Abstract
Purpose.:
To describe the association between refractive errors, ocular biometry, and age-related macular degeneration (AMD) in an Asian Malay population in Singapore.
Methods.:
A population-based study of 3280 Malay individuals aged 40 to 80 years was conducted in Singapore. Early- and late-AMD signs were graded from retinal photographs according to the Wisconsin grading system. Autorefraction, followed by subjective refraction, was performed to obtain spherical equivalent refraction (SER) in diopters, with emmetropia defined as SER −0.5 to +0.5 D, hyperopia as > +0.5 D, and myopia as < −0.5 D. Partial coherence laser interferometry was used to measure axial length, anterior chamber depth, and corneal curvature. The association between refractive status, ocular biometry and the prevalence of both early and late AMD were analyzed.
Results.:
Hyperopic refractive error (odds ratio [OR] 1.54; 95% confidence interval [CI] 1.00–2.36; compared with myopia, P = 0.05), shorter axial length (OR, 1.91; CI, 1.05–3.46, comparing 1st vs. 4th quartiles; P = 0.03), and steeper corneal curvature (OR, 1.93; CI, 1.16–3.20, comparing 1st vs. 4th quartiles, P = 0.01) were significantly associated with early AMD, after adjustment for age, sex, smoking, education, height, and systolic blood pressure. Each diopter increase in hyperopic refraction and each millimeter decrease in axial length was associated with an 8% (OR, 1.08; CI, 1.01–1.16; P = 0.03) and 29% (OR, 1.29; CI, 1.06–1.57; P = 0.01) increased risk of early AMD, respectively. No significant association was noted of refractive error and ocular biometry with late AMD.
Conclusions.:
Hyperopic refractive error and shorter axial length are associated with early AMD in Asian eyes.
Age-related macular degeneration (AMD) is the leading cause of blindness in elderly patients, not only in the Western world, but also increasingly so in Asian countries.
1 –9 Although many risk factors for AMD have been examined, only cigarette smoking and genetic markers (e.g., complement factor H) have been consistently found to be associated with AMD.
8 –18
Hyperopia has been reported to be associated with AMD in several case–control studies
19 –26 and a few population-based surveys,
12,27 –31 but the findings have been conflicting. The Blue Mountains Eye study (BMES) reported a weak cross-sectional association between hyperopia and early AMD,
27 but found no association with the 5-year incidence of either early or late AMD.
28 The Rotterdam Study reported an association between increasing hyperopia and 5-year incident AMD,
29 but the Beaver Dam Study found no significant association between baseline refractive status and either the 5- or 10-year incidence of early or late AMD.
30,31 Two other large studies, the Eye Disease Case–Control Study
24 and the Age-Related Eye Disease Study (AREDS),
25 found that subjects with hyperopia were 1.5 to 2.3 times more likely to have exudative AMD than were those with myopia, after adjustment for age and other risk factors. However, few of these studies have been in Asians, where refractive errors, particularly myopia, are more prevalent. There have been no population-based studies that have evaluated the association between ocular biometric factors, such as axial length, and AMD.
The purpose of this study was to evaluate the relationship of refractive error and ocular biometric parameters with the prevalence of AMD in a large population-based study of Malays in Singapore.
This population-based study of Asian Malays in Singapore showed a strong association of hyperopic refractive error and shorter AL with early AMD. Subjects with hyperopic refractive errors were 1.5 times more likely to have early AMD than were those with myopia, even after adjustment for AMD risk factors, including age, sex, smoking, education, height, and systolic blood pressure. Each diopter increase in SER was associated with an 8% increased odds of having early AMD. Consistent with this, we demonstrate strong associations between shorter AL and early AMD, with each milliliter decrease in AL associated with a 29% increased odds of early AMD.
Although investigators in several population-based and case–control studies have examined the association between refractive error and AMD, the findings have remained inconsistent and inconclusive. The results of the The Rotterdam Study
29 the Age-Related Eye Disease Study,
25 the French DMLA Study,
19 and the Beijing Eye Study
12 showed an association between hyperopia and AMD, whereas the Beaver Dam study did not show an association between refractive errors and either the 5-
30 or 10-year incidence of AMD.
31 The BMES described a weak cross-sectional association between AMD and hyperopia.
27 However, a subsequent report on the 5-year incidence of AMD did not support the previous observations.
28 Among Asian studies, the Beijing Eye Study found that hyperopic refractive error, apart from age, was the single most important risk factor for early AMD in adult Chinese.
12 Furthermore, in a second report on the characteristics of highly myopic eyes,
40 the highly myopic eyes had a significantly lower prevalence of both early (OR, 3.0; CI, 1.21–7.51;
P = 0.03) and late (OR, 6.33;
P = 0.001) AMD, compared with eyes that did not have high myopia.
In contrast to population-based studies, clinical and case–control studies
19 –25 have reported stronger associations between hyperopia and AMD, particularly exudative AMD. In the Eye Disease Case–Control Study
24 and the AREDS,
25 after adjustment for age and other risk factors, persons with hyperopia were 1.5 to 2.3 times more likely to have exudative AMD than were those who were myopic. Sandberg et al.
20 compared the refractive error of 198 patients with unilateral exudative AMD with the refractive error of 129 patients with bilateral dry AMD. In a comparison of the better eyes of the two groups (better eye was defined as the fellow eye in unilateral cases and the better-seeing eye in bilateral cases), patients with the unilateral exudative AMD had an average spherical equivalent that was 1.0 D more hyperopic than that of patients with the bilateral dry AMD (
P < 0.001). Patients with a refractive error of +0.75 D or greater were more likely to have exudative AMD than were patients with other refractive errors (OR, 2.40;
P < 0.001).
Our findings support an association between hyperopic refractive error and early AMD. More important, our study is the first population-based study to report that subjects with shorter AL and steeper curvature of the cornea are more likely to have early signs of AMD. This association was independent of education level and height. It has been argued that the association of hyperopia and AMD can be confounded by the presence of nuclear cataract. However, the strong correlation of short AL with early AMD validates the link between hyperopic refraction and AMD, independent of the cataract-related myopic shift. The risk estimate of 8% per diopter of progress toward hyperopia and 29% toward each millimeter decrease in AL is considerable, suggesting that refraction and ocular biometric parameters have a plausible role in the pathophysiology of AMD. In view of these findings, older subjects with short AL (≤22.8 mm) and hyperopia may need more careful monitoring for the development of AMD.
Case–control studies have examined AL and AMD without finding any relationship.
41,42 For example, a Norwegian cohort of the EUREYE multicenter community point prevalence study of ARM also found no association between AMD and AL.
43 More recently, Tao and Jonas
26 reported a clinical study examining 379 patients treated with an antivascular endothelial growth factor drug for exudative AMD and compared them with a control group of 191 patients undergoing surgery for age-related cataract, but without ophthalmoscopic signs of exudative AMD. The patients with AMD had a significantly shorter AL (23.31 ± 0.75 vs. 24.20 ± 1.56 mm;
P < 0.001) and were significantly more hyperopic (0.65 ± 2.14 vs. −1.71 ± 4.57 D;
P < 0.001) than were the patients with cataract. Although we found a statistically significant association of hyperopia and biometric parameters only in early AMD in our study and none in late AMD, we believe that this could have resulted from the small number of subjects with late AMD.
A biologically plausible explanation for these observations is not apparent. Boker et al.
21 hypothesized that the association between hyperopia and AMD is related to a reduction in choroidal blood flow in eyes with shorter AL, which could then predispose these eyes to the development of choroidal neovascularization. A hemodynamic model of the pathogenesis of AMD postulated that a degenerative process begins with decreased compliance of the sclera caused by lipoid infiltration.
44 It is therefore hypothesized that shorter, thicker hyperopic eyes, with higher scleral rigidity, cause an increase in resistance of the choroidal venous outflow. An increased choroidal resistance in AMD cases compared with sex- and age-matched controls has been documented by laser Doppler flow measurements
45 in both histologic and in vivo studies. It is possible that the decreased flow prevents easy exchange of nutrients and metabolic products across the RPE and results in drusen formation and thickening of Bruch's membrane. Another speculation is that poorer cooling of the retina by an impaired choroidal blood flow leads to a higher susceptibility to oxidative stress, in a thicker hyperopic eye with a higher demand for oxygen and nutrients.
29 A further possible explanation is a genetic link between the two conditions.
The strengths of this study are the representativeness of the sample of the general population; the high response rate; and the standardized protocol, including the photographic documentation of the macula; and ocular biometric measurements. The limitations include the relatively few cases of late AMD, which decreases the power of the study to identify significant risk factors. Also, being a cross-sectional study, it could not answer temporal questions that a longitudinal study with sufficient power could resolve.
In conclusion, our population-based study in Asian Malays in Singapore demonstrated a significant association between hyperopic refraction and shorter AL and early AMD. These data offer further clues to the pathogenesis of a major blinding condition.
Supported by National Medical Research Council Grants 0796/2003, 0863/2004, and CSI/0002/2005, and Biomedical Research Council Grant 501/1/25-5, with additional support from the Singapore Tissue Network and the Ministry of Health, Singapore.
Disclosure:
R. Lavanya, None;
R. Kawasaki, None;
W.T. Tay, None;
G.C.M. Cheung, None;
P. Mitchell, None;
S.-M. Saw, None;
T. Aung, None;
T.Y. Wong, None