Advertisement
Research Article

Elevated High-Density Lipoprotein Cholesterol and Age-Related Macular Degeneration: The Alienor Study

  • Audrey Cougnard-Grégoire mail,

    Audrey.Cougnard-Gregoire@isped.u-bordeaux2.fr

    Affiliations: Université de Bordeaux, Bordeaux, France, INSERM (Institut National de la Santé Et de la Recherche Médicale), ISPED (Institut de Santé Publique d’Épidémiologie et de Développement), Centre INSERM U897-Epidemiologie-Biostatistique, Bordeaux, France

    X
  • Marie-Noëlle Delyfer,

    Affiliations: Université de Bordeaux, Bordeaux, France, INSERM (Institut National de la Santé Et de la Recherche Médicale), ISPED (Institut de Santé Publique d’Épidémiologie et de Développement), Centre INSERM U897-Epidemiologie-Biostatistique, Bordeaux, France, Centre Hospitalier Universitaire (CHU) de Bordeaux, Service d’Ophtalmologie, Bordeaux, France

    X
  • Jean-François Korobelnik,

    Affiliations: Université de Bordeaux, Bordeaux, France, INSERM (Institut National de la Santé Et de la Recherche Médicale), ISPED (Institut de Santé Publique d’Épidémiologie et de Développement), Centre INSERM U897-Epidemiologie-Biostatistique, Bordeaux, France, Centre Hospitalier Universitaire (CHU) de Bordeaux, Service d’Ophtalmologie, Bordeaux, France

    X
  • Marie-Bénédicte Rougier,

    Affiliation: Centre Hospitalier Universitaire (CHU) de Bordeaux, Service d’Ophtalmologie, Bordeaux, France

    X
  • Mélanie Le Goff,

    Affiliations: Université de Bordeaux, Bordeaux, France, INSERM (Institut National de la Santé Et de la Recherche Médicale), ISPED (Institut de Santé Publique d’Épidémiologie et de Développement), Centre INSERM U897-Epidemiologie-Biostatistique, Bordeaux, France

    X
  • Jean-François Dartigues,

    Affiliations: Université de Bordeaux, Bordeaux, France, INSERM (Institut National de la Santé Et de la Recherche Médicale), ISPED (Institut de Santé Publique d’Épidémiologie et de Développement), Centre INSERM U897-Epidemiologie-Biostatistique, Bordeaux, France

    X
  • Pascale Barberger-Gateau,

    Affiliations: Université de Bordeaux, Bordeaux, France, INSERM (Institut National de la Santé Et de la Recherche Médicale), ISPED (Institut de Santé Publique d’Épidémiologie et de Développement), Centre INSERM U897-Epidemiologie-Biostatistique, Bordeaux, France

    X
  • Cécile Delcourt

    Affiliations: Université de Bordeaux, Bordeaux, France, INSERM (Institut National de la Santé Et de la Recherche Médicale), ISPED (Institut de Santé Publique d’Épidémiologie et de Développement), Centre INSERM U897-Epidemiologie-Biostatistique, Bordeaux, France

    X
  • Published: March 07, 2014
  • DOI: 10.1371/journal.pone.0090973

Abstract

Background

Lipid metabolism and particularly high-density lipoprotein (HDL) may be involved in the pathogenic mechanism of age-related macular degeneration (AMD). However, conflicting results have been reported in the associations of AMD with plasma HDL and other lipids, which may be confounded by the recently reported associations of AMD with HDL-related genes. We explored the association of AMD with plasma lipid levels and lipid-lowering medication use, taking into account most of HDL-related genes associated with AMD.

Methods

The Alienor study is a population-based study on age-related eye diseases performed in 963 elderly residents of Bordeaux (France). AMD was graded from non mydriatic color retinal photographs in three exclusive stages: no AMD (n = 430 subjects, 938 eyes); large soft distinct drusen and/or large soft indistinct drusen and/or reticular drusen and/or pigmentary abnormalities (early AMD, n = 176, 247); late AMD (n = 40, 61). Associations of AMD with plasma lipids (HDL, total cholesterol (TC), Low-density lipoprotein (LDL), and triglycerides (TG)) were estimated using Generalized Estimating Equation logistic regressions. Statistical analyses included 646 subjects with complete data.

Results

After multivariate adjustment for age, sex, educational level, smoking, BMI, lipid-lowering medication use, cardiovascular disease and diabetes, and for all relevant genetic polymorphisms (ApoE2, ApoE4, CFH Y402H, ARMS2 A69S, LIPC rs10468017, LIPC rs493258, LPL rs12678919, ABCA1 rs1883025 and CETP rs3764261), higher HDL was significantly associated with an increased risk of early (OR = 2.45, 95%CI: 1.54–3.90; P = 0.0002) and any AMD (OR = 2.29, 95%CI: 1.46–3.59; P = 0.0003). Association with late AMD was far from statistical significance (OR = 1.58, 95%CI: 0.48–5.17; p = 0.45). No associations were found for any stage of AMD with TC, LDL and TG levels, statin or fibrate drug use.

Conclusions

This study suggests that elderly patients with high HDL concentration may be at increased risk for AMD and, further, that HDL dysfunction might be implicated in AMD pathogenesis.

Introduction

Age-related macular degeneration (AMD) is the leading cause of blindness in high-income countries, and the third global cause of blindness in the world [1]. This disease affects 2.5 million subjects in Europe [2] and 1.75 million in the USA [3]. While the pathophysiology of AMD remains elusive, a number of risk factors, such as smoking, nutrition and several genetic polymorphisms have been evidenced [4]. The early stage of AMD is characterized by the presence of large and soft drusen (extracellular deposits, seen as yellow spots on the retina) and/or of pigmentary abnormalities. The later stages involve atrophy of the retinal pigment epithelium (RPE) (dry form) or the development of choroidal neovascularization (wet form).

With advancing age, there is a deposit of lipid particles in normal Bruch’s membrane (BrM) leading to the creation of a lipid wall, external to the RPE basal lamina, impairing nutrient exchange between the choriocapillaris and the RPE and compromising retinal function [5][8]. The observation that the location of the lipid wall was the same as and precedes the basal linear deposits and drusen suggested its contribution to drusen formation [6], [8]. Indeed, lipids (both esterified and unesterified cholesterol, and phosphatidylcholine) represent at least 40% of the volume of drusen [6], [9], [10].

Furthermore, within the genomic era, several lipid-related genes have been reported to be associated with AMD. The E4 allele of the Apolipoprotein E gene (ApoE4) is associated with a reduced risk for AMD, while the ApoE2 increases the risk for AMD [11], [12]. ApoE plays a key role in cholesterol metabolism [13] and is associated with macular pigment optical density [14]. Other genes present particularly in the high-density lipoprotein cholesterol (HDL) pathway as the hepatic lipase gene (LIPC) [15][22], the lipoprotein lipase gene (LPL) [15], [17], [18], the cholesterol ester transferase gene (CETP) [16], [17], [21] and the ABC-binding cassette A1 (ABCA1) gene [15][18], [21] have been shown to be associated with AMD in genome-wide association (GWAS) studies and have been confirmed in several epidemiological studies [21], [23], including the Alienor study [22].

These findings have led to the hypothesis that lipid metabolism and particularly HDL is involved in the pathogenic mechanism of AMD [6], [9], [24]. However, conflicting results have been reported with regard to the associations of AMD with serum HDL concentration. An increasing number of studies reported higher risk for AMD among subjects with elevated HDL [25][31], few others reported a reduced risk [32][34] and some others reported no significant associations [35][38].

Other associations between serum lipids such as total cholesterol (TC), low-density lipoprotein (LDL) and triglycerides (TG), and AMD have also been investigated with still conflicting findings. In 1992, the Eye Disease Case Control Study Group, reported a significant 4-fold increased risk for exudative AMD with the highest serum cholesterol concentration [39]. Since then, only five studies reported a significant increased risk of AMD with high level of total cholesterol [23], [33], [40][42], while 13 reported no significant association [26], [27], [30], [32], [34][38], [43][46], and two an inverse relationship [47], [48].

Recently, Ebrahimi et al suggested that before excluding the role of systemic lipids in AMD, the role of plasma lipids in the context of genotype could be examined to identify predisposition in a subset of patients at risk for AMD due to genotype and plasma lipid levels [24].

Thus, the aim of this study was to explore the association between plasma lipid levels, lipid-lowering drug use and AMD, taking into account most of HDL-related genes associated with AMD, in the framework of a population-based study.

Subjects and Methods

Study Purpose

The Alienor (Antioxydants, LIpids Essentiels, Nutrition et maladies OculaiRes) Study is a population-based study aimed at assessing the associations of age-related eye diseases (AMD, glaucoma, cataract, dry eye syndrome) with nutritional factors (in particular antioxidants, macular pigment, and fatty acids), determined from plasma measurements and estimations of dietary intake [49]. It also takes into account other major determinants of eye disease, including gene polymorphisms, lifestyle and vascular factors.

Study Sample

Subjects of the Alienor Study were recruited from an ongoing population-based study (Three-City [3C] Study) on the vascular risk factors for dementia [50]. The 3C Study included 9294 subjects aged 65 years and older from three French cities (Bordeaux, Dijon, Montpellier), among whom 2104 were recruited in Bordeaux. Subjects were contacted individually from the electoral rolls. They were initially recruited in 1999 to 2001 and were followed-up about every 2 years since baseline (Figure 1). Data collected at each examination included cognitive testing with diagnoses of dementia and assessment of vascular risk factors. In addition, fasting blood and DNA samples were collected at baseline and kept frozen at −80°C.

thumbnail

Figure 1. Design of the Alienor study.

Abbreviations: AMD: age-related macular degeneration.

doi:10.1371/journal.pone.0090973.g001

The Alienor Study consisted in an eye examination, which was proposed to all participants of the third follow-up (2006–2008) of the 3C cohort in Bordeaux. Among the 1450 alive participants re-examined in 2006 to 2008, 963 (66.4%) participated in the Alienor Study, and 487 (33.6%) declined participation. Detailed characteristics of participants and nonparticipants have been published elsewhere [49].

This research followed the tenets of the Declaration of Helsinki. Participants gave written consent for participation in the study. The design of the Alienor Study has been approved by the Ethical Committee of Bordeaux (Comite de Protection des Personnes Sud-Ouest et Outre-Mer III) in May 2006.

Eye Examination

The eye examination took place in the Department of Ophthalmology of the University Hospital of Bordeaux, France. It included a recording of ophthalmological history, measures of visual acuity, refraction, two 45° nonmydriatic color retinal photographs (one centered on the macula, the other centered on the optic disc), measures of intraocular pressure and central corneal thickness, and break-up time test. A self-completed questionnaire on risk factors specific to the eye and dry eye symptoms was completed at home and brought back on the day of the eye examination.

Retinal photographs were performed using a nonmydriatic retinograph (TRC NW6S; Topcon, Tokyo, Japan) and were interpreted in duplicate by two specially trained technicians. Inconsistencies between the two interpretations were adjudicated by a retina specialist for classification of AMD and other retinal diseases and by a glaucoma specialist for classification of glaucoma. All cases of late AMD, other retinal diseases, and glaucoma were reviewed and confirmed by specialists.

Classification of AMD

Retinal photographs were interpreted according to the international classification [51] and to a modification of the grading scheme used in the Multi-Ethnic Study of Atherosclerosis for drusen size, location, and area [52]. Late AMD was defined by the presence of neovascular AMD or geographic atrophy within the grid (3000 µm from the foveola). Neovascular AMD included serous or hemorrhagic detachment of the retinal pigment epithelium (RPE) or sensory retina, subretinal or sub-RPE hemorrhages, and fibrous scar tissue. Geographic atrophy was defined as a discrete area of retinal depigmentation, 175 µm in diameter or larger, characterized by a sharp border and the presence of visible choroidal vessels. Five cases of late AMD had no gradable photographs and were classified by ophthalmological history of AMD and AMD therapy (in particular, antiangiogenic agents and photodynamic therapy) and confirmed by their treating ophthalmologist. Early AMD was defined by the presence of soft distinct drusen and/or soft indistinct drusen and/or reticular drusen and/or pigmentary abnormalities. Soft distinct and soft indistinct drusen were larger than 125 µm in diameter and had, respectively, uniform density and sharp edges or decreasing density from the center outward and fuzzy edges. Pigmentary abnormalities were defined as areas of hyperpigmentation and/or hypopigmentation (without visibility of choroidal vessels). Eyes were classified according to 3 exclusive groups: no AMD, early AMD, late AMD.

Plasma Lipids Measurements

Plasma measurements were determined from fasting blood samples collected at the 3C baseline visit (1999–2001) into heparinized evacuated tubes and centrifuged at 1000 g for 10 min. Plasma lipids (TC, LDL, HDL, and TG) were measured at the Biochemistry Laboratory of the University Hospital of Dijon.

Lipid Lowering Medications

The clinical baseline (from 1999 to 2001) and follow-up examinations (1st follow-up examination from 2001 to 2002; 2nd follow-up examination from 2003 to 2004 and 3rd follow-up examination from 2006 to 2007) included an inventory of all drugs used during the preceding month. Medical prescriptions and, where feasible, the medications themselves were seen by the interviewer. The name of the medication was recorded, and all drugs were subsequently coded according to the French translation of the world health organization (WHO) anatomical therapeutic chemical (ATC) classification [53]. Three classes of lipid-lowering medications were defined according to the ATC classification: 1) Statins (ATC codes: C10AA; C10BA; C10BX); 2) Fibrates (ATC codes: C10AB); 3) Others (ATC codes: C10AC; C10AD; C10AX). Lipid-lowering medication use was defined as the use of at least one of the preceding classes of drugs between the baseline and the last follow-up.

Other Variables

The following potential confounders have been selected based on literature results reporting significant associations of AMD or serum lipid concentrations with age, gender, educational level, smoking, body mass index (BMI), hypertension, cardiovascular disease, diabetes, Complement Factor H (CFH) Y402H (rs1061170), Age-Related Maculopathy Susceptibility 2 (ARMS2, rs10490924) A69S, apolipoproteins E2 (ApoE2) and E4 (ApoE4), LIPC (rs10468017), LIPC (rs493258), LPL (rs12678919), ABCA1 (rs1883025) and CETP (rs3764261) polymorphisms.

Data were collected during a face-to-face interview using a standardized questionnaire administered by a trained psychologist or nurse. At baseline, general data included: demographic characteristics, educational level and smoking. BMI (kg/m2) was calculated as weight/height2 using weight and height measured at baseline. Two separate measures of blood pressure in a seated position were performed in all participants. The first blood pressure measurement was recorded at the beginning of the interview and the second one at the end, using a digital electronic tensiometer (OMRON M4, France). The average systolic blood pressure (SBP) was the average of these two SBP measures. The same calculation was made for the average diastolic blood pressure (DBP). Hypertension was defined as average SBP≥140 mmHg and/or average DBP≥90 mmHg and/or antihypertensive medication use at baseline examination.

Genetic polymorphisms were determined by the Lille Génopôle, from the DNA samples collected at baseline (1999–2001). The included genetic factors have been shown to be very strong predictors of risk for AMD and/or cardiovascular disease in previous studies, including the Alienor Study [19], [54][56].

Statistical Analyses

Associations of baseline demographic, behavioural, anthropometric, medical and genetic characteristics with plasma lipid concentrations, statin and fibrate drug use were examined with Student test, Analysis of variance (ANOVA), and Chi-square test, as appropriate.

Associations of early and late AMD with plasma lipid variables, statin and fibrate drug use were estimated using logistic Generalized Estimating Equation (GEE) models, taking into account the data from both eyes and their intra-individual correlation. [57] In all analyses, subjects without any AMD were considered as the reference group.

GEE models for plasma lipids, statin and fibrate drug use were adjusted first for age and gender only (Model 1); in Model 2 we performed additional adjustment for educational level (no education or primary school or short secondary school vs. long secondary school or high school or university), smoking (never, 1 to less than 20 pack-years, 20 pack-years or more), BMI (kg/m2, <25, [25][30], ≥30), hypertension, cardiovascular disease, diabetes (Fasting glycemia ≥6.1 mmol/L or nonfasting glycemia ≥11.0 mmol/l or antidiabetic medication) and for lipid-lowering medications (at one examination or more), for plasma lipid concentrations; and for HDL, LDL and TG, only for statin and fibrate drug use. Finally, Model 3 was adjusted with all previous variables and genetic risk factors (ApoE2, ApoE4, CFH Y402H, ARMS2 A69S, LIPC rs10468017, LIPC rs493258, LPL rs12678919, ABCA1 rs1883025 and CETP rs3764261 polymorphisms).

Potential interactions between plasma lipid levels and lipid-lowering medication use and between plasma lipid levels and genetic polymorphisms were assessed. Lipid-lowering medications use and genetic polymorphisms were introduced in the models one by one. We withdrew interaction terms when not statistically significant (P>0.05).

False positive results are a critical concern when a number of association tests are performed. To address this issue, we applied Bonferroni correction to correct for multiple testing.

All statistical analyses were performed using SAS version 9.2 (SAS Institute Inc, Cary, NC; procedure GENMOD for the GEE analysis).

Results

Among the 963 subjects of the ALIENOR study, subjects were aged 80.2 years on average and the proportion of women was 61.9%. Among the 963 subjects, 84 (8.7%) subjects had ungradable photographs in both eyes and 54 (5.6%) had missing data for plasma lipid measurement and/or lipid-lowering drug use. Thus the statistical analyses were conducted on 825 subjects (85.7%) corresponding to 1595 eyes.

Table 1 presents the plasma lipid concentrations and lipid lowering drug use of the ALIENOR subjects according to AMD status. HDL was higher in early and late AMD cases, while there were no differences for TC, LDL or TG. No associations were found for use of statin or fibrates.

thumbnail

Table 1. Plasma lipid levels and statin and fibrate drug use according to AMD status, in subjects of the Alienor study (N = 825).

doi:10.1371/journal.pone.0090973.t001

Tables 2 and 3 present the associations of plasma lipids and lipid lowering medications with genetic polymorphisms. After Bonferroni correction (P = 0.0055), subjects with at least one Apo E2 allele had lower mean level of TC and LDL and higher mean level of TG than those with no Apo E2 allele. Subjects with at least one Apo E4 allele used significantly more statins than subjects with no ApoE4 allele. For CETP rs3764261, subjects with AA genotype had significantly higher mean level of HDL than subjects with CC or AC genotypes. No associations were found between ApoE4, CFH Y402H, ARMS2 A69S, LIPC rs493258, LIPC rs10468017, ABCA1 rs1883025 polymorphisms and plasma lipid levels. No associations were found between CFH Y402H, ARMS2 A69S, LIPC rs493258, LIPC rs10468017, LPL, ABCA1 and CETP polymorphisms and statin and fibrate drug use.

thumbnail

Table 2. Plasma lipid levels according to genetic characteristics in subjects of the Alienor study (N = 825).

doi:10.1371/journal.pone.0090973.t002
thumbnail

Table 3. Statin and fibrate drug use according to genetic characteristics in subjects of the Alienor study (N = 825).

doi:10.1371/journal.pone.0090973.t003

Associations with baseline demographic, behavioural and anthropometric characteristics and plasma lipid concentrations are presented in Table S1 in File S1. After Bonferroni correction (P = 0.0083), TC and HDL were significantly higher in women, never smokers and subjects with lower BMI. TG was significantly higher in smokers and subjects with higher BMI. No associations were found for LDL, Statin and Fibrates use (Table S1 in File S1). With regard to medical characteristics at baseline, after Bonferroni correction (P<0.017), TC and LDL were significantly higher in the absence of cardiovascular disease, HDL was higher in the absence of cardiovascular disease, hypertension or diabetes, and TG was higher in the presence of cardiovascular disease, hypertension or diabetes (Table S2 in File S1). Statin use was significantly associated with the presence of cardiovascular disease, hypertension and diabetes, and having higher levels of LDL and TG and lower level of HDL. No such associations were found for use of fibrates (Tables S2 and S3 in File S1).

Table 4 presents association of AMD with plasma lipids levels, statin and fibrate drug use. After adjustment for age and sex (model 1) and Bonferroni correction (P = 0.0125), higher HDL was significantly associated with an increased risk of early and any AMD (OR ranging from 1.77–1.84 per 1 mmol/L, P values ranging from 0.0008–0.003). HDL was associated with late AMD (OR = 2.41, P = 0.04) with a P value<0.05, but did not remained significant after Bonferroni correction. No associations were found for any stage of AMD with TC, LDL and TG concentrations, or statin and fibrate drug use.

thumbnail

Table 4. Associations of AMD with plasma lipids levels in the Alienor study (odds-ratios (OR) and [95% confidence interval (CI)] for 1 mmol/L increase).

doi:10.1371/journal.pone.0090973.t004

After further adjustment for educational level, smoking, BMI, lipid-lowering medication use, cardiovascular disease and diabetes, higher HDL remained significantly associated with an increased risk of early (OR = 1.71, P = 0.008) or any AMD (OR = 1.83, P = 0.002) and tended to be associated with increased risk of late AMD, but did not reach statistical significance (OR = 2.58, P = 0.06) especially after Bonferroni correction. No associations were found for any stage of AMD with TC, LDL and TG levels and statin and fibrate drug use.

After further adjustment for all relevant genetic polymorphisms (apoE2, ApoE4, CFH Y402H, ARMS2 A69S, LIPC rs10468017, LIPC rs493258, LPL rs12678919, ABCA1 rs1883025 and CETP rs3764261), higher HDL remained significantly associated with an increased risk of early (OR = 2.45, P = 0.0002) or any AMD (OR = 2.29, P = 0.0003). Association with late AMD was far from statistical significance (OR = 1.58, p = 0.45). No associations were found for any stage of AMD with TC, LDL and TG levels and statin and fibrate drug use (Table 5).

thumbnail

Table 5. Associations of AMD with statin and fibrate drug use in the Alienor study (odds-ratios (OR) and [95% confidence interval (CI)] for 1 mmol/L increase).

doi:10.1371/journal.pone.0090973.t005

No significant interactions were found between plasma lipid levels and genetic polymorphisms, or between plasma lipid levels and lipid-lowering medication use, with regard to the risk for AMD, suggesting that genetic background and use of lipid-lowering medication do not modify the association of plasma lipid levels with AMD (data not shown).

Discussion

In the present study, after full adjustment, elevated HDL was significantly associated with an increased risk of any and early AMD, independent of many potential confounders, including the major genetic polymorphisms involved in the risk for AMD. Results for late AMD were in the same direction, but far from statistical significance. No associations were found for any stage of AMD with other plasma lipids as well as statin or fibrate drug use.

Our results are consistent with findings of several previous studies which did not adjust for genetic polymorphisms. In cross-sectional studies, high HDL concentration was associated with early AMD in the Beaver Dam study [28]; with soft drusen in the POLA study [26] and with AMD in the Oklahoma Indians population AMD [25]. In a case-control study, Hyman et al reported a positive association between HDL and neovascular AMD (OR of highest quintile vs. lowest quintile serum HDL, 2.3; 95%CI, 1.1–4.7) [27]. In the prospective Rotterdam study, HDL was associated with an increased incidence of any AMD [31]. In the Beaver Dam study, higher HDL at baseline was associated with the 10 year incidence of geographic atrophy (RR per 10 mg/dl HDL cholesterol, 1.29; 95% CI, 1.05–1.58; P = 0.01) [30].

Data from other studies have been inconsistent regarding the association between HDL and AMD. In the Blue Mountains Eye Study, there was no significant cross-sectional association of HDL with geographic atrophy (OR: 0.82; 95%CI: 0.19–3.46), or exudative macular degeneration (OR: 1.73; 95%CI: 0.83–3.62) [37], whereas elevated HDL was associated with a decreased 5-years incidence of late AMD (RR per standard deviation increase, 0.74; 95% CI, 0.56–0.99) [34]. In the Beaver Dam study Offspring study, higher HDL was associated with lower risk of early AMD (OR per 5 mg.dl:0.91, 95%CI: 0.83–0.998) [32]. In a case control study, Nowak et al found a significant decrease of HDL concentration in AMD patients in comparison with controls, supported by the findings of Reynolds et al. where elevated HDL was associated with a reduced risk of late AMD (P<0.05), especially for the neovascular form (P = 0.03) [23], [33]. The pooled data from the Beaver Dam, the Blue Mountains and the Rotterdam studies showed no significant associations between HDL and incident AMD [38]. The cross sectional study of the Singapore Malay Eye Study (SiMES) found no significant associations between HDL and early (OR per mmol/l: 1.14; 95%CI: 0.72–1.82) or late AMD (OR per mmol/l: 0.42; 95%CI: 0.10–1.80) [35]. Similarly, a meta-analysis did not report significant associations between HDL and late AMD for prospective cohort studies (RR: 1.00; 95%CI: 0.97–1.02) as well as cross sectional studies (OR: 1.06; 95%CI: 0.80–1.39) or case-control study (RR: 3.35; 95%CI: 0.92–12.23) [36].

In the present study, no statistically significant associations of AMD with TC, LDL or TG were found. Findings on cholesterol have been inconsistent in the literature. Some studies reported that elevated total cholesterol concentration was associated with an increased risk of AMD [23], [33], [39][42]. In contrast, few studies found a significant inverse relation between total serum cholesterol and AMD [47], [48] while numerous other studies reported no significant association [26], [27], [30], [32], [35], [36], [43][45]. Few studies reported an increased risk of AMD with high level of LDL [23], [33], [38], [58] and TG [58].

We found no association between statin or fibrate drug use and AMD. In the literature, the association between the use of cholesterol-lowering medications and AMD has been intensively studied. Again, the results have been inconsistent. Several studies suggested a protective effect of statins use on the AMD risk [59][66] while many others reported either no protective effect [26], [40], [67][75] or even further a potential deleterious role [76], [77]. Finally, recent reviews reported that available data on RCT or prospective studies are insufficient to conclude that statins exhibit any role in preventing or delaying the onset or progression of AMD [78], [79].

The reasons underlying these inconsistencies are not clearly understood. A difficulty in the interpretation of the positive relationship between elevated HDL and AMD is that plasma lipids concentrations may not reflect tissue-specific effects. Indeed, results obtained with multiple biochemical, histochemical, and ultrastructural methods, mainly performed by Cristina Curcio’s team, suggest that RPE secretes apolipoprotein B (ApoB)-lipoprotein particles of unusual composition into BrM, where they accumulate with age eventually forming a lipid wall that is a precursor of basal linear deposit [9], [24]. In addition, an accumulation of oxidized ApoB100 lipoproteins in BrM, drusen and basal deposits have been observed in AMD. In atherosclerosis, the oxidation of ApoB100 lipoproteins lead to mainly innate immune system-mediated inflammation which initiates a cascade of pathological events ending with the formation of atherosclerotic plaques [24]. Thus, the oxidized ApoB100 in BrM have been suggested to initiate inflammation, innate immune response and drusen formation sharing with the “response to retention” hypothesis of atherosclerosis [24]. In this hypothesis, the retention of cholesterol-rich, atherogenic lipoproteins provokes a cascade of responses that lead to disease in a previously non-lesional artery. Similarly, it has been suggested that in AMD, the retention of a sub-endothelial apolipoprotein B may lead to the formation of AMD lesion [24]. However, this theory does not exclude the potential contribution of lipoprotein synthesized in the liver or in intestine transported by bloodstream [10].

The increasing number of studies associating high HDL with increased risk for AMD suggests the possibility of a real relationship between high HDL and AMD, which might be due to a dysfunction of HDL. Recent findings on strategies to reduce cardiovascular risk turned attention to HDL quality (the HDL functional capability such as anti-oxidative, anti-inflammatory, anti-apoptotic, anti-infectious or anti-thrombotic functions of HDL) rather than quantity. Some studies suggested that plasma HDL concentrations do not predict functionality and composition of HDL [80] and may be a potential factor of conflicting results in the literature [81]. Indeed, HDL are highly heterogeneous in structure (density, size, charge and protein) and biologic function [80]. The anti-oxidant and anti-inflammatory activities of HDL can become ineffective due to inflammation and other factors such as myeloperoxidase-mediated oxidation. Consequently, HDL may turn into dysfunctional, pro-inflammatory and pro-oxidant particles that promote LDL oxidation and impair cholesterol efflux and reverse cholesterol transport [80], [81]. Thus, recent studies suggested that testing functionality, composition (such as concentration of HDL subfractions) and anti-inflammatory properties of HDL will be better markers than testing plasma HDL concentration for identifying subjects at risk for coronary heart disease [81], [82]. Briefly, HDL subclasses can be classified by their density (HDL2, HDL3), their size (2a, 2b, 3a, 3b, 3c) their charge (pre-β, α, pre-α) and their main apolipoprotein content (apoA-I or both apoA1 and apoA-II) [81]. Under dyslipidaemic conditions, changes in HDL subfraction levels and functions are currently observed. HDL2 and more particularly HDL2b seem to be more predictive of coronary heart disease risk than HDL or HDL3 [81]. Accordingly, it has been reported that, HDL2b levels are lower in subjects with coronary artery disease compared to healthy subjects and inversely related to disease severity and progression of coronary lesions. Furthermore, the concentration of pre-β-particles has been found to increase in subjects with coronary artery and heart diseases and with myocardial infarction. Inversely, the levels of large α1- and pre-α particles have been reported to decrease in subjects with coronary heart disease in comparison with healthy subjects [81]. To our knowledge, no such studies have been conducted in the field of AMD.

One strength of the present study is that major potential confounding factors were taken into account, including socio-demographic status, factors related to vascular diseases, use of lipid-lowering medications and the major genetic polymorphisms. Indeed, regarding genetic polymorphism, GWAS studies of AMD identified new loci that were associated with blood lipids and particularly HDL levels [83], [84]. Most of the variants discovered affected blood lipid levels and are also associated with coronary artery disease [84]. In the present study, the association of AMD with HDL remained significant after taking these polymorphisms into account and no interactions of HDL concentration with genetic polymorphisms were identified.

One limitation of our study could come from the representativeness of the sample. The Alienor subsample tends to over-represent younger subjects and high socioeconomic status, among subjects participating to the 3C Study [49]. The individuals included in this study may accordingly be healthier and present different lifestyles, mainly concerning their diet and physical activity, in comparison with the general population. The distribution of vascular characteristics or the prevalence of eye diseases may have been affected due to these differences. However, participants from the 3C Study which were included in the Alienor study were not different from those who were not included for most parameters of interest in our study [49]. Moreover, as described previously [49], the age- and gender-specific prevalence rates of AMD in the Alienor study were similar to those observed in other studies performed in Europe [2], [85] and other industrialized countries [3]. Data collection was performed in the same way in all individuals irrespective of their AMD stage and photograph graders had no access to data related to plasma lipids, or any other cardiovascular or genetic characteristics. Consequently, we can assume that the error was not differential and was unlikely to have biased the estimation of any of the associations of AMD with vascular parameters.

Another limitation of our study is the relatively small number of late AMD cases, which may have induced insufficient statistical power for detecting some associations with serum lipids concentrations (in particular for HDL, which presented a tendency to an increased risk for late AMD, but did not reach statistical significance).

Lastly, a potential limitation is the high number of comparisons performed. Therefore, we cannot exclude that some of the observed associations were due to chance finding. However, we adjusted for this by using Bonferroni correction with many associations remaining highly significant. In addition our findings are mostly consistent with previous studies in this field.

In conclusion, our results suggest that elderly patients with high HDL concentration may be at increased risk for AMD. This association might reflect HDL dysfunction in AMD. In accordance with the field of cardiovascular diseases, epidemiological studies are needed on the associations of AMD with HDL subfractions and functions, in order to better understand the potential role of lipid metabolism, and in particular of cholesterol reverse transport, in AMD.

Supporting Information

File S1.

Tables. Table S1, Plasma lipid levels and statin and fibrate drug use according to baseline demographic, behavioural and anthropometric characteristics, in subjects of the Alienor study (N = 825); Table S2, Plasma lipid levels and statin and fibrate drug use according to baseline medical characteristics, in subjects of the Alienor study (N = 825); Table S3, Plasma lipid levels according to statin and fibrate drug use, in subjects of the Alienor study (N = 825).

doi:10.1371/journal.pone.0090973.s001

(DOCX)

Author Contributions

Conceived and designed the experiments: MND JFK MBR JFD PBG CD. Performed the experiments: MND JFK MBR JFD PBG CD. Analyzed the data: ACG MLG CD. Contributed reagents/materials/analysis tools: MND JFK MBR JFD PBG CD. Wrote the paper: ACG CD. Revised the manuscript for important intellectual content: MND JFK MBR MLG JFD PBG CD.

References

  1. 1. Resnikoff S, Pascolini D, Etya’ale D, Kocur I, Pararajasegaram R, et al. (2004) Global data on visual impairment in the year 2002. Bull World Health Organ 82: 844–851.
  2. 2. Augood CA, Vingerling JR, de Jong PT, Chakravarthy U, Seland J, et al. (2006) Prevalence of age-related maculopathy in older Europeans: the European Eye Study (EUREYE). Arch Ophthalmol 124: 529–535. doi: 10.1001/archopht.124.4.529
  3. 3. Friedman DS, O’Colmain BJ, Munoz B, Tomany SC, McCarty C, et al. (2004) Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 122: 564–572. doi: 10.1001/archopht.122.4.564
  4. 4. Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY (2012) Age-related macular degeneration. Lancet 379: 1728–1738. doi: 10.1016/s0140-6736(12)60282-7
  5. 5. Bretillon L, Acar N, Seeliger MW, Santos M, Maire MA, et al. (2008) ApoB100,LDLR−/− mice exhibit reduced electroretinographic response and cholesteryl esters deposits in the retina. Invest Ophthalmol Vis Sci 49: 1307–1314. doi: 10.1167/iovs.07-0808
  6. 6. Curcio CA, Johnson M, Rudolf M, Huang JD (2011) The oil spill in ageing Bruch membrane. Br J Ophthalmol 95: 1638–1645. doi: 10.1136/bjophthalmol-2011-300344
  7. 7. Fliesler SJ, Bretillon L (2010) The ins and outs of cholesterol in the vertebrate retina. J Lipid Res 51: 3399–3413. doi: 10.1194/jlr.r010538
  8. 8. Kishan AU, Modjtahedi BS, Martins EN, Modjtahedi SP, Morse LS (2011) Lipids and age-related macular degeneration. Surv Ophthalmol 56: 195–213. doi: 10.1016/j.survophthal.2010.08.008
  9. 9. Curcio CA, Johnson M, Huang JD, Rudolf M (2010) Apolipoprotein B-containing lipoproteins in retinal aging and age-related macular degeneration. J Lipid Res 51: 451–467. doi: 10.1194/jlr.r002238
  10. 10. Wang L, Clark ME, Crossman DK, Kojima K, Messinger JD, et al. (2010) Abundant lipid and protein components of drusen. PLoS One 5: e10329. doi: 10.1371/journal.pone.0010329
  11. 11. Souied EH, Benlian P, Amouyel P, Feingold J, Lagarde JP, et al. (1998) The epsilon4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration. Am J Ophthalmol 125: 353–359. doi: 10.1016/s0002-9394(99)80146-9
  12. 12. Thakkinstian A, Bowe S, McEvoy M, Smith W, Attia J (2006) Association between apolipoprotein E polymorphisms and age-related macular degeneration: A HuGE review and meta-analysis. Am J Epidemiol 164: 813–822. doi: 10.1093/aje/kwj279
  13. 13. Mahley RW, Rall SC Jr (2000) Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1: 507–537. doi: 10.1146/annurev.genom.1.1.507
  14. 14. Loane E, McKay GJ, Nolan JM, Beatty S (2010) Apolipoprotein E genotype is associated with macular pigment optical density. Invest Ophthalmol Vis Sci 51: 2636–2643. doi: 10.1167/iovs.09-4397
  15. 15. Chen W, Stambolian D, Edwards AO, Branham KE, Othman M, et al. (2010) Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci U S A 107: 7401–7406.
  16. 16. Conley YP, Thalamuthu A, Jakobsdottir J, Weeks DE, Mah T, et al. (2005) Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy. Hum Mol Genet 14: 1991–2002. doi: 10.1093/hmg/ddi204
  17. 17. Kanda A, Chen W, Othman M, Branham KE, Brooks M, et al. (2007) A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc Natl Acad Sci U S A 104: 16227–16232. doi: 10.1073/pnas.0703933104
  18. 18. Neale BM, Fagerness J, Reynolds R, Sobrin L, Parker M, et al. (2010) Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci U S A 107: 7395–7400. doi: 10.1073/pnas.0912019107
  19. 19. Scholl HP, Fleckenstein M, Charbel Issa P, Keilhauer C, Holz FG, et al. (2007) An update on the genetics of age-related macular degeneration. Mol Vis 13: 196–205. doi: 10.1007/978-3-540-33672-3_3
  20. 20. Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, et al. (2007) Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 357: 553–561. doi: 10.1056/nejmoa072618
  21. 21. Yu Y, Reynolds R, Fagerness J, Rosner B, Daly MJ, et al. (2011) Association of variants in the LIPC and ABCA1 genes with intermediate and large drusen and advanced age-related macular degeneration. Invest Ophthalmol Vis Sci 52: 4663–4670. doi: 10.1167/iovs.10-7070
  22. 22. Merle BM, Maubaret C, Korobelnik JF, Delyfer MN, Rougier MB, et al. Association of HDL-related loci with age-related macular degeneration and plasma lutein and zeaxanthin: the Alienor Study. PLoS One in press.
  23. 23. Reynolds R, Rosner B, Seddon JM (2010) Serum lipid biomarkers and hepatic lipase gene associations with age-related macular degeneration. Ophthalmology 117: 1989–1995. doi: 10.1016/j.ophtha.2010.07.009
  24. 24. Ebrahimi KB, Handa JT (2011) Lipids, lipoproteins, and age-related macular degeneration. J Lipids 2011: 802059. doi: 10.1155/2011/802059
  25. 25. Butt AL, Lee ET, Klein R, Russell D, Ogola G, et al. (2011) Prevalence and risks factors of age-related macular degeneration in Oklahoma Indians: the Vision Keepers Study. Ophthalmology 118: 1380–1385. doi: 10.1016/j.ophtha.2010.11.007
  26. 26. Delcourt C, Michel F, Colvez A, Lacroux A, Delage M, et al. (2001) Associations of cardiovascular disease and its risk factors with age-related macular degeneration: the POLA study. Ophthalmic Epidemiol 8: 237–249. doi: 10.1076/opep.8.4.237.1613
  27. 27. Hyman L, Schachat AP, He Q, Leske MC (2000) Hypertension, cardiovascular disease, and age-related macular degeneration. Age-Related Macular Degeneration Risk Factors Study Group. Arch Ophthalmol 118: 351–358. doi: 10.1001/archopht.118.3.351
  28. 28. Klein R, Klein BE, Franke T (1993) The relationship of cardiovascular disease and its risk factors to age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology 100: 406–414. doi: 10.1016/s0161-6420(93)31634-9
  29. 29. Klein R, Klein BE, Jensen SC (1997) The relation of cardiovascular disease and its risk factors to the 5-year incidence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 104: 1804–1812. doi: 10.1016/s0161-6420(97)30023-2
  30. 30. Klein R, Klein BE, Tomany SC, Cruickshanks KJ (2003) The association of cardiovascular disease with the long-term incidence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 110: 1273–1280. doi: 10.1016/s0161-6420(03)00599-2
  31. 31. van Leeuwen R, Klaver CC, Vingerling JR, Hofman A, van Duijn CM, et al. (2004) Cholesterol and age-related macular degeneration: is there a link? Am J Ophthalmol 137: 750–752. doi: 10.1016/j.ajo.2003.09.015
  32. 32. Klein R, Cruickshanks KJ, Nash SD, Krantz EM, Nieto FJ, et al. (2010) The prevalence of age-related macular degeneration and associated risk factors. Arch Ophthalmol 128: 750–758. doi: 10.1001/archophthalmol.2010.92
  33. 33. Nowak M, Swietochowska E, Marek B, Szapska B, Wielkoszynski T, et al. (2005) Changes in lipid metabolism in women with age-related macular degeneration. Clin Exp Med 4: 183–187. doi: 10.1007/s10238-004-0054-z
  34. 34. Tan JS, Mitchell P, Smith W, Wang JJ (2007) Cardiovascular risk factors and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Ophthalmology 114: 1143–1150. doi: 10.1016/j.ophtha.2006.09.033
  35. 35. Cackett P, Wong TY, Aung T, Saw SM, Tay WT, et al. (2008) Smoking, cardiovascular risk factors, and age-related macular degeneration in Asians: the Singapore Malay Eye Study. Am J Ophthalmol 146: 960–967 e961.
  36. 36. Chakravarthy U, Wong TY, Fletcher A, Piault E, Evans C, et al. (2010) Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis. BMC Ophthalmol 10: 31. doi: 10.1186/1471-2415-10-31
  37. 37. Smith W, Mitchell P, Leeder SR, Wang JJ (1998) Plasma fibrinogen levels, other cardiovascular risk factors, and age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 116: 583–587. doi: 10.1001/archopht.116.5.583
  38. 38. Tomany SC, Wang JJ, Van Leeuwen R, Klein R, Mitchell P, et al. (2004) Risk factors for incident age-related macular degeneration: pooled findings from 3 continents. Ophthalmology 111: 1280–1287. doi: 10.1016/j.ophtha.2003.11.010
  39. 39. The Eye Disease Case-Control study-Goup (1992) Risk factors for neovascular age-related macular degeneration. The Eye Disease Case-Control Study Group. Arch Ophthalmol 110: 1701–1708. doi: 10.1001/archopht.1992.01080240041025
  40. 40. Hogg RE, Woodside JV, Gilchrist SE, Graydon R, Fletcher AE, et al. (2008) Cardiovascular disease and hypertension are strong risk factors for choroidal neovascularization. Ophthalmology 115: 1046–1052 e1042.
  41. 41. Mitchell P, Wang JJ, Foran S, Smith W (2002) Five-year incidence of age-related maculopathy lesions: the Blue Mountains Eye Study. Ophthalmology 109: 1092–1097. doi: 10.1016/s0161-6420(02)01055-2
  42. 42. Ulas F, Balbaba M, Ozmen S, Celebi S, Dogan U (2013) Association of dehydroepiandrosterone sulfate, serum lipids, C-reactive protein and body mass index with age-related macular degeneration. Int Ophthalmol.
  43. 43. Buch H (2005) Fourteen-year incidence of age-related maculopathy and cause-specific prevalence of visual impairment and blindness in a Caucasian population: the Copenhagen City Eye Study. Acta Ophthalmol Scand 83: 400–401. doi: 10.1111/j.1600-0420.2005.00474.x
  44. 44. Blumenkranz MS, Russell SR, Robey MG, Kott-Blumenkranz R, Penneys N (1986) Risk factors in age-related maculopathy complicated by choroidal neovascularization. Ophthalmology 93: 552–558. doi: 10.1016/s0161-6420(86)33702-3
  45. 45. Sanders TA, Haines AP, Wormald R, Wright LA, Obeid O (1993) Essential fatty acids, plasma cholesterol, and fat-soluble vitamins in subjects with age-related maculopathy and matched control subjects. Am J Clin Nutr 57: 428–433.
  46. 46. Tsang NC, Penfold PL, Snitch PJ, Billson F (1992) Serum levels of antioxidants and age-related macular degeneration. Doc Ophthalmol 81: 387–400. doi: 10.1007/bf00169100
  47. 47. Klein R, Clegg L, Cooper LS, Hubbard LD, Klein BE, et al. (1999) Prevalence of age-related maculopathy in the Atherosclerosis Risk in Communities Study. Arch Ophthalmol 117: 1203–1210. doi: 10.1001/archopht.117.9.1203
  48. 48. Klein R, Klein BE, Marino EK, Kuller LH, Furberg C, et al. (2003) Early age-related maculopathy in the cardiovascular health study. Ophthalmology 110: 25–33. doi: 10.1016/s0161-6420(02)01565-8
  49. 49. Delcourt C, Korobelnik JF, Barberger-Gateau P, Delyfer MN, Rougier MB, et al. (2010) Nutrition and age-related eye diseases: the ALIENOR (Antioxydants, Lipides Essentiels, Nutrition et maladies OculaiRes) Study. Journal Nutr Health Aging 14(10): 854–861. doi: 10.1007/s12603-010-0131-9
  50. 50. 3C Study Group (2003) Vascular factors and risk of dementia: design of the Three-City Study and baseline characteristics of the study population. Neuroepidemiology 22: 316–325. doi: 10.1159/000072920
  51. 51. Bird AC, Bressler NM, Bressler SB, Chisholm IH, Coscas G, et al. (1995) An international classification and grading system for age-related maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group. Surv Ophthalmol 39: 367–374. doi: 10.1016/s0039-6257(05)80092-x
  52. 52. Klein R, Klein BE, Knudtson MD, Wong TY, Cotch MF, et al. (2006) Prevalence of age-related macular degeneration in 4 racial/ethnic groups in the multi-ethnic study of atherosclerosis. Ophthalmology 113: 373–380. doi: 10.1016/j.ophtha.2005.12.013
  53. 53. Centre National Hospitalier d’Information sur le Médicament(CNHIM). Theriaque Web site. Available: https://www.theriaque.org. Accessed February 1, 2013.
  54. 54. Baird PN, Richardson AJ, Robman LD, Dimitrov PN, Tikellis G, et al. (2006) Apolipoprotein (APOE) gene is associated with progression of age-related macular degeneration (AMD). Hum Mutat 27: 337–342. doi: 10.1002/humu.20288
  55. 55. Delcourt C, Delyfer MN, Rougier MB, Amouyel P, Colin J, et al. (2011) Associations of Complement Factor H and smoking with early age-related macular degeneration: the ALIENOR study. Invest Ophthalmol Vis Sci.
  56. 56. Seddon JM, Francis PJ, George S, Schultz DW, Rosner B, et al. (2007) Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. JAMA 297: 1793–1800. doi: 10.1001/jama.297.16.1793
  57. 57. Zeger SL, Liang KY, Albert PS (1988) Models for longitudinal data: a generalized estimating equation approach. Biometrics 44: 1049–1060. doi: 10.2307/2531734
  58. 58. Davari MH, Gheitasi H, Yaghobi G, Heydari B (2012) Correlation between Serum Lipids and Age-related Macular Degeneration: A Case-Control Study. J Res Health Sci 13: 98–101.
  59. 59. Hall NF, Martyn CN (2002) Could statins prevent age-related macular degeneration? Expert Opin Pharmacother 3: 803–807. doi: 10.1517/14656566.3.7.803
  60. 60. McCarty CA, Mukesh BN, Guymer RH, Baird PN, Taylor HR (2001) Cholesterol-lowering medications reduce the risk of age-related maculopathy progression. Med J Aust 175: 340.
  61. 61. Wilson HL, Schwartz DM, Bhatt HR, McCulloch CE, Duncan JL (2004) Statin and aspirin therapy are associated with decreased rates of choroidal neovascularization among patients with age-related macular degeneration. Am J Ophthalmol 137: 615–624. doi: 10.1016/j.ajo.2003.10.025
  62. 62. McGwin G Jr, Owsley C, Curcio CA, Crain RJ (2003) The association between statin use and age related maculopathy. Br J Ophthalmol 87: 1121–1125. doi: 10.1136/bjo.87.9.1121
  63. 63. Friedman E, Rigas IK, Makar K (2005) The relationship of statin use to the development of age-related macular degeneration. IOVS 46: 199.
  64. 64. McGwin G Jr, Xie A, Owsley C (2005) The use of cholesterol-lowering medications and age-related macular degeneration. Ophthalmology 112: 488–494. doi: 10.1016/j.ophtha.2004.10.027
  65. 65. Tan JS, Mitchell P, Rochtchina E, Wang JJ (2007) Statins and the long-term risk of incident age-related macular degeneration: the Blue Mountains Eye Study. Am J Ophthalmol 143: 685–687. doi: 10.1016/j.ajo.2006.11.021
  66. 66. Drobek-Slowik M, Karczewicz D, Safranow K, Jakubowska K, Chlubek D (2008) [Use of statins as a form of protection against age-related macular degeneration (AMD)]. Klin Oczna 110: 50–54.
  67. 67. Klein R, Klein BE, Jensen SC, Cruickshanks KJ, Lee KE, et al. (2001) Medication use and the 5-year incidence of early age-related maculopathy: the Beaver Dam Eye Study. Arch Ophthalmol 119: 1354–1359. doi: 10.1001/archopht.119.9.1354
  68. 68. Klein R, Klein BE, Tomany SC, Danforth LG, Cruickshanks KJ (2003) Relation of statin use to the 5-year incidence and progression of age-related maculopathy. Arch Ophthalmol 121: 1151–1155. doi: 10.1001/archopht.121.8.1151
  69. 69. van Leeuwen R, Vingerling JR, Hofman A, de Jong PT, Stricker BH (2003) Cholesterol lowering drugs and risk of age related maculopathy: prospective cohort study with cumulative exposure measurement. BMJ 326: 255–256. doi: 10.1136/bmj.326.7383.255
  70. 70. Smeeth L, Cook C, Chakravarthy U, Hubbard R, Fletcher AE (2005) A case control study of age related macular degeneration and use of statins. Br J Ophthalmol 89: 1171–1175. doi: 10.1136/bjo.2004.064477
  71. 71. McGwin G Jr, Modjarrad K, Hall TA, Xie A, Owsley C (2006) 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors and the presence of age-related macular degeneration in the Cardiovascular Health Study. Arch Ophthalmol 124: 33–37. doi: 10.1001/archopht.124.1.33
  72. 72. Klein R, Knudtson MD, Klein BE (2007) Statin use and the five-year incidence and progression of age-related macular degeneration. Am J Ophthalmol 144: 1–6. doi: 10.1016/j.ajo.2007.02.047
  73. 73. Kaiserman N, Vinker S, Kaiserman I (2009) Statins do not decrease the risk for wet age-related macular degeneration. Curr Eye Res 34: 304–310. doi: 10.1080/02713680902741670
  74. 74. Maguire MG, Ying GS, McCannel CA, Liu C, Dai Y (2009) Statin use and the incidence of advanced age-related macular degeneration in the Complications of Age-related Macular Degeneration Prevention Trial. Ophthalmology 116: 2381–2385. doi: 10.1016/j.ophtha.2009.06.055
  75. 75. Shalev V, Sror M, Goldshtein I, Kokia E, Chodick G (2011) Statin use and the risk of age related macular degeneration in a large health organization in Israel. Ophthalmic Epidemiol 18: 83–90. doi: 10.1016/j.jval.2011.02.305
  76. 76. Etminan M, Brophy JM, Maberley D (2008) Use of statins and angiotensin converting enzyme inhibitors (ACE-Is) and the risk of age-related macular degeneration: nested case-control study. Curr Drug Saf 3: 24–26. doi: 10.2174/157488608783333952
  77. 77. VanderBeek BL, Zacks DN, Talwar N, Nan B, Stein JD (2013) Role of statins in the development and progression of age-related macular degeneration. Retina 33: 414–422. doi: 10.1097/iae.0b013e318276e0cf
  78. 78. Peponis V, Chalkiadakis SE, Bonovas S, Sitaras NM (2010) The controversy over the association between statins use and progression of age-related macular degeneration: a mini review. Clin Ophthalmol 4: 865–869. doi: 10.2147/opth.s12869
  79. 79. Gehlbach P, Li T, Hatef E (2012) Statins for age-related macular degeneration. Cochrane Database Syst Rev 3: CD006927. doi: 10.1002/14651858.cd006927.pub3
  80. 80. G HB, Rao VS, Kakkar VV (2011) Friend Turns Foe: Transformation of Anti-Inflammatory HDL to Proinflammatory HDL during Acute-Phase Response. Cholesterol 2011: 274629. doi: 10.1155/2011/274629
  81. 81. Eren E, Yilmaz N, Aydin O (2012) High Density Lipoprotein and it’s Dysfunction. Open Biochem J 6: 78–93. doi: 10.2174/1874091x01206010078
  82. 82. Fisher EA, Feig JE, Hewing B, Hazen SL, Smith JD (2012) High-density lipoprotein function, dysfunction, and reverse cholesterol transport. Arterioscler Thromb Vasc Biol 32: 2813–2820. doi: 10.1161/atvbaha.112.300133
  83. 83. Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, et al. (2009) Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 41: 56–65. doi: 10.1038/ng.291
  84. 84. Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, et al. (2010) Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466: 707–713.
  85. 85. Vingerling JR, Dielemans I, Hofman A, Grobbee DE, Hijmering M, et al. (1995) The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology 102: 205–210. doi: 10.1016/s0161-6420(95)31034-2