linton K L.et al The Beaver Dam Eye Study: the relation of age‐related maculopathy to smoking. Am J Epidemiol 1993137190–200. [DOI] [PubMed] [Google Scholar]
- 10.Vingerling J R, Hofman A, Grobbee D E.et al Age‐related macular degeneration and smoking. The Rotterdam Study. Arch Ophthalmol 19961141193–1196. [DOI] [PubMed] [Google Scholar]
- 11.McCarty C A, Mukesh B N, Fu C L.et al Risk factors for age‐related maculopathy: the Visual Impairment Project. Arch Ophthalmol 20011191455–1462. [DOI] [PubMed] [Google Scholar]
- 12.Delcourt C, Diaz J L, Ponton‐Sanchez A.et al Smoking and age‐related macular degeneration. The POLA Study. Pathologies Oculaires Liees a l'Age. Arch Ophthalmol 19981161031–1035. [DOI] [PubMed] [Google Scholar]
- 13.Christen W G, Glynn R J, Manson J E.et al A prospective study of cigarette smoking and risk of age‐related macular degeneration in men. JAMA 19962761147–1151. [PubMed] [Google Scholar]
- 14.Seddon J M, Willett W C, Speizer F E.et al A prospective study of cigarette smoking and age‐related macular degeneration in women. JAMA 19962761141–1146. [PubMed] [Google Scholar]
- 15.Smith W, Mitchell P, Leeder S R. Smoking and age‐related maculopathy. The Blue Mountains Eye Study. Arch Ophthalmol 19961141518–1523. [DOI] [PubMed] [Google Scholar]
- 16.Hyman L G, Lilienfeld A M, Ferris FL I I I.et al Senile macular degeneration: a case‐control study. Am J Epidemiol 1983118213–227. [DOI] [PubMed] [Google Scholar]
- 17.Kahn H A, Leibowitz H M, Ganley J P.et al The Framingham Eye Study. I. Outline and major prevalence findings. Am J Epidemiol 197710617–32. [DOI] [PubMed] [Google Scholar]
- 18.Maltzman B A, Mulvihill M N, Greenbaum A. Senile macular degeneration and risk factors: a case‐control study. Ann Ophthalmol 1979111197–1201. [PubMed] [Google Scholar]
- 19.Blumenkranz M S, Russell S R, Robey M G.et al Risk factors in age‐related maculopathy complicated by choroidal neovascularization. Ophthalmology 198693552–558. [DOI] [PubMed] [Google Scholar]
- 20.West S K, Rosenthal F S, Bressler N M.et al Exposure to sunlight and other risk factors for age‐related macular degeneration. Arch Ophthalmol 1989107875–879. [DOI] [PubMed] [Google Scholar]
- 21.Chaine G, Hullo A, Sahel J.et al Case‐control study of the risk factors for age related macular degeneration. France‐DMLA Study Group. Br J Ophthalmol 199882996–1002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Klein R, Klein B E, Jensen S C.et al Age‐related maculopathy in a multiracial United States population: the National Health and Nutrition Examination Survey III. Ophthalmology 19991061056–1065. [DOI] [PubMed] [Google Scholar]
- 23.Diabetic Retinopathy Study Report Number 6. Design, methods, and baseline results. Report Number 7. A modification of the Airlie House classification of diabetic retinopathy. Prepared by the Diabetic Retinopathy. Invest Ophthalmol Vis Sci 1981211–226. [PubMed] [Google Scholar]
- 24.Bird A C, Bressler N M, Bressler S B.et al An international classification and grading system for age‐related maculopathy and age‐related macular degeneration. The International ARM Epidemiological Study Group. Surv Ophthalmol 199539367–374. [DOI] [PubMed] [Google Scholar]
- 25.Smith M R, Kinmonth A L, Luben R N.et al Smoking status and differential white cell count in men and women in the EPIC‐Norfolk population. Atherosclerosis 2003169331–337. [DOI] [PubMed] [Google Scholar]
- 26.Bernaards C M, Twisk J W, Snel J.et al Is calculating pack‐years retrospectively a valid method to estimate life‐time tobacco smoking? A comparison between prospectively calculated pack‐years and retrospectively calculated pack‐years. Addiction 2001961653–1661. [DOI] [PubMed] [Google Scholar]
- 27.Smith W, Assink J, Klein R.et al Risk factors for age‐related macular degeneration: pooled findings from three continents. Ophthalmology 2001108697–704. [DOI] [PubMed] [Google Scholar]
- 28.Klein R, Klein B E, Linton K L. Prevalence of age‐related maculopathy. The Beaver Dam Eye Study. Ophthalmology 199299933–943. [DOI] [PubMed] [Google Scholar]
- 29.Mitchell P, Smith W, Attebo K.et al Prevalence of age‐related maculopathy in Australia. The Blue Mountains Eye Study. Ophthalmology 19951021450–1460. [DOI] [PubMed] [Google Scholar]
- 30.Vingerling J R, Dielemans I, Hofman A.et al The prevalence of age‐related maculopathy in the Rotterdam Study. Ophthalmology 1995102205–210. [DOI] [PubMed] [Google Scholar]
- 31.Wald N J, Watt H C. Prospective study of effect of switching from cigarettes to pipes or cigars on mortality from three smoking related diseases. BMJ 19973141860–1863. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Bailey T A, Kanuga N, Romero I A.et al Oxidative stress affects the junctional integrity of retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 200445675–684. [DOI] [PubMed] [Google Scholar]
- 33.Suner I J, Espinosa‐Heidmann D G, Marin‐Castano M E.et al Nicotine increases size and severity of experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 200445311–317. [DOI] [PubMed] [Google Scholar]
- 34.Sastry B V, Hemontolor M E. Influence of nicotine and cotinine on retinal phospholipase A2 and its significance to macular function. J Ocul Pharmacol Ther 199814447–458. [DOI] [PubMed] [Google Scholar]
- 35.Haines J L, Hauser M A, Schmidt S.et al Complement factor H variant increases the risk of age‐related macular degeneration. Science 2005308419–421. [DOI] [PubMed] [Google Scholar]
- 36.Edwards A O, Ritter R I I I, Abel K J.et al Complement factor H polymorphism and age‐related macular degeneration. Science 2005308421–424. [DOI] [PubMed] [Google Scholar]
- 37.Klein R J, Zeiss C, Chew E Y.et al Complement factor H polymorphism in age‐related macular degeneration. Science 2005308385–389. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Hageman G S, Anderson D H, Johnson L V.et al A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age‐related macular degeneration. Proc Natl Acad Sci USA 20051027227–7232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Zareparsi S, Branham K E, Li M.et al Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age‐related macular degeneration. Am J Hum Genet 200577149–153. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Esparza‐Gordillo J, Soria J M, Buil A.et al Genetic and environmental factors influencing the human factor H plasma levels. Immunogenetics 20045677–82. [DOI] [PubMed] [Google Scholar]