(TLRs) are involved in innate immunity, and can function as pathogen recognition receptors in the RPE, leading to cytokine induction and apoptosis [225, 226]. Yang et al. reported an association between TLR3 rs3775291 and protection against GA (OR, 0.71; 95% CI, 0.50–1.00), while Zareparsi et al. found an increased risk of AMD associated with TLR4 D299G (OR, 2.25; 95% CI, 1.42–3.56). However, these findings have been disputed by several other study groups with larger datasets [227–235]. Variants in the vascular endothelial growth factor (VEGF) gene, encoding a cytokine that enhances angiogenesis and is expressed by the RPE, have been implicated in AMD by some studies (OR, 1.24–2.61) [236–238], whereas others did not replicate this finding [239]. The superoxide dismutase 2 (SOD2) gene, of which the gene product catalyzes the reaction of superoxide anion into oxygen and hydrogen peroxide, was associated with AMD in one study (OR, 1.63; 95% CI, 1.11–2.54) [240]; however, subsequent analyses did not support their observation [241–243].

Inconsistent results were also observed concerning the variants of the paraoxonase 1 (PON1) gene: M55L and Q192R. Two studies reported a weak causative association between M55L and CNV, but not with GA. They also reported a protective role for homozygous carriers of Q192R, mainly against CNV (OR, 0.25; 95% CI, 0.16–0.41) [244, 245]. Conversely, two other groups reported no correlation [243, 246]. The ABCA4 (ABCR) gene produces an ATP-binding cassette superfamily transmembrane protein expressed exclusively in retinal photoreceptors which is involved in the clearance of all-trans-retinal aldehyde–a by-product of the retinoid cycle of vision–from photoreceptor cells. Alleles at the ABCA4 gene were initially associated with an increased risk of AMD. G1961E had an OR of 5.0 (95% CI, 1.6–20) and D2177N had an OR of 2.8 (95% CI, 1.2–7.4) [247–249]; however, subsequent research has contradicted this.

Two genes encoding extracellular matrix proteins may modify the integrity of the central elastic lamina of Bruch’s membrane by reduced elastogenesis, and predispose to AMD. These are fibulin-5 (FBLN5) [250–253] and hemicentin-1 (FBLN6, HMCN1) [254– 256]. Involvement of HMCN1 has not been validated in several studies [50, 70, 90, 257–259]. Rs2511989 in the SERPING1 gene, which encodes C1INH, an inhibitor of the classical and lectin pathways of complement activation, was recently described to be associated with AMD [260]. The odds ratio for AMD for

heterozygous and homozygous carriers of the minor “A” allele was 0.63 (95% CI, 0.47–0.84) and 0.44 (95% CI, 0.31–0.64) compared to noncarriers. This protective effect has not been confirmed by others [261–264].

1.6Environmental Factors

1.6.1Smoking

Second to age, smoking is the most consistently documented environmental risk factor for AMD. Smoking may enhance the onset and progression of AMD through oxidative insults to the retina, decline of choroidal blood flow, increase of ischemia, hypoxia, and micro-infarctions, stimulation of choroidal neovascularization, and reduction of serum antioxidants [265]. A recent meta-analysis of the BDES, BMES, RS, Physicians’ Health Study, and the Muenster Ageing and Retina Study showed a pooled ageand sexadjusted risk ratio for incident AMD of 2.75 (95% CI, 1.52–4.98) in current vs never smokers [266]. For former vs never smokers, the adjusted risk ratio of AMD was 1.21 (95% CI, 0.88–1.66). Neuner et al. found a protective effect for time since smoking cessation in former smokers with an adjusted risk ratio = 0.50 (95% CI, 0.29–0.89) per log(year) [266]. Others reported that persons who stopped smoking more than 20 years earlier were not at increased risk of the blinding stages of AMD [267, 268]. Seddon et al. reported ever smoking (i.e., current or former vs never smoking) was associated with a 30% (95% CI, 10–70%) increased risk for the progression to either subtype of late AMD in one or both eyes after a mean follow-up of 6.3 years [148].

1.6.2Antioxidants

The only protective factors for AMD known to date are antioxidants. AREDS showed that a combination of zinc, b-carotene, and vitamins C, and E reduced the risk of progression from intermediate to advanced AMD by 25% [34]. The RS found that an above-median intake of these nutrients was associated with a 35% lower risk of incident AMD [269]. The BMES showed that persons in the top tertile of lutein/zeaxanthin intake had a reduced risk of incident CNV (RR 0.35, 95% CI 0.13–0.92). For zinc, the RR comparing the top decile intake with the remaining population was 0.56 (95% CI 0.32–0.97) for any AMD

and 0.54 (95% CI, 0.30–0.97) for early AMD. Higher b-carotene and vitamin E intake were associated with an increased risk of AMD; when comparing the highest vs the lowest intake tertile, the RR were 2.68 (95% CI 1.03– 6.96) and 2.55 (95% CI 1.14–5.70), respectively [270]. The BDES studied the 5-year incidence of early AMD in relation to antioxidant intake, and did not find an association. However, inverse associations were observed for the development of specific macular lesions, large drusen, and pigmentary abnormalities [271]. AREDS reported a reduced likelihood of progression from bilateral drusen to GA with higher levels of w-3 long-chain polyunsaturated fatty acids [272]. Persons with the highest intake of eicosapentaenoic/docosahexaenoic acid had an increased risk of progression to GA compared to persons with the lowest intake (0.45, 95% CI 0.23–0.90). Similarly, several studies have shown that higher dietary intake of omega-3 fatty acids reduced progression of AMD by 30–59% [273–275].

1.6.3Body Mass Index (BMI)

Another modifiable risk factor repeatedly implicated in the pathogenesis of AMD is a higher BMI. LALES reported that persons with a high BMI (³25) were at greater risk of early AMD (OR 1.34, 95% CI 0.99– 1.82), and increased retinal pigment (OR 1.55, 95% CI 1.03–2.34) relative to those with a BMI under 25 [276]. The BMES reported an increased risk for early AMD for underweight (OR 1.92, 95% CI 1.16–3.18), overweight (OR 1.44, 95% CI 1.03–1.99), and obese (OR 1.78, 95% CI 1.19–2.68) persons compared to those with normal BMI (20–25) [277]. The BDES found that women had an increased risk for early AMD with a higher BMI (³28) [278]. No significant associations for BMI were seen with late AMD in the BDES, BMES, or LALES [276–278]. However, the POLA Study did observe an increased risk of late AMD and pigmentary abnormalities in obese subjects [279]. AREDS also found significant associations between a higher BMI and both subtypes of late AMD [280, 281].

These findings support the role of overweight/obesity in the susceptibility to AMD, perhaps through changes in the lipoprotein profile or an increase in oxidative damage and inflammation in overweight/obese persons mediated among others by a dietary pattern with low intake of antioxidants and polyunsaturated fatty acids or even an overall unhealthy lifestyle [282–284].

1.6.4Hypertension

Because of its effect on the choroidal blood flow, hypertension has long been hypothesized as a risk factor for AMD [285, 286]. Though data from most epidemiologic studies has been inconsistent [16, 21, 267, 276, 279, 280, 287–291]. In the BDES, hypertension was associated with the 10-year incidence of late AMD, and in particular of CNV [292]. Persons with treated uncontrolled hypertension had a RR of 2.26 (95% CI 1.00–5.13) for late AMD, and a RR of 3.29 (95% CI 1.24–8.79) for CNV compared to normotensives at baseline. Persons with treated controlled hypertension had an increased risk of CNV (2.29, 95% CI 1.12–4.69). Higher systolic blood pressure at baseline was associated with the incidence of retinal pigment epithelial depigmentation (RR per 10 mmHg systolic blood pressure: 1.10, 95% CI 1.01–1.18) and CNV (RR 1.22, 95% CI 1.06–1.41). Higher pulse pressure at baseline was associated with the incidence of retinal pigment epithelial depigmentation (RR per 10 mmHg: 1.17, 95% CI 1.07–1.28), increased retinal pigment (RR 1.10, 95% CI 1.01–1.19), CNV (RR 1.34, 95% CI 1.14–1.60), and progression of AMD (RR 1.08, 95% CI 1.01–1.17). In the RS, a clear dosedependent association was found between elevated systolic blood pressure and increased risk of incident AMD; OR per 10-mmHg increase was 1.08 (95% CI 1.03–1.14) [293]. Contrarily, the BMES found no evidence of an association between pulse pressure, systolic or diastolic blood pressure, or presence of hypertension at baseline and incident AMD [289].

1.6.5Cataract Surgery

There have been reports of an association between cataract surgery and AMD [294–304]. Cross-sectional data from the BDES showed an association between cataract surgery and early AMD [295]. In the NHANES (National Health and Nutrition Examination Survey), a cross-sectional association was reported between aphakia and AMD [294]. Freeman and colleagues investigated three populations cross-sectionally and described an association of cataract surgery with late AMD [300]. However, the prevalence survey in the BMES did not find a significant association between cataract surgery and early or late AMD [305]. Crosssectional analyses from the Rotterdam Study showed no increased risk of GA or CNV in pseudophakic eyes