Lipids, Lipid Genes, and Incident Age-Related Macular Degeneration: The Three Continent Age-Related Macular Degeneration Consortium




Purpose


To describe associations of serum lipid levels and lipid pathway genes to the incidence of age-related macular degeneration (AMD).


Design


Meta-analysis.


Methods


setting : Three population-based cohorts. population : A total of 6950 participants from the Beaver Dam Eye Study (BDES), Blue Mountains Eye Study (BMES), and Rotterdam Study (RS). observation procedures : Participants were followed over 20 years and examined at 5-year intervals. Hazard ratios associated with lipid levels per standard deviation above the mean or associated with each additional risk allele for each lipid pathway gene were calculated using random-effects inverse-weighted meta-analysis models, adjusting for known AMD risk factors. main outcome measures : Incidence of AMD.


Results


The average 5-year incidences of early AMD were 8.1%, 15.1%, and 13.0% in the BDES, BMES, and RS, respectively. Substantial heterogeneity in the effect of cholesterol and lipid pathway genes on the incidence and progression of AMD was evident when the data from the 3 studies were combined in meta-analysis. After correction for multiple comparisons, we did not find a statistically significant association between any of the cholesterol measures, statin use, or serum lipid genes and any of the AMD outcomes in the meta-analysis.


Conclusion


In a meta-analysis, there were no associations of cholesterol measures, history of statin use, or lipid pathway genes to the incidence and progression of AMD. These findings add to inconsistencies in earlier reports from our studies and others showing weak associations, no associations, or inverse associations of high-density lipoprotein cholesterol and total cholesterol with AMD.


One of the functions of the retinal pigment epithelium (RPE) is to digest the lipid-rich photoreceptor outer segments shed each day. Some residual lipids deposit in the Bruch membrane as lipoproteins. These deposits increase with age and have been hypothesized to increase the risk of age-related macular degeneration (AMD), an important cause of severe visual impairment in older people. The lipoprotein particles in the Bruch membrane contain free and esterfied cholesterol thought not to be derived from the plasma. The finding of lipids in retinal drusen and the associations of a number of candidate genes involving lipid metabolism (eg, hepatic lipase gene [ LIPC ], cholesteryl ester transfer protein [ CETP ], apolipoprotein E [ APOE ], and lipoprotein lipase [ LPL ]) with AMD provide further support of a role of lipids in the pathogenesis of AMD.


However, epidemiologic data have been inconsistent regarding the associations of serum lipid levels and AMD. Few of these studies have examined the associations of both serum lipids and candidate lipid pathway genes for AMD and their interactions with the incidence and progression of AMD. The purpose of this report is to examine the associations of serum high-density lipoprotein cholesterol (HDL-C) and total cholesterol levels, lipid pathway genes, and history of statin use with the incidence and progression of AMD in meta-analyses of findings from 3 large population-based cohort studies within the Three Continent AMD Consortium, the Beaver Dam Eye Study (BDES), the Blue Mountains Eye Study (BMES), and the Rotterdam Study (RS).


Methods


Populations


The current study extends previous pooled data analyses or meta-analyses of baseline and 5-year follow-up data from the 3 population-based studies to assess risk factors associated with prevalent and incident AMD. Methods used in the BDES, the BMES, and the RS, and descriptions of the 3 populations, have been previously reported. The second RS examination occurred approximately 2 years after baseline and 3 years before the third follow-up examination. To correspond with the 5-year spacing in the BDES and BMES, data from the second RS examination were not included in analyses and future RS examinations 3–5 were renumbered as 2–4 for these analyses. Approvals for each study and for the Three Continent AMD Consortium projects were granted by the Institutional Review Boards at all 3 study sites. Informed consent was obtained from each participant before every examination of each study. The tenets of the Declaration of Helsinki were observed.


Serum lipid levels were measured at the first 3 examination phases of each study. The incidence of AMD and AMD lesions was examined over the first 3 examination intervals. The timing of each examination phase, the number of participants at risk for AMD, and the median follow-up time to the next examination are presented for each study in Table 1 .



Table 1

Timing of the Examination Phases, Number of Persons at Risk for Incident Age-Related Macular Degeneration, and Median Follow-up Time From the Three Continent Age-Related Macular Degeneration Consortium




















































Study Baseline Examination Second Examination Third Examination
Years N at Risk Median Follow-up Time (y) Years N at Risk Median Follow-up Time (y) Years N at Risk Median Follow-up Time (y)
BDES 1988–1990 2230 4.8 1993–1995 1644 5.3 1998–2000 1248 4.8
BMES 1992–1994 1595 4.9 1997–1999 1115 5.2 2002–2004 613 5.2
RS 1990–1993 3128 6.4 1997–1999 2109 4.5 2000–2004 1096 6.6

BDES = Beaver Dam Eye Study; BMES = Blue Mountains Eye Study; RS = Rotterdam Study.


Of the 4926 participants at the BDES baseline examination, the following were excluded: 162 because photographs of both eyes were not gradable for AMD, 62 because cholesterol was not measured, 1250 because the individual died or was lost to follow-up, 3 because data on statin use were not available, and 1222 because genotype data were not available. This left 2227 individuals eligible for analyses.


Of the 3654 participants at the BMES baseline examination, the following were excluded: 175 because photographs of both eyes were not gradable for AMD, 360 because cholesterol was not measured, 1042 because the individual died or was lost to follow-up, and 482 because genotype data were not available. This left 1595 individuals eligible for analyses.


Of the 5232 participants in the RS baseline examination, the following were excluded: 47 because photographs of both eyes were not gradable for AMD, 1589 because the individual died or was lost to follow-up, and 468 because genotype data were not available. This left 3128 individuals eligible for analyses.


In total, there were 14 778 person-visits from 6950 individuals over a 23-year period (approximately 15 years of follow-up for each study). More than 99% of the participants in the 3 studies were white. In general, individuals who participated in follow-up examinations were more likely to be younger than nonparticipants who were alive or individuals who died and, while adjusting for age, were less likely to have AMD.


Procedures


Similar procedures were used at baseline and follow-up examinations. A standardized interview and examination were administered at each visit. Information on demographic characteristics; history of diabetes, myocardial infarction (MI), stroke, and angina; and a current history of hypertension, physical activity, smoking, and use of lipid-lowering drugs by type were obtained from the questionnaire. Body weight, height, and blood pressure were measured in all studies.


Casual blood specimens were obtained at the time of each examination in the BDES and at the RS baseline examination, and fasting blood specimens were obtained at all BMES and the RS follow-up examinations. In the BDES, serum was used to measure total and HDL-C levels. Serum total cholesterol and HDL-C levels at each of the 4 visits were measured by reflectance spectrophotometry. In the BMES, fasting blood specimens were drawn, centrifuged on site, and then sent by courier within the same day to the Westmead Hospital, Sydney, for hematologic analysis and clinical biochemistry assessment. Serum total cholesterol and HDL-C were measured on a Reflotron reflectance photometric analyzer (Boehringer Mannheim Diagnostics, currently Roche Diagnostics, Indianapolis, Indiana, USA). In the RS, blood was drawn directly into Vacutainer tubes (BD Biosciences, Heidelberg, Germany) and nonfasting serum total cholesterol and HDL-C concentrations were measured according to the CHOD-PAP method (Monotest Cholesterol kit; Boehringer Mannheim Diagnostics, Basel, Switzerland). Fasting serum total cholesterol and HDL-C concentrations were measured with a Roche Hitachi 917 (Roche Diagnostics) until April 2007. From April 2007 onward, parameters were measured with a Roche Modular P800 (Roche Diagnostics).


Definitions


In all 3 studies, body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Presence of hypertension was defined as systolic blood pressure >140 mm Hg and/or diastolic blood pressure >90 mm Hg and/or antihypertensive medication use. Smoking status was categorized as current (defined as having smoked ≥100 cigarettes in one’s lifetime and still smoking at the time of the examination) or not current. A current history of cardiovascular disease was defined as a current history of MI, stroke, or angina.


In each analysis, the risk allele for each single nucleotide polymorphism (SNP) was defined as the minor allele. The minor allele was the same for all 3 studies for all of the SNPs assessed. The risk alleles for CETP (16q21) rs3764261 and rs1864163, ABCA1 (9q31.1) rs1883025, LIPC (15q21–q23) rs7163555, and LPL (8p22) rs281 were “A,” “A,” “T,” “G,” and “T,” respectively.


In the BDES, participants were asked to bring all current medications to the examination and medication names were recorded by a trained examiner. Statin use was defined as currently taking a medication with an active ingredient identified as a statin. Information on dosing and duration of use were not recorded. In the BMES, participants were asked to bring their medications when they attended the study examinations and the interviewer recorded names of the medications during the face-to-face interview. Some participants brought a list of their medications instead of actual medications. Statin use was defined as currently taking a medication with an active ingredient identified as a statin. In the RS, a home interview took place before every examination at which all medication names were recorded by a trained examiner. Statin use was defined as currently taking a medication with an active ingredient identified as a statin.


Analysts for each of the 3 studies were in regular contact to ensure that common definitions of risk factors and covariates were used. In some cases, covariates could not be harmonized because of differences in the questions asked by each study at each examination phase. When this occurred, we did not adjust for these variables when modeling but presented data for these factors in Table 2 . For example, in the BDES, a participant was considered physically active if he or she worked up a sweat at least once a week; in the BMES, if he or she did vigorous exercise in the past 2 weeks; and in the RS, if he or she participated in sports (this was asked only at the third RS examination). All 3 studies asked participants about a history of MI at every visit. Both the BDES and BMES asked questions about history of stroke and angina at each examination phase. The RS asked about a history of stroke at the baseline examination but only about a history of transient ischemic attack or “mini-stroke” at the follow-up visits, and did not ask a question about a history of angina.



Table 2

Characteristics at the Baseline Examinations of Participants Included in Analyses From the Three Continent Age-Related Macular Degeneration Consortium
































































































































































































































































































































































































































Risk Factor BDES 1988–1990 (N = 2227) BMES 1992–1994 (N = 1595) RS 1990–1993 (N = 3128) P Value a
% or Mean ± SD Median (IQR) Min−Max % or Mean ± SD Median (IQR) Min−Max % or Mean ± SD Median (IQR) Min−Max
Age, y 59.7 ± 10.1 59.0 (16.0) 43.0–86.0 63.8 ± 8.1 64.0 (12.0) 49.0–91.0 65.8 ± 6.9 65.0 (10.1) 55.1–95.1 <.0001
Sex, male 43.8 42.8 56.3 <.0001
Hypertension present 46.7 69.1 50.1 <.0001
Currently smoking 19.3 12.1 21.9 <.0001
Diabetes present 8.4 6.0 6.8 .0001
Pulse pressure, mm Hg 52.2 ± 16.1 50.0 (21.0) 16.0–121.0 61.1 ± 16.3 60.0 (20.0) 25.0–152.0 65.2 ± 17.7 64.0 (24.0) 20.0–157.0 <.0001
Currently physically active 26.9 50.7 <.0001
Body mass index, kg/m² 28.6 ± 5.3 27.9 (6.3) 15.0–68.4 26.2 ± 4.1 25.8 (4.9) 15.2–49.5 26.3 ± 3.5 25.9 (4.3) 16.4–44.2 <.0001
Total cholesterol, mg/dL 232.7 ± 42.8 230.0 (54.0) 102.0–503.0 234.2 ± 40.8 232.0 (50.3) 116.0–491.1 258.2 ± 45.8 255.2 (58.0) 108.3–696.1 <.0001
HDL-C, mg/dL 53.2 ± 17.9 50.0 (23.0) 8.0–143.0 55.8 ± 16.7 54.1 (23.2) 15.5–143.1 52.3 ± 14.0 50.3 (19.3) 15.5–243.6 <.0001
Non-HDL-C, mg/dL 179.6 ± 44.7 177.0 (56.0) 56.0–447.0 178.4 ± 42.4 174.0 (50.3) 69.6–448.6 205.9 ± 46.4 201.1 (58.0) 19.3–653.5 <.0001
Total/HDL-C ratio 4.9 ± 1.9 4.6 (2.2) 1.6–34.4 4.5 ± 1.5 4.3 (2.0) 1.6–12.9 5.3 ± 1.6 5.0 (2.0) 1.1–22.8 <.0001
Using statins 0.6 3.3 2.8 <.0001
History of MI present 4.9 7.4 8.3 .006
History of angina present 8.6 10.4 .96
History of stroke present 2.2 2.8 2.1 .10
History of CVD present 11.3 15.1 .20
% MAF IQS % MAF IQS % MAF IQS P Value a
CETP rs3764261 genotype 1.00 1.00 .21
A/C 44.5 0.32 45.4 0.32 43.2 0.33
A/A 11.0 Typed 9.5 Imputed 10.6 Imputed
CETP rs1864163 genotype 1.00 1.00 .07
A/G 36.7 0.25 36.6 0.25 37.2 0.25
A/A 5.6 Typed 6.3 Imputed 6.5 Imputed
ABCA1 rs1883025 genotype 0.98 0.98 0.94 .33
C/T 37.9 0.24 37.7 0.25 38.8 0.25
T/T 5.6 Imputed 5.9 Imputed 6.3 Imputed
LIPC rs7163555 genotype 0.98 1.00 .48
G/T 22.7 0.13 22.9 0.13 20.9 0.12
G/G 1.6 Typed 1.3 Imputed 1.5 Imputed
LPL rs281 genotype 0.87 0.92 0.90 <.0001
T/A 44.2 0.31 33.3 0.21 42.9 0.31
T/T 9.2 Imputed 4.2 Imputed 9.0 Imputed

ABCA1 = adenosine triphosphate-binding cassette transporter 1; AMD = age-related macular degeneration; BDES = Beaver Dam Eye Study; BMES = Blue Mountains Eye Study; CETP = cholesteryl ester transfer protein; CVD = cardiovascular disease; HDL-C = high-density lipoprotein cholesterol; IQR = interquartile range; IQS = imputation quality score; LIPC = lipase C precursor; LPL = lipoprotein lipase; MAF = minor allele frequency; MI = myocardial infarction; Min-Max = minimum-maximum; RS = Rotterdam Study.

a For any difference among studies; adjusted for age and sex.



Table 3

Differences in Characteristics at Baseline Between Individuals Included and Excluded in the Cohorts From the Three Continent Age-Related Macular Degeneration Consortium
























































































































































































































Risk Factor Included (N = 6950) Excluded for Missing Genotype (N = 2172) P Value a Excluded for Other Reasons (N = 4690) P Value b P Value c
% or Mean ± SD % or Mean ± SD % or Mean ± SD
Age, y 63.4 ± 8.7 62.5 ± 9.9 .01 69.2 ± 10.6 <.0001 <.0001
Serum total cholesterol, mg/dL 244.5 ± 45.5 239.6 ± 45.2 .53 242.6 ± 47.6 .69 .65
Serum HDL cholesterol, mg/dL 53.4 ± 16.0 52.8 ± 16.5 .01 52.3 ± 16.7 <.0001 .31
Serum non-HDL cholesterol, mg/dL 191.1 ± 46.9 186.8 ± 46.4 .16 190.3 ± 48.2 .37 .97
Serum total/HDL cholesterol ratio 4.96 ± 1.7 4.95 ± 1.7 .03 5.1 ± 1.8 <.0001 .10
Hypertension present 53.4 53.7 .47 65.6 <.0001 .06
Pulse pressure, mm Hg 60.0 ± 17.9 57.9 ± 18.1 .10 64.3 ± 19.0 .29 .65
Body mass index, kg/m² 27.0 ± 4.4 28.0 ± 5.2 <.0001 26.9 ± 4.8 .03 .11
Sex, male 43.5 41.6 .19 39.6 .43 .01
Diabetes present 7.1 8.5 .18 13.8 <.0001 <.0001
Currently smoking 18.8 18.2 .61 21.0 <.0001 <.0001
History of myocardial infarction present 7.0 6.7 .57 10.6 .00 .01
History of angina present d 9.3 9.7 .65 15.0 .00 .01
History of stroke present d 2.4 3.3 .05 5.5 <.0001 .01
History of cardiovascular disease present d 12.8 13.8 .28 24.1 <.0001 <.0001
Currently physically active d 36.7 29.4 <.0001 26.1 <.0001 <.0001
Prevalent early AMD 15.8 16.9 .51 19.1 .11 .16
Prevalent large drusen area 5.3 4.4 .71 7.1 .86 .52
Prevalent large soft indistinct drusen 8.7 9.2 .84 10.2 .02 .01
Prevalent pigmentary abnormality 9.0 9.5 .57 12.0 .96 .92
CETP rs3764261, ≥1 A risk allele present 54.6 54.4 .40
CETP rs1864163, ≥1 A risk allele present 43.0 45.0 .14
ABCA1 rs1883025, ≥1 T risk allele present 44.2 46.0 .51
LIPC rs7163555, ≥1 G risk allele present 23.4 23.3 .65
LPL rs281, ≥1 T risk allele present 49.8 51.3 .94

ABCA1 = adenosine triphosphate-binding cassette transporter 1; AMD = age-related macular degeneration; CETP= cholesteryl ester transfer protein; HDL = high-density lipoprotein; LIPC = lipase C precursor; LPL = lipoprotein lipase; SD = standard deviation.

a For individuals excluded for missing genotype data vs individuals included, adjusting for age, sex, and study.


b For individuals excluded for reasons other than missing genetic data (both eyes ungradable for AMD, cholesterol not measured, statin use not recorded, or died/lost to follow-up) vs individuals included, adjusting for age, sex, and study.


c For individuals excluded for missing genotype data vs individuals excluded for other reasons, adjusting for age, sex, and study.


d Measured only in the Beaver Dam Eye Study and Blue Mountains Eye Study; N included = 3797, N excluded = 4688.



Genetic Measurements


All eligible BDES study participants were genotyped using Taqman assays (Applied Biosystems, Foster City, California, USA) and/or a custom Illumina Infinium Panel (Illumina Inc, San Diego, California, USA). In addition to the custom Illumina genotyping, we also genotyped 10 SNPs that are reported to be associated with AMD in 2 recent meta-analyses using the KASP assay (LCG Genomics, Teddington, Middlesex, UK). To maximize the number of markers, we imputed the untyped genotypes at 12 known AMD loci using the MACH program version 1 with HapMap CEU haplotypes (release #22) as the reference. Hardy-Weinberg equilibrium (HWE) tests were carried out for each SNP using PLINK and SNPs with HWE test P value less than 1 × 10 −5 among the controls were excluded from the study.


In the BMES, all eligible study participants were genotyped using an Illumina Human670-Quad v1 custom array at the Wellcome Trust Centre for Human Genetics, Sanger Institute, Cambridge, UK as part of the Wellcome Trust Case Control Consortium 2. A smaller subset of participants (n = 1356) was also independently genotyped using the Illumina 610-Quad genotyping array at the Hunter Medical Research Institute, Newcastle, Australia. Following quality control, the genotyped data were imputed from the 1000 Genomes (Version 1) reference using IMPUTE software. Genomic DNA was extracted from peripheral blood leukocytes. HWE tests were carried out and SNPs with P value less than 1 × 10 −6 were excluded.


All eligible study participants in the RS were genotyped with the Illumina Infinium II HumanHap550 array. HapMap CEU data (release #22) was used for imputation. During quality control the genotypes were checked twice for HWE: once after genotyping (HWE > 1 × 10 −7 ) and after imputation (HWE > 1 × 10 −6 ).


Fundus Photography and Grading


Details regarding fundus photography, grading, and harmonization of the phenotype are described elsewhere. The severity of AMD was determined using the Three Continent AMD severity scale (a modification of the 5-step BDES AMD Severity Scale).


Analyses were performed using data from the worse eye. When one eye was not gradable, it was assumed to have the same AMD level/lesions as the fellow eye. Eyes with late AMD were excluded from analyses of incident early AMD lesions. Early AMD was defined as the presence of small to intermediate-sized drusen (<125 μm in diameter), regardless of area of involvement, with any pigmentary abnormality; or large drusen (≥125 μm in diameter) with drusen area <331 820 μm² (equivalent to O-2 circle, defined as a circle with diameter of 650 μm) and with or without pigmentary abnormalities in the absence of late AMD. Large soft indistinct (SI) drusen were defined as the presence of SI drusen ≥125 μm in diameter. Large drusen area was defined as the presence of a total area of drusen in the macula ≥650 μm in diameter. A pigmentary abnormality was defined as the presence of increased retinal pigment or RPE depigmentation. Late AMD was defined as pure geographic atrophy in the absence of exudative macular degeneration; or exudative macular degeneration with or without geographic atrophy present. Exudative AMD was defined as the presence of exudative macular degeneration with or without geographic atrophy (GA) present.


The incidence of a specific AMD lesion or level was defined by its presence at follow-up when it was absent at all previous examinations.


Statistical Methods


We first examined the incidence of each AMD outcome and the association of serum lipids, statin use, and lipid pathway genes to the incidence of AMD in each cohort, separately adjusting for age, sex, BMI, history of smoking habits, diabetes, and hypertension. We further adjusted for statin use in the serum lipids models and adjusted for HDL-C in the statin use models. Serum lipid levels were standardized for each study by subtracting the population-specific mean and dividing by the standard deviation. Each AMD candidate gene SNP was examined using an additive model.


Incidence was modeled in each 5-year interval conditional upon being free of disease at all previous examinations. Serum lipids, statin use, AMD status, and other risk factors were updated at each examination. Associations of study factors with AMD outcomes were assessed using discrete-time hazard models using the complementary log-log link function. Heterogeneity was measured using the I 2 statistic. The results from each study were combined in a meta-analysis. Heterogeneity (>50%) was present in several meta-analysis models; therefore, we computed an overall hazard ratio (HR) using a random-effects inverse-weighted meta-analysis with the study indicator as the random effect variable. This model incorporates information about the sample size and variability in each study to more accurately reflect the amount of variability between the studies when calculating the overall HR and confidence interval for the meta-analysis. The same terms entered in the models for each individual study (cholesterol measure/statin use/genotype and covariates) were included in each meta-analysis model. Multiplicative interactions were tested for each SNP and serum lipid measure using product terms in models adjusting for age, sex, and other covariates. SAS software version 9.3 (SAS Institute, Cary, North Carolina, USA) was used for all analyses.


To be included in analyses, a participant must have had information on AMD level, serum lipids, statin use, and lipid genes available at baseline and at all consecutive follow-up examinations until the individual developed AMD or was censored.




Results


Characteristics of those included and excluded from the analyses are presented in Table 3 . Compared to those included, participants excluded owing to missing genotype data were younger and, after adjusting for age and sex, were more likely to have lower serum HDL-C and greater BMI, and were less likely to be physically active.


Compared to those included, individuals excluded owing to reasons other than missing genotype data (ie, ungradable AMD lesions in both eyes, missing data on cholesterol or statin use, death, or loss to follow-up) were older and, after adjusting for age and sex, had lower serum HDL-C; higher total/HDL-C ratio; higher frequencies of hypertension, diabetes, current smoking, MI, angina, and stroke; a higher frequency of prevalent large SI drusen; and a lower frequency of current physical activity. No other differences in the prevalence of early AMD or early AMD lesions were found between those included and those excluded.


Baseline characteristics of individuals included in analyses from each of the 3 studies are presented in Table 2 . There were statistically significant differences in age, sex, serum lipid measures, pulse pressure, BMI, and LPL genotype, as well as percentage of participants with hypertension, history of MI, and diabetes, and percentage of participants who were current smokers, using statins, and physically active among the 3 studies. Genotype distributions for the other AMD candidate gene SNPs were similar among the 3 studies.


Results From Individual Studies


The average incidence within each 5-year interval for early and late AMD and AMD lesions for each cohort are presented in Table 4 . While adjusting for age, there were statistically significant differences in the incidence of all AMD outcomes except for late AMD and exudative AMD across the 3 study populations.



Table 4

Five-year Incidence Averaged Over 15 Years of Follow-up for Age-Related Macular Degeneration Endpoints in the Three Continent Age-Related Macular Degeneration Consortium




















































Outcome BDES BMES RS P Value a
Early AMD 8.1 15.1 13.0 <.0001
Large soft indistinct drusen 3.3 6.3 8.6 <.0001
Large drusen area 3.7 4.5 8.6 <.0001
Any pigmentary abnormality 4.2 12.0 9.3 <.0001
Late AMD 1.2 1.7 1.7 .22
Pure geographic atrophy 0.6 0.8 0.7 .05
Exudative AMD 0.7 1.2 1.1 .24

AMD = age-related macular degeneration; BDES = Beaver Dam Eye Study; BMES = Blue Mountains Eye Study; RS = Rotterdam Study.

a For any difference among studies; adjusted for age and sex.



The associations of lipids, lipid pathway genes, and statins and the incidence of early and late AMD, SI drusen, large drusen area in the macula, pure GA, and exudative AMD, adjusting for age, sex, BMI, smoking status, hypertension, diabetes, history of MI, and history of statin use in each cohort, are presented in Table 5 . There were few associations among total cholesterol, HDL-C, total cholesterol/HDL-C ratio, and non-HDL-C and incident early AMD, SI drusen, large area of drusen, pigmentary abnormalities, late AMD, and exudative AMD. Associations of lipids with AMD outcomes were most frequent in the RS cohort (10 significant associations in the RS compared with 2 in the BDES and 0 in the BMES). Direct associations of HDL-C with incident pure GA were present in the BDES and RS cohorts but not in the BMES cohort. Use of statins was not associated with any incident AMD outcome in any of the cohorts.



Table 5

Associations of Lipid Levels and Lipid Genes to the Incidence of Age-Related Macular Degeneration Outcomes by Cohort and Overall Meta-analysis














































































































































































































































































































































































































































































































































































































































































































































































































































































































Outcome and Risk Factors BDES BMES RS Overall a
HR (95% CI) b P HR (95% CI) b P HR (95% CI) b P HR (95% CI) b P
Early AMD
Lipid measure c /statin use
Total cholesterol 1.01 (0.91, 1.13) .86 0.99 (0.89, 1.10) .86 0.87 (0.78, 0.97) .01 52.9 0.96 (0.87, 1.05) .33
HDL-C 0.98 (0.87, 1.11) .76 1.00 (0.89, 1.12) .99 1.13 (1.03, 1.25) .01 52.8 1.04 (0.95, 1.14) .39
Non-HDL-C 1.02 (0.91, 1.13) .78 0.99 (0.90, 1.10) .87 0.84 (0.76, 0.94) .002 70.7 0.95 (0.85, 1.06) .35
Total/HDL-C ratio 1.00 (0.89, 1.12) .99 0.99 (0.89, 1.10) .83 0.84 (0.75, 0.94) .002 67.1 0.94 (0.84, 1.05) .27
Statin use 0.89 (0.55, 1.42) .61 0.93 (0.64, 1.35) .69 1.02 (0.69, 1.52) .91 0.0 0.95 (0.75, 1.20) .66
SNP/risk allele
CETP rs3764261/A 1.04 (0.88, 1.23) .62 1.09 (0.94, 1.27) .25 1.05 (0.90, 1.21) .56 0.0 1.06 (0.97, 1.16) .19
CETP rs1864163/A 0.95 (0.79, 1.16) .63 0.95 (0.81, 1.12) .55 0.81 (0.68, 0.97) .02 5.0 0.90 (0.81, 1.00) .05
ABCA1 rs1883025/T 1.03 (0.84, 1.25) .79 1.07 (0.91, 1.25) .43 0.85 (0.72, 1.00) .06 51.4 0.98 (0.85, 1.13) .73
LIPC rs7163555/G 1.11 (0.89, 1.40) .36 1.03 (0.83, 1.27) .79 1.13 (0.92, 1.38) .25 0.0 1.09 (0.96, 1.23) .17
LPL rs281/T 0.99 (0.83, 1.19) .91 0.92 (0.74, 1.14) .43 0.95 (0.81, 1.10) .48 0.0 0.95 (0.86, 1.06) .36
Large soft indistinct drusen
Lipid measure c /statin use
Total cholesterol 1.01 (0.85, 1.19) .95 1.04 (0.89, 1.21) .65 1.00 (0.88, 1.13) .97 0.0 1.01 (0.93, 1.10) .81
HDL-C 0.99 (0.83, 1.19) .94 1.04 (0.90, 1.21) .59 1.10 (0.98, 1.24) .10 0.0 1.06 (0.98, 1.15) .15
Non-HDL-C 1.01 (0.86, 1.19) .90 1.02 (0.88, 1.18) .82 0.97 (0.86, 1.10) .61 0.0 0.99 (0.91, 1.08) .88
Total/HDL-C ratio 0.97 (0.81, 1.16) .71 0.96 (0.81, 1.12) .58 0.92 (0.81, 1.05) .23 0.0 0.94 (0.86, 1.03) .19
Statin use 1.13 (0.59, 2.18) .71 0.82 (0.48, 1.39) .46 1.10 (0.70, 1.71) .68 0.0 1.01 (0.74, 1.36) .97
SNP/risk allele
CETP rs3764261/A 1.04 (0.80, 1.35) .78 1.14 (0.92, 1.41) .23 0.91 (0.76, 1.09) .33 18.7 1.01 (0.88, 1.17) .84
CETP rs1864163/A 0.80 (0.58, 1.11) .18 0.95 (0.74, 1.20) .64 0.85 (0.70, 1.04) .10 0.0 0.87 (0.76, 1.00) .05
ABCA1 rs1883025/T 1.09 (0.81, 1.49) .57 1.00 (0.79, 1.28) .99 0.83 (0.69, 1.00) .05 30.7 0.94 (0.79, 1.11) .47
LIPC rs7163555/G 1.15 (0.81, 1.63) .44 0.97 (0.70, 1.34) .85 1.19 (0.94, 1.51) .15 0.0 1.12 (0.94, 1.32) .20
LPL rs281/T 0.86 (0.65, 1.14) .29 0.96 (0.71, 1.31) .80 0.83 (0.69, 1.00) .05 0.0 0.86 (0.75, 0.99) .04
Large drusen area
Lipid measure c /statin use
Total cholesterol 1.14 (1.00, 1.30) .05 1.03 (0.85, 1.24) .80 0.93 (0.82, 1.06) .26 57.6 1.03 (0.90, 1.17) .68
HDL-C 1.05 (0.89, 1.23) .57 1.08 (0.91, 1.28) .38 1.15 (1.01, 1.30) .03 0.0 1.10 (1.01, 1.20) .03
Non-HDL-C 1.12 (0.98, 1.27) .09 0.99 (0.83, 1.19) .93 0.90 (0.79, 1.02) .09 64.8 1.00 (0.87, 1.14) .97
Total/HDL-C ratio 1.01 (0.87, 1.17) .89 0.92 (0.76, 1.11) .39 0.87 (0.77, 1.00) .05 2.9 0.93 (0.85, 1.02) .14
Statin use 0.64 (0.32, 1.30) .22 0.75 (0.40, 1.43) .39 0.80 (0.47, 1.37) .42 0.0 0.74 (0.52, 1.06) .10
SNP/risk allele
CETP rs3764261/A 1.12 (0.89, 1.41) .33 1.12 (0.87, 1.44) .39 0.96 (0.80, 1.14) .62 0.0 1.04 (0.92, 1.17) .55
CETP rs1864163/A 0.70 (0.53, 0.94) .02 1.05 (0.80, 1.38) .73 0.81 (0.66, 0.99) .03 52.1 0.84 (0.68, 1.04) .11
ABCA1 rs1883025/T 0.88 (0.66, 1.16) .35 0.95 (0.70, 1.28) .72 0.88 (0.73, 1.06) .17 0.0 0.89 (0.78, 1.02) .10
LIPC rs7163555/G 1.00 (0.71, 1.39) .99 0.91 (0.62, 1.35) .64 1.00 (0.77, 1.29) .97 0.0 0.98 (0.82, 1.17) .81
LPL rs281/T 0.78 (0.62, 0.99) .04 0.80 (0.54, 1.18) .26 0.83 (0.69, 0.99) .04 0.0 0.81 (0.71, 0.93) .002
Late AMD
Lipid measure c /statin use
Total cholesterol 0.98 (0.79, 1.21) .83 1.16 (0.84, 1.59) .37 1.00 (0.78, 1.30) .98 0.0 1.02 (0.88, 1.18) .78
HDL-C 1.25 (1.00, 1.57) .05 0.89 (0.65, 1.21) .45 1.18 (0.94, 1.49) .16 39.0 1.13 (0.94, 1.34) .20
Non-HDL-C 0.90 (0.70, 1.15) .38 1.21 (0.89, 1.64) .23 0.95 (0.72, 1.26) .73 13.2 0.99 (0.84, 1.17) .91
Total/HDL-C ratio 0.76 (0.55, 1.04) .08 1.29 (0.96, 1.73) .09 0.94 (0.71, 1.24) .65 66.5 0.97 (0.72, 1.31) .86
Statin use 1.79 (0.81, 3.91) .15 0.76 (0.26, 2.23) .61 0.95 (0.29, 3.06) .93 0.0 1.22 (0.68, 2.18) .51
SNP/risk allele
CETP rs3764261/A 0.73 (0.49, 1.09) .12 1.15 (0.78, 1.71) .48 2.34 (1.66, 3.31) <.001 89.8 1.26 (0.64, 2.47) .50
CETP rs1864163/A 0.87 (0.55, 1.36) .53 1.22 (0.80, 1.85) .35 0.63 (0.39, 1.02) .06 52.0 0.89 (0.61, 1.29) .52
ABCA1 rs1883025/T 0.86 (0.53, 1.40) .55 1.12 (0.72, 1.74) .63 1.09 (0.71, 1.68) .68 0.0 1.03 (0.79, 1.33) .83
LIPC rs7163555/G 1.08 (0.65, 1.81) .77 1.40 (0.84, 2.31) .19 0.61 (0.32, 1.17) .14 48.5 1.01 (0.65, 1.58) .95
LPL rs281/T 1.02 (0.70, 1.48) .93 0.95 (0.56, 1.60) .84 0.93 (0.63, 1.37) .71 0.0 0.97 (0.76, 1.23) .79
Pure GA
Lipid measure c /statin use
Total cholesterol 0.88 (0.61, 1.26) .47 1.03 (0.61, 1.73) .91 1.04 (0.78, 1.39) .79 0.0 1.03 (0.84, 1.25) .80
HDL-C 1.52 (1.16, 2.00) .002 0.83 (0.50, 1.36) .45 1.23 (1.03, 1.47) .02 60.2 1.20 (0.90, 1.61) .22
Non-HDL-C 0.72 (0.46, 1.14) .16 1.12 (0.68, 1.84) .65 0.94 (0.68, 1.31) .72 0.0 0.96 (0.75, 1.23) .75
Total/HDL-C ratio 0.51 (0.29, 0.90) .02 1.44 (0.96, 2.15) .08 0.84 (0.57, 1.22) .36 78.3 0.91 (0.50, 1.64) .75
Statin use 2.60 (0.91, 7.44) .08 0.27 (0.03, 2.43) .25 0.64 (0.15, 2.77) .55 38.5 0.91 (0.50, 1.64) .75
SNP/risk allele
CETP rs3764261/A 0.54 (0.29, 1.01) .05 1.37 (0.81, 2.32) .25 2.33 (1.46, 3.73) <.001 86.0 1.20 (0.52, 2.77) .66
CETP rs1864163/A 1.13 (0.61, 2.08) .71 1.07 (0.57, 2.04) .83 0.50 (0.24, 1.02) .06 42.4 0.90 (0.60, 1.36) .63
ABCA1 rs1883025/T 0.95 (0.49, 1.87) .89 1.65 (1.00, 2.71) .05 0.88 (0.50, 1.55) .66 35.8 1.16 (0.76, 1.76) .50
LIPC rs7163555/G 0.99 (0.48, 2.04) .97 0.96 (0.44, 2.10) .91 0.89 (0.45, 1.79) .75 0.0 0.91 (0.58, 1.42) .68
LPL rs281/T 0.92 (0.53, 1.59) .75 1.16 (0.50, 2.70) .73 0.75 (0.46, 1.21) .24 0.0 0.89 (0.64, 1.25) .51
Exudative AMD
Lipid measure c /statin use
Total cholesterol 1.10 (0.86, 1.40) .44 1.12 (0.77, 1.64) .56 0.92 (0.63, 1.34) .66 0.0 1.06 (0.88, 1.27) .53
HDL-C 1.05 (0.74, 1.47) .80 0.77 (0.53, 1.12) .17 1.03 (0.72, 1.49) .86 0.0 0.95 (0.78, 1.17) .65
Non-HDL-C 1.08 (0.85, 1.37) .53 1.23 (0.87, 1.75) .24 0.91 (0.62, 1.35) .65 0.0 1.08 (0.90, 1.28) .42
Total/HDL-C ratio 0.98 (0.69, 1.38) .89 1.32 (0.98, 1.80) .07 0.97 (0.68, 1.40) .88 13.9 1.09 (0.89, 1.34) .40
Statin use 1.72 (0.56, 5.26) .34 0.98 (0.30, 3.24) .97 1.68 (0.51, 5.59) .40 0.0 1.43 (0.73, 2.80) .30
SNP/risk allele
CETP rs3764261/A 0.89 (0.53, 1.51) .67 0.88 (0.52, 1.47) .61 1.99 (1.34, 2.94) .001 77.0 1.18 (0.68, 2.05) .55
CETP rs1864163/A 0.61 (0.31, 1.23) .17 1.17 (0.75, 1.84) .49 0.82 (0.48, 1.41) .48 22.6 0.90 (0.62, 1.29) .56
ABCA1 rs1883025/T 0.76 (0.37, 1.53) .44 0.80 (0.45, 1.42) .45 1.14 (0.67, 1.94) .64 0.0 0.91 (0.65, 1.28) .58
LIPC rs7163555/G 1.13 (0.57, 2.23) .73 1.68 (0.97, 2.90) .06 0.47 (0.18, 1.26) .13 59.7 1.06 (0.55, 2.07) .86
LPL rs281/T 1.08 (0.66, 1.76) .77 0.67 (0.35, 1.29) .23 1.02 (0.63, 1.65) .95 0.0 0.95 (0.70, 1.28) .73

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Jan 8, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Lipids, Lipid Genes, and Incident Age-Related Macular Degeneration: The Three Continent Age-Related Macular Degeneration Consortium
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