Ординатура / Офтальмология / Английские материалы / Retinal Degenerations biology, diagnostics, and therapeutics_Tombran-Tink, Barnstable_2007

The complexity of AMD genetics, including heterogeneity in both phenotypes and genotypes, unknown correlations between specific genotypes and phenotypes, low penetrance, and a high susceptibility to nongenetic factors, is well summarized by Gorin et al. (143) and Tuo et al. (24). Despite these difficulties, the recent replication of associations of AMD with gene variants in the CFH, LOC387715 (353–355) and C2/BF (356) genes is encouraging and will accelerate revealing the pathogenesis of AMD. Using a quantitative trait linkage approach to increase power in detecting linkage signals from genomewide screening may help to partially overcome some of these difficulties (24,46,147).

Lifestyle and Environmental Factors

Smoking

To date, smoking is the only modifiable AMD risk factor consistently found across different study populations (148–159). This association is also consistent in cross-sec- tional analytic studies of clinical case-control study samples (148,157–159), in popula- tion-based samples (41,149–154,160) (Fig. 3A–C), and in longitudinal analytic studies of large samples (42,155,156,161–163) (Fig. 4). In the BDES population, people who smoked at baseline were more likely to develop early AMD lesions 5 yr (162) and 10 yr later (163), though a significant association between smoking and 10-yr incident neovascular AMD was evident only in men (163).The magnitude of the risk for late AMD in current vs noncurrent smokers, or in ever smokers vs never smokers, is between twoand sixfold higher (Fig. 4). In the BMES population (161,164), baseline current smokers developed late AMD at a mean age of 67 yr, whereas past smokers developed this at a mean age of 73 yr and never smokers at a mean age of 77 yr. This 10-yr earlier development of late AMD among current smokers implies a substantial increase in the burden on affected individuals, their families and aged/disability care.

In an experimental choroidal neovascularization (CNV) mouse model, Suner et al. (165) demonstrated that nicotine increased both the size and vascularity of CNV and that this effect can be blocked by subconjunctival injection of hexamethonium, a nonspecific nicotinic receptor antagonist.

Based on current, available evidence from epidemiological studies (15,16,19,21–23, 25,164,166–168) and experiments in animal models (165), smoking is likely to have a causal role (as trigger and/or promoter) in the course of the development of neovascular AMD (164,168). Currently, eye health practitioners give too little weight to smoking cessation and tobacco control, and public health specialists insufficient attention to

Fig. 3. (Opposite page) (A) Smoking and prevalence of late AMD. (B) Smoking and prevalence of geographic atrophy. (C) Smoking and prevalence of neovascular AMD. *Pathologies Oculaires Liees al’Age (POLA) study N = 2196, aged 60+ yr, risk for current smokers (154); #Melbourne Visual Impairment Project N = 4744, aged 40+ yr, risk for smoking more than 40 yr (153); †Blue Mountains Eye Study N = 3654, aged 49–97 yr, risk for current smokers (41,152); ^Rotterdam Study N = 7983, aged 55–106 yr, risk for current smokers (41,160); ‡Beaver Dam Eye Study N = 4756, aged 43–86 yr, risk for current smokers (41); **Age-related Eye Disease Study N = 4757, aged 60–80 yr, risk for past and current smokers (158); ##Case-Control Study in Japan N = 138, aged 50–69 yr, risk for current smokers (157); ^^Eye Disease Case-Control Study N = 1036, aged 55–80 yr, risk for current smokers (148).

Fig. 4. Smoking and incidence of late AMD. ^Rotterdam Study N = 7983, aged 55+ yr, follow-up for 6 yr, risk for current smokers at baseline (42); †Blue Mountains Eye Study N = 3654, aged 49+ yr, follow-up for 5 yr, risk for current smokers at baseline (42); ‡Beaver Dam Eye Study N = 4926, aged 43–86 yr, follow-up for 5 yr, risk for current smokers at baseline (42); *Nurses’ Health Study N = 31,843, aged 50–59 yr, follow-up for 12 yr, current smokers who smoke ≥25 cigarettes/d (156); **Physicians’ Health Study N = 21,157, aged 40–84 yr, follow-up for 12.2 yr, risk for current smokers at baseline (155).

eye disease (164). The ocular hazards of smoking should be publicized more, and appropriate smoking cessation support should be offered in eye and medical services

(164,168,169).

Alcohol Consumption

In a subsample of the NHANES I study population (170), persons who reported moderate wine consumption were significantly less likely to have AMD than nondrinkers. The subsample (n = 3072 out of 10,127) was chosen based on the age criterion (45–74 yr) and the availability of alcohol consumption data. The proportion of participants who responded to the alcohol questionnaire, however, was not stated (170). AMD was defined during a clinical examination (170) and so could not be validated. This association between wine and AMD, however, was not confirmed in either cross-sectional (171,172) or longitudinal data (173–175) obtained from other large population-based studies. The BDES 5-yr follow-up data showed that beer drinking in men was associated with an increased risk of soft indistinct drusen (173). The BDES 10-yr follow-up data also showed that people who reported being heavy drinkers at baseline were more likely to develop late AMD (163). This was not found in either the BMES or RS (unpublished data). To date,

accumulated evidence on the association between alcohol consumption and AMD appears to suggest a U-shape association: moderate alcohol consumption associated with a reduced risk, and no or heavy consumption associated with an increased risk.

Diet/Supplement Intake

ANTIOXIDANT NUTRIENTS (CAROTENOIDS/LUTEIN/ZEAXANTHIN)

The hypothesis that oxidative damage may be involved in the pathogenesis of AMD (176,177) is supported by a number of factors: (1) a high concentration of polyunsaturated fatty acids is present in the outer segments of photoreceptors in the retina; (2) there is high photo-oxidative stress (178) and relatively high oxygen tension in this region; and

(3) the well-known susceptibility of polyunsaturated fatty acids to undergo oxidation in the presence of oxygen or oxygen-derived radical species (177). Therefore, antioxidant nutrients may have a protective effect on AMD (177,179–182). Findings from most case-control studies (148,179,183–185), except one (186), support this hypothesis. Observations from large study samples suggest that consumption of fruits and vegetables is associated with a reduced likelihood of AMD (187–189). Whether the beneficial effect from consumption of fruits and vegetables is caused by carotenoids (a precursor of vitamin A), including lutein and zeaxanthin, is less conclusive (190,191). An inverse association between AMD prevalence and serum carotenoids was suggested by one study (192), but has not been evident in the majority of population-based nested casecontrol studies (193–195). Nor has there been an inverse association evident between AMD prevalence and dietary carotenoid intake (195–197) or the use of vitamin and zinc supplements (192,198) in cross-sectional analytical studies of population-based data. Positive findings that were only observed in stratified analyses in the NHANES III (195) could have been because of chance, resulting from multiple comparisons (195). In the Pathologies Oculaires Liees a l’Age (POLA) study population, plasma α-tocopherol (vitamin E) level was associated with a reduced AMD prevalence (199), whereas glutathione peroxidase was significantly associated with an increased late-AMD prevalence (200). Further, apart from an inverse association between intakes of pro-vitamin A carotenoids, dietary vitamin E, and the 5-yr incidence of large drusen observed in the BDES population (201), findings from most population-based longitudinal studies have not provided convincing evidence supporting an inverse association between antioxidant or zinc intake (diet or supplements) and the subsequent development of AMD (189,201–204). Potential misclassification in phenotype identification could have played a role in the negative findings from some of these studies (189,202,203), as self-reported study outcomes with confirmation from doctors’ records were used.

Direct evidence supporting a link between antioxidant nutrient intake and a protective effect on AMD needs to come from intervention trials (191), a number of which have been conducted in recent years (48,205–210). Currently, evidence as to the effectiveness of intervention with antioxidant vitamin and mineral supplementation on slowing AMD progression is dominated by the findings from one large randomized clinical trial, the AREDS (48,205). In this study, a modest beneficial effect (25% reduction) from antioxidant and zinc supplementation on progression to late AMD was observed in persons with moderate to relatively advanced AMD (48). Although the majority of intervention trials conducted so far were underpowered to detect small differences

(206–210), there is limited evidence at present suggesting that people with early AMD lesions should take supplements (190,205), despite commercial advertisements and preparations already available in the market. AREDS findings should only be applied with caution to appropriate at-risk patients (211,212).

Coffee and caffeine consumption have not been found to be associated with AMD risk (213).

FATTY ACIDS AND LIPIDS

The hypothesis behind the postulated association between cholesterol, dietary fat intake, and AMD is that AMD and cardiovascular disease may share some common risk factors (214) or share a similar pathogenesis like atherosclerosis and arteriosclerosis (215–218). In an experimental animal model, young transgenic mice fed a high-fat diet to achieve elevated plasma triglyceride and cholesterol levels, then exposed to nonphototoxic levels of blue-green light, showed a high frequency of developing basal laminar deposits (BLD) (219), an early degenerative change in RPE cells associated with risk of CNV (220).

An early case-control study conducted in the United Kingdom (221) found no difference between 65 AMD cases and 65 controls in plasma polyunsaturated acid content and erythrocyte phospholipids. In the Eye Disease Case-Control Study (148), elevated serum total cholesterol level was associated with an increased likelihood of neovascular AMD. Cross-sectional population-based data showed that a high intake of saturated fat and cholesterol was associated with an increased prevalence of early AMD in the BDES population (215), and that high intake of cholesterol was associated with an increased prevalence of late AMD in the BMES population (222). However, in the NHANES III (223) and the CHS (38) populations, no significant association between dietary fat intake and AMD prevalence was found.

Recently, in the older subsamples of the Nurses’ Health Study (NHS) and Health Professionals Follow-Up Study (HPFS) populations, Cho et al. (217) reported that a high total fat intake, including saturated, mono-unsaturated, and trans-unsaturated fats, were all associated with a modest, marginally significant increase in AMD risk. In two hospital-based samples, Seddon et al. (214,224) reported an increased risk for AMD progression in subjects with high intake of fat, including vegetable, monoand polyunsaturated fats. However, these associations could not be replicated in 5-yr incident analyses using BMES population data (unpublished data).

High intake of omega-3 fatty acids was associated with a reduced AMD risk in the Eye Disease Case-Control Study population (224). Regular consumption of fish has been consistently found to be associated with a reduced AMD prevalence (222) and incidence (unpublished data) in the BMES population, an observation consistent across different populations (214,217,224).

Use of cholesterol-lowering medications (statins) appeared to have an inverse association with AMD (225,226) in hospital-based clinical samples, but no significant protective effect on AMD prevalence (227) or incidence (43,228–230) was evident in analyses of large population-based samples.

Interpretation of findings from hospital-based case-control populations (214,224) and the NHS and HPFS (217) needs to consider possible indication bias, with changes in health behavior and diet occurring after the diagnosis of early AMD. Furthermore, people with high total fat dietary intakes are also more likely to have high intakes of all fat subtypes.

difference has been found for AMD incidence (45,50,67,71), although in the BMES population, women were (nonsignificantly) more likely to develop both early and late AMD (60), and in the BDES population, a similar trend was observed in the oldest old group (aged >75 yr) (67). Greater longevity in women could be a possible explanation for these observed, nonsignificant gender differences (19). Interestingly, in the LALES population (40,95), Hispanic men (12.3%) were significantly more likely than women (7.8%) to have early AMD, independent of other AMD risk factors (95). In the Hisayama study population (249), Japanese men (1.0%) were also much more likely to have late AMD than women (0.1%). The participation rate in the Hisayama Study, however, was relatively low (60.4%), so that a possible differential distribution of potential risk factors between participants and nonparticipants could have led to the huge observed gender difference in late AMD prevalence found in this study.

An association between exogenous estrogen exposure and AMD was postulated by investigators of the Eye Disease Case-Control Study Group based on findings from a hospital-based clinic sample (148). This hypothesis of an association between female hormones and AMD has been investigated in basic research (250,251) and supported by some, but not all, observational studies (252,253). Estrogen receptors have been found in human RPE cells (250). In laser-induced CNV mice models, estrogen supplementation appeared to increase the severity of CNV and was found to interact with macrophages (251). An inverse association between the prevalence of AMD and the duration of endogenous estrogen exposure (number of years between menarche and menopause) was observed in a nested case-control study of the baseline RS population (252) and in a cross-sectional analytic study of baseline BMES data (253), but not in the BDES (254) or in pooled data from the BDES, RS, and BMES studies (41). In the POLA study (255), no association was evident between hormone replacement therapy (HRT) and AMD prevalence in 1451 postmenopausal women aged 60 yr or older.

There have also been no longitudinal associations from population-based studies in support of the estrogen–AMD hypothesis (42,256). Findings from case-control studies in postmenopausal women (257,258) share these inconsistent findings. One study (257) lent support to the hypothesis that longer lifetime exposure to endogenous estrogen, or that exposure to exogenous estrogen (HRT) after menopause, is associated with a reduced likelihood of having advanced AMD, defined as grades 4 and 5 (level 4) using the AREDS classification system (47). Another study found no evidence in support of this hypothesis (258). An influence from selection and recall biases on these case-control study findings, however, cannot be ruled out. On the other hand, a possible role for estrogen interacting with other factors during the development of AMD also cannot be ruled out. A recent report from the Women’s Health Initiative (WHI) Study (357) showed that women who received conjugated equine estrogens combined with progestin for an average of 5 yr had a reduced prevalence of soft drusen and neovascular AMD.

Socio-Economic Factors

No biologically plausible mechanism supports a causal association between socioeconomic factors and AMD. However, socio-economic factors can serve as surrogates for other causal or noncausal factors. The AREDS reported a cross-sectional association between lower education level and AMD prevalence in this large, multisite clinic-based

study sample (259). In the BDES population, lower socio-economic status was not related to AMD in a cross-sectional analytic study of baseline data (260), but nonprofessional occupation was found to be related to the 5-yr incidence of early AMD (261). The inconsistency of these findings suggests that the positive associations found are likely to be the result of either chance, selection bias, or residual confounding effects from measured and unmeasured risk factors (95,158,187,261).

Systemic Factors

Cardiovascular Disease and Risk Factors

Many cardiovascular disease risk factors have also been suggested as potential risk factors for AMD. These include age (41,249,262), smoking (41,148–154,157–159), atherosclerosis (263), elevated blood pressure (153,158,249,264,265), elevated total cholesterol level (148), high body mass index (BMI) (158,266,267), alcohol consumption (170), and past history of cardiovascular diseases (91). These observations have led to the proposal that AMD and cardiovascular disease may share common etiologic pathways (19,148,218). Negative associations between AMD and cardiovascular risk factors from cross-sectional analytical studies have also been reported (38,159,267, 268). Longitudinal observational studies have provided support for a link between AMD progression or development and smoking (42,155,156,161,162), heavy drinking (163), high BMI (269,270), high pulse pressure (271–273) or elevated systolic blood pressure (272,273), atherosclerosis (273), elevated serum total cholesterol level (42), and hypertensive retinal vessel wall signs (274). However, longitudinal analytical findings of an association between high levels of serum high-density lipoprotein and increased AMD risk (272,275), and an inverse association between serum total cholesterol and incident neovascular AMD (42) run counter to the cardiovascular disease associations with these lipids. These observed lipid–AMD associations could also be caused by genetic influences or interaction with susceptibility gene variations (275). An association between AMD and cardiovascular mortality has also been reported (276,277).

Use of antihypertensive or cholesterol-lowering medications and low-dose aspirin has not been found to have a significant protective effect on AMD prevalence (227,278) or incidence (43,228–230,279) in large population-based samples.

Inflammatory Markers

Leukocytes were observed in CNV tissues from post mortem eyes with neovascular AMD (280). In laser-induced CNV mice models, macrophages have been shown to have a role in relation to the extent of choroidal neovascularization (281). The possibility that infectious agents may play a role in the pathogenesis of vascular diseases and AMD is partially attributed to the recognition that atherosclerosis is an inflammatory disease initiated by endothelial injury (282,283). Some inflammatory markers, such as high leukocyte count (268,284) and high plasma fibrinogen level (266), were found to be associated with AMD prevalence (266,268) and incidence (284) in the BDES and BMES. C-reactive protein was found to be significantly higher among patients with advanced AMD compared to controls in the AREDS (285). Recent reports (286,287) also suggest possible links between AMD and Chlamydia pneumoniae infection (286), neovascular AMD and prior cytomegalovirus infection (287), and neovascular AMD

and monocyte/macrophage activation status (288). Neither the BDES (358) nor BMES studies (unpublished data) could confirm the association between Chlamydia pneumoniae infection and AMD. These findings need further confirmation (283,289). Clarification is also needed regarding whether: (1) the inflammatory process or the infection is specific or nonspecific (283) in terms of the link to AMD etiology, as these infectious agents are known to cause chronic, persistent inflammation (283) or (2) the inflammation is an antecedent or a consequential phenomenon in the course of neovascular AMD.

Use of anti-inflammatory medications was not found to have a beneficial effect on AMD prevalence or incidence (279,290).

Hyperglycemia or Diabetes

There has been little evidence supporting an association between glycosylated hemoglobin, impaired fasting glucose, or presence of diabetes and AMD (276,291,292).

Ocular Factors

Cataract and AMD

Aside from the fact that cataract and AMD are both strongly age related, findings have been inconsistent for an association between cataract and AMD in case-control studies (158,232,248) and in population-based cross-sectional (245,293–296) or longitudinal studies (236), and no definite link can be confirmed between these two conditions. The positive associations between cataract and AMD found in case-control studies are likely the result of selection bias, a residual confounding effect or a chance finding (158).

Cataract Surgery and the Risk of AMD

Whether the risk of late AMD is increased in eyes after cataract surgery is a longstanding but unresolved clinical question. Early clinical case series reports suggested a link between AMD and cataract surgery (297–299). A report from post mortem eyes also suggested that neovascular AMD was more frequently observed in pseudophakic than phakic eyes (300). These case series, however, cannot exclude the possibility that subtle, unrecognized, new vessels existed before surgery.

In a small number of cases, Pollack et al. (301,302) carefully documented that the risk of AMD increased within 6 to 12 mo after surgery in cataract patients with bilateral, symmetric early AMD. Each patient had only one eye operated, where the fellow eye served as a control, and fluorescein angiography was performed preand postoperatively. In contrast, Armbrecht et al. (303) could not confirm such an observation between surgical and nonsurgical cataract patients. In addition to small sample size and possible selection bias, shortcomings of clinical case series also include that no randomization procedure was used to decide which patient or which eye should be operated. Doctors’ decisions could have been biased towards eyes or patients with worse vision. Hence the comparability of the operated and the nonoperated groups in these studies is likely to be low.

A recent report using pooled cross-sectional data from the SEE Project, the Proyecto VER, and the Baltimore Eye Survey (59) supported an association between prior cataract surgery (performed before baseline) and an increased prevalence of AMD. The

link was stronger among persons who had cataract surgery at least 5 yr earlier. The BDES longitudinal data have consistently indicated a link between cataract surgery prior to the baseline examination and the incidence of AMD after 5 (236) and 10 yr (304) (Fig. 5A,B). The increased AMD risk was around fourfold in pseudophakic compared to phakic eyes (Fig. 5B). Presence of AMD lesions at baseline was not significantly related to 5-yr incident cataract surgery in the BDES population (305).

Both the BDES and the BMES followed similar study protocols in diagnosing AMD, with all incident late-AMD cases confirmed using side-by-side grading and mutual cross-checking by investigators of the two studies. Pooled, longitudinal data from these two studies have shown an approx 10 times higher crude incidence of late AMD in operated compared to nonoperated eyes (306). The age-adjusted relative risk was around 4; after multivariable adjustment the increased odds for subsequent development of late AMD was between 3 to 5, a magnitude similar to the effect of smoking on AMD (Fig. 5A). Higher odds were observed in models that also adjusted for baseline early AMD status (306), suggesting that nonphakic eyes that developed late AMD did not have as much advanced early AMD at baseline as phakic eyes that developed late AMD.

Cataract surgery is currently the most commonly performed and most successful ophthalmic surgical procedure worldwide, with case numbers continuously increasing. In the BMES examination of two cross-sectional surveys, prevalence of cataract surgery increased by one-third over a mean 7-yr interval, from 6 to nearly 8%, in crosssectional population samples with a similar age range (307). The increase in surgical procedures was predominantly for the eldest old group (aged 80+ yr) and for second eyes (307). If the link between prior cataract surgery and higher risk of subsequent late AMD is confirmed, it is likely that AMD incidence will increase further, over and above the increase from population aging alone. Longitudinal cohort studies on cataract surgical patients are needed to answer this important, but still unresolved, clinical question. A few such studies are currently underway. Discussion of a possible higher risk of progression with patients who already have risk signs (unilateral late AMD or significant early signs bilaterally) by their doctors prior to cataract surgery is potentially important.

Refractive Errors

Previous case series (308), case-control studies (91,148,158,232,309,310), and population-based cross-sectional analyses (187,311,312) have indicated a possible link between hyperopia and AMD. However, apart from the RS (312), the majority of population-based longitudinal data do not support a link between refractive error and incident AMD (236,313,314). Without a biologically plausible mechanism (311,312), the previous positive findings of weak association could have been as a result of selection bias or chance findings (158).

IMPACT OF AMD

Vision-Related Quality of Life, Depression, and Other Disabilities

Links between AMD and visual impairment (1–11,315,316) and decreased scores on measures of vision-related quality of life (315,317,318) via impaired vision (317) are