May 2010
Volume 51, Issue 5
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Clinical Trials  |   May 2010
Small, Hard Macular Drusen and Peripheral Drusen: Associations with AMD Genotypes in the Inter99 Eye Study
Author Affiliations & Notes
  • Inger Christine Munch
    From the Department of Ophthalmology, Glostrup Hospital, Glostrup, Denmark;
    the Research Center for Prevention and Health, Copenhagen, Denmark;
    the Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; and
  • Jakob Ek
    the Kennedy Center, Glostrup, Denmark.
  • Line Kessel
    From the Department of Ophthalmology, Glostrup Hospital, Glostrup, Denmark;
  • Birgit Sander
    From the Department of Ophthalmology, Glostrup Hospital, Glostrup, Denmark;
  • Gitte Juul Almind
    the Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; and
    the Kennedy Center, Glostrup, Denmark.
  • Karen Brøndum-Nielsen
    the Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; and
    the Kennedy Center, Glostrup, Denmark.
  • Allan Linneberg
    the Research Center for Prevention and Health, Copenhagen, Denmark;
  • Michael Larsen
    From the Department of Ophthalmology, Glostrup Hospital, Glostrup, Denmark;
    the Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; and
    the Kennedy Center, Glostrup, Denmark.
  • Corresponding author: Inger Christine Munch, Department of Ophthalmology, Glostrup Hospital, Nordre Ringvej 59, DK-2600 Glostrup, Denmark; icm@dadlnet.dk
Investigative Ophthalmology & Visual Science May 2010, Vol.51, 2317-2321. doi:10.1167/iovs.09-4482
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      Inger Christine Munch, Jakob Ek, Line Kessel, Birgit Sander, Gitte Juul Almind, Karen Brøndum-Nielsen, Allan Linneberg, Michael Larsen; Small, Hard Macular Drusen and Peripheral Drusen: Associations with AMD Genotypes in the Inter99 Eye Study. Invest. Ophthalmol. Vis. Sci. 2010;51(5):2317-2321. doi: 10.1167/iovs.09-4482.

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Abstract

Purpose.: To study associations of small, hard macular drusen and peripheral drusen with genotypes associated with age-related macular degeneration (AMD).

Methods.: Digital grayscale fundus photographs recorded in red-free illumination were graded for the presence of drusen in 1107 subjects aged 30 to 66 years. Participants were genotyped for AMD-related polymorphisms in complement factor H (CFH), in LOC387715, and in complement factor B (CFB).

Results.: The prevalence of 20 or more small, hard macular drusen per eye was 14%, with no association to the investigated polymorphisms. Peripheral drusen were associated with CFHY402H (odds ratio [OR], 4.3; 95% confidence interval [95% CI], 1.4–13, for CC versus TT genotypes) as was macular drusen >63 μm (OR, 1.9; 95% CI, 1.1–3.1, for CC versus TT genotypes). Macular drusen >63 μm were associated with the presence of 20 or more small, hard macular drusen (OR, 1.7; 95% CI, 1.1–2.6) and with peripheral drusen (OR, 2.5; 95% CI,1.2–5.4)

Conclusions.: In this study, the presence of 20 or more small, hard macular drusen per eye was not associated with known AMD-related polymorphisms, whereas the study confirmed an association of peripheral drusen with CFHY402H. (ClinicalTrials.gov number, NCT00289237.)

Small, hard drusen in the retinal pigment epithelium are common in humans. 1 The prevalence was 93.6% in the Beaver Dam Eye study of subjects aged 43 to 86 years. 2 A large number of small, hard drusen in the macula is associated with increased risk of developing large, soft drusen and fundus pigment abnormalities. 37 Specifically, the Beaver Dam Eye Study found a more than threefold increased age-adjusted incidence of soft, indistinct drusen over 15 years in eyes with eight or more small, hard drusen at baseline, compared with eyes with one or two small, hard drusen per eye at baseline. 5  
We found a heritability of 99% of the characteristic of more than 20 small, hard drusen in twins aged 20 to 46 years. 8 Comparable results have been found in a study of women aged 49 to 79 years, 9 in which 11.9% of participants had 20 or more small, hard macular drusen. 
The prominent heritability of small, hard drusen and their association with age-related macular degeneration (AMD) has prompted us to examine small, hard drusen in relation to genetic polymorphisms known to be associated with AMD. 1015  
Methods
Study Population
The Inter99 Study is a population-based study of cardiovascular and metabolic characteristics and lifestyle. 16 An age- and sex-stratified random sample of 13,016 subjects from seven birth cohorts (years of birth 1939–40, 1944–45, 1949–50, 1954–55, 1959–60, 1964–65, and 1969–70) from suburban Copenhagen were invited to participate, of which 6,906 volunteered. From the main study, 122 individuals were excluded because of alcoholism, drug abuse, or limited cooperation, leaving 6784 (52.5%) for analysis. The Inter99 Eye Study 17 was designed to investigate retinal characteristics in relation to risk factors for cardiovascular disease such as diabetes, elevated blood pressure, and high body mass index (BMI). The Inter99 Eye Study examined 1107 subjects from the Inter99 Study, comprising 567 subjects representative of the background population and a skewed sample of 540 subjects with cardiovascular high-risk profile. Parameters used to calculate the risk of cardiovascular disease were oral glucose tolerance test data, systolic blood pressure, total cholesterol and high density lipoprotein level, BMI, history of diabetes, history of cardiovascular disease, and family history of cardiovascular disease. Exclusions made before data analysis comprised 6 subjects with diabetic retinopathy that precluded reliable drusen counting, 86 with photographs of one or both maculae missing or of inferior quality, 1 with macular dystrophy, and 7 with clerical data errors. Inter99 Eye Study baseline examinations were conducted from 1999 to 2001 and from 2004 to 2006. All participants gave their informed consent. Ethics committee approval was obtained, and the research adhered to the tenets of the Declaration of Helsinki. 
Phenotyping
All subjects underwent a general ophthalmic examination including fundus photography with seven-field monochromatic 60° digital fundus photography (TRC-50X camera; Topcon Corp., Tokyo, Japan, with 1024 × 1024 pixel CV-1000 back-piece, AngioVision 1000; MediVision, Yokneam Elit, Israel) in red-free illumination (Wratten 54 filter; Eastman Kodak, Inc., Rochester, NY) and color diapositive photography (Ektachrome Elite 100; Eastman Kodak, Rochester, NY). 
Fundus characteristics were assessed by a single ophthalmologist (ICM) masked to sex, age, systemic parameters, and genotypes. Digital images were examined on a computer screen and diapositive photographs by using a hand-held pair of 15-D lenses. Histogram stretching was allowed during the evaluation of the digital photographs. Small, hard drusen were defined as any bright element with a diameter equal to or smaller than 63 μm, the shape, color or proximity to adjacent disease of which did not suggest that it could be hard exudate, subretinal precipitate, or focal loss of retinal pigment epithelium without drusen formation. This definition excluded drusen associated with nevi. When lesions on digital images were deemed questionable or other retinal disease was present, color diapositives were inspected, and a second ophthalmologist was consulted. 
The number of small, hard drusen ≤63 μm was counted within a circle centered on the foveola, with a radius stretching to the temporal rim of the optic disc. Within this circle, the presence of drusen >63 μm was also noted. Both eyes were evaluated. Only subjects with gradable photographs from both eyes were included. Stippling of the retinal pigment epithelium was defined as diffusely scattered, minute, drusenlike elements resulting in a granular appearance of the fundus. 18 Peripheral drusen were defined as drusen >63 μm or confluent small, hard drusen located outside the temporal vascular arcades or nasal to the optic disc. Cuticular and reticular drusen were not graded separately, because they were included in the definition of peripheral drusen. Images of the peripheral retina were obtained only in red-free illumination, which precludes visualization of pigmentation features. Drusen anterior to the equator were not graded because this part of the fundus was covered only partly by the photography protocol. 
The diagnosis of diabetes mellitus was based on oral glucose tolerance testing according to the WHO1999 criteria. 19 Blood pressure was measured twice with the patient supine and having rested for at least 5 minutes, by using standard mercury sphygmomanometry with an appropriately sized cuff. Smoking information was assessed by questionnaire. 
Genotyping
DNA from whole blood was analyzed for five single-nucleotide polymorphisms (SNPs) associated with AMD: (1) complement factor H (CFH), variant Y402H (rs1061170), nucleotide change T→C; (2) LOC387715 (age-related macular degeneration susceptibility, ARMS2), variant A69S (rs10490924), nucleotide change C→T; (3) high temperature requirement factor A1(HtrA1), variant in the promoter region (rs11200638), nucleotide change G→A; (4) complement factor B (CFB), variant R32Q (rs641153), nucleotide change G→A; and (5) CFB, variant L9H (rs4151667), nucleotide change T→A. Genotyping of the five SNPs was performed by allelic discrimination (TaqMan; KBiosciences, Herts, UK). All genotyping success rates were above 95% (95.2%–98.8%). For each variant, 469 samples were genotyped in duplicate, with a mismatch rate below 0.7%. The distribution of genotypes for all variants was in Hardy-Weinberg equilibrium. 
Statistical Analyses
In all analyses (SAS ver. 9.1; SAS Institute, Inc., Cary, NC), age was treated categorically in the following groups: 30 to 31, 35 to 36, 40 to 41, 45 to 46, 50 to 51, 55 to 56, 60 to 61, and 65 to 66 years (some individuals had their first examination in 2004–2006). Smoking history was coded into two groups: having smoked and never having smoked. Logistic regression (PROC LOGISTIC) was used to estimate odds ratio (OR) and its 95% confidence interval (95% CI). Test for trend was performed for categorical variables at several levels by considering the variable as a continuous ordered factor in logistic regression models. Test for multiplicative interaction between CFHY402H and recruitment group was calculated by inserting a cross-product term in the model. Power estimation was performed using the analyst application in SAS. The number of small, hard drusen was given as the mean of the subject's eyes. In all analyses, the individual subject was the unit of analysis. 
Results
Genotype distributions in the eye study participants were comparable to those of the overall population of 6784 Inter 99 Study participants (Table 1). In agreement with the prespecified subgroup composition, the eye study participants were slightly older (48.4 vs. 45.7 years), had a higher BMI (28.0 vs. 26.1 kg/m2), higher systolic (133 vs. 128 mm Hg) and diastolic (84.1 vs. 80.8 mm Hg) blood pressures, and a higher prevalence of diabetes (30.5% vs. 3.13%; Table 1). 
Table 1.
 
Characteristics of the Study Population
Table 1.
 
Characteristics of the Study Population
Characteristic Included (n = 1007) Not Included (n = 5777) P *
Age, y mean (SD) 48.4 (7.95) 45.7 (8.0) <0.0001*
BMI, kg/m2 mean (SD) 28.0 (5.3) 26.1 (4.5) <0.0001*
Systolic blood pressure, mm Hg mean (SD) 133 (17.8) 128 (15.6) <0.0001*
Diastolic blood pressure, mm Hg mean (SD) 84.1 (11.1) 80.8 (10.5) <0.0001*
Sex, n (%) 0.42†
    Males 502 (49.8) 2800 (48.5)
    Females 505 (50.2) 2977 (51.5)
Smoking, n (%) 398 (39.8) 2233 (39.0) 0.61†
Diabetes, n (%) 307 (30.5) 181 (3.13) <0.0001†
CFHY402H:rs1061170, TT/TC/CC (%) 355/436/152 (38/46/16) 2085/2587/783 (38/47/14) 0.36†
Number with genotype information 943 5455
LOC387715A69S:rs10490924, CC/CT/TT (%) 610/286/45 (65/30/5) 3443/1783/255 (63/33/5) 0.43†
Number with genotype information 941 5481
HtrA1:rs11200638, GG/GA/AA (%) 589/279/44 (65/31/5) 3348/1706/247 (63/32/5) 0.63†
Number with genotype information 912 5301
CFBR32Q:rs641153, GG/GA/AA (%) 824/127/3 (86/13/0.31) 4742/737/26 (86/13/0.47) 0.79†
Number with genotype information 954 5505
CFBL9H:rs4151667, TT/TA/AA (%) 874/78/4 (91/8.2/0.42) 5051/446/13 (92/8.1/0.24) 0.59†
Number with genotype information 956 5510
Five or more small, hard drusen per eye (mean of two eyes) were found in 39% of the subjects, 10 or more in 26%, 20 or more in 14%, and 50 or more in 4.1% of the subjects (data not presented). The frequency of having 20 or more small, hard macular drusen increased with age, from 5.8% in subjects 30 to 36 years old, >13% in subjects aged 40 to 46 years, and 14% in subjects aged 50 to 56 years, to 19% in subjects aged 60 to 67 years (Table 2). The presence of peripheral drusen was significantly more frequent in women than in men (OR, 2.6; 95% CI, 1.2–5.6; Table 2). 
Table 2.
 
Distribution of Drusen
Table 2.
 
Distribution of Drusen
Age Group (y) n Males n (%) Macular Drusen >63 μm n (%) Peripheral Drusen n (%) Stippling n (%) ≥20 Small, Hard Macular Drusen n (%)
30–36 87 26 (29) 4 (4.6) 0 1 (1.2) 5 (5.8)
40–46 356 174 (49) 35 (9.8) 4 (1.1) 13 (3.7) 47 (13)
50–56 437 225 (51) 72 (16) 15 (3.4) 16 (3.7) 61 (14)
60–66 127 77 (61) 38 (30) 14 (11) 5 (3.9) 24 (19)
Total 1007 502 (50) 149 (15) 33 (3.3) 35 (3.5) 137 (14)
Sex adjusted for age group, OR (95% CI)
    Male 1 1 1 1
    Female 1.4 (0.96–2.0) 2.6 (1.2–5.6) 1.3 (0.64–2.5) 1.4 (0.96–2.0)
P = 0.087 P = 0.012 P = 0.51 P = 0.081
Age group adjusted for sex, OR (95% CI)
    30–36 0.42 (0.14–1.2) 0.29 (0.038–2.3) 0.38 (0.15–0.98)
    40–46 1 1 1 1
    50–56 1.8 (1.2–2.8)) 3.2 (1.1–9.8) 1.0 (0.48–2.1) 1.1 (0.71–1.6)
    60–66 4.1 (2.4–6.9) 12 (4.0–39) 1.1 (0.30–3.2) 1.6 (0.93–2.7)
P < 0.0001* P < 0.0001* P = 0.68* P = 0.0084*
One or more macular drusen >63 μm in either eye was found in 15% of subjects. The prevalence increased with age, from 4.6% in subjects aged 30 to 36 years to 30% in subjects aged 60 to 66 years (Table 2). Peripheral drusen were present in 33 subjects. The prevalence increased with age from 0 in subjects aged 30 to 36 year to 11% in subjects aged 60 to 66 years (Table 2). Of the 33 participants with peripheral drusen, 17 had no drusen in the macula, 3 had 20 or more small, hard drusen in the absence of other graded features, 10 had macular drusen >63 μm, and 3 had both macular drusen >63 μm and 20 or more small, hard drusen (data not presented). Stippling was observed in 3.5% of subjects, without any discernible effect of age or sex (Table 2). 
The presence of macular drusen >63 μm was associated with the presence of 20 or more small, hard macular drusen (OR, 1.7; 95% CI, 1.1–2.6; P = 0.029, adjusted for age and sex; Table 3) and remained so after further adjustment for CFHY402H (OR, 1.8; 95% CI, 1.4–3.0; P = 0.012). Macular drusen >63 μm were also associated with peripheral drusen (OR, 2.5; 95% CI, 1.1–5.4; P = 0.015; Table 3). 
Table 3.
 
Association of Macular Drusen ≤63 μm and >63 μm with the Presence of Other Drusen
Table 3.
 
Association of Macular Drusen ≤63 μm and >63 μm with the Presence of Other Drusen
All Macular Drusen ≤63 μm n (%) Macular Drusen >63 μm n (%)
≥20 Small, hard macular drusen OR (95% CI)* 106/858 (12) 31/149 (21)
1 1.7 (1.1–2.6)
P = 0.029
Peripheral drusen OR (95% CI)* 20/858 (2.3) 13/149 (8.7)
1 2.5 (1.2–5.4)
P = 0.015
Stippling OR (95% CI)* 29/858 (3.4) 6/149 (4)
1 1.1 (0.44–2.8)
P = 0.83
Peripheral drusen were associated with CFHY402H with an OR of 4.3 (95% CI, 1.4–13) for genotype CC versus genotype TT and an OR of 2.4 (95% CI, 0.87–6.7) for the heterozygous genotype CT versus the homozygous genotype TT (ORs adjusted for the presence of macular drusen >63 μm). Likewise, an association was found between CFHY402H and the presence of macular drusen >63 μm, with an OR of 1.8 (95% CI, 1.1–3.0), for CC versus TT, and an OR of 1.2 (95% CI, 0.79–1.8), for CT versus TT (Table 4). In the subgroup analysis, the association between CFHY402H and macular drusen >63 μm was present only in the group of persons recruited because of cardiovascular high-risk profile, and there was significant interaction between recruitment group and CFHY402H (Table 4). For the presence of 20 or more small, hard macular drusen, there was no significant interaction between CFHY402H and recruitment group. Subgroup analysis on peripheral drusen and stippling was not performed because of the small sample. 
Table 4.
 
Drusen Phenotypes in Relation to CFHY402H by Recruitment Subgroup
Table 4.
 
Drusen Phenotypes in Relation to CFHY402H by Recruitment Subgroup
CFHY402H:rs1061170
TT TC CC
Macular Drusen >63 μm
All participants
    n (%) 44/355 (12) 63/436 (14) 31/152 (20)
    OR (95% CI) 1 1.2 (0.79–1.8) 1.8 (1.1–3.0)
    P (trend) 0.029
Stratified by recruitment group, P-value for interaction = 0.0045
Cardiovascular disease high-risk characteristics
    n (%) 17/167 (10) 36/210 (17) 21/72 (29)
    OR (95% CI) 1 1.8 (0.99–3.4) 3.6 (1.8–7.4)
    P (trend) 0.0004
Population-matched
    n (%) 27/188 (14) 27/226 (12) 10/80 (13)
    OR (95% CI) 1 0.81 (0.46–1.4) 0.85 (0.39–1.9)
    P (trend) 0.57
≥20 Small Hard Drusen *
All participants
    n (%) 43/355 (12) 72/436 (17) 14/152 (9)
    OR (95% CI) 1 1.4 (0.94–2.1) 0.69 (0.36–1.3)
    P (trend) 0.70
Stratified by recruitment group P-value for interaction = 0.24
Cardiovascular disease high-risk characteristics
    n (%) 24/167 (14) 37/210 (18) 6/72 (8.3)
    OR (95% CI) 1 1.2 (0.70–2.2) 0.49 (0.19–1.3)
    P (trend) 0.36
Population-matched
    n (%) 19/188 (10) 35/226 (15) 8/80 (10)
    OR (95% CI) 1 1.7 (0.93–3.11) 1.0 (0.42–2.4)
    P (trend) 0.56
Stippling *
All participants
    n (%) 11/355 (3.1) 16/436 (3.7) 7/152 (4.6)
    OR (95% CI) 1 1.2 (0.55–2.6) 1.5 (0.57–4.0)
    P (trend) 0.41
Peripheral Drusen *
All participants
    n (%) 5/355 (1.4) 15/436 (3.4) 10/152 (6.6)
    OR (95 % CI) 1 2.4 (0.87–6.7) 4.3 (1.4–13)
    P (trend) 0.0073
Stippling and the presence of more than 20 small, hard macular drusen were not associated with CFHY402H (Table 4) or any other of the polymorphisms assessed in the study. The power to detect a twofold increase in the proportion of having 20 or more small, hard macular drusen in subjects with one or two copies of CFHY402H was 0.93 at a significance level of 0.05. No significant association was found between any investigated phenotype and the polymorphisms LOC387715A69S, HtrA1:rs11200638, CFBR32Q, and CFBL9H (data not presented). 
Discussion
This study provided a unique opportunity to examine small, hard drusen and early AMD-related retinal lesions in a population of relatively young subjects aged 30 to 66 years, of which few had AMD, but many are destined to develop the disease. The prevalence of numerous small, hard drusen in the macula increased with age. Despite being a highly heritable condition 8,9 associated with future development of AMD, 3,57,20 the presence of numerous small, hard drusen lacked a detectable association with known AMD-related genotypes. Specifically, no association was found between the presence of more than 20 small, hard macular drusen and the polymorphisms CFHY402H, LOC387715A69S, HtrA1:rs11200638, CFBR32Q, and CFBL9H
Previous studies of AMD genetics have emphasized advanced stages of AMD 21,22 and applied a threshold definition of AMD of one soft, distinct drusen >63 μm 2325 or >125 μm. 25,26 Consequently, subjects with only small, hard drusen have systematically been assigned to control groups. Other studies have been confined entirely to subjects with AMD. 27,28 Such study designs cannot yield information about the genetic background of small, hard macular drusen. 
Several studies have shown a decreasing number of small, hard drusen with age, concomitant with an increasing prevalence of larger drusen. 20,29,30 Our finding of an increasing prevalence of small, hard drusen with increasing age is not in conflict with these studies because nearly all our participants were sufficiently young not to have had their small, hard drusen replaced by larger drusen. Our result is comparable to a study of female twins aged 49 to 74 years, in which the prevalence of having 20 or more small, hard macular drusen was found to increase with age. 9  
The present study confirmed that the prevalence of macular drusen >63 μm, a trait that falls within the definition of AMD, increases with age and that these drusen were associated with CFHY402H. We observed a significant association between CFHY402H in patients who had a high-risk cardiovascular profile. This finding suggests that CFHY402H may exert its effect through cardiovascular risk factors, although previous studies of advanced AMD have failed to identify a significant interaction between cardiovascular risk factors and CFHY402H. 31,32 We observed no association between macular drusen >63 μm and the polymorphisms LOC387715A69S, HtrA1:rs11200638, CFBL9H, or CFBR32Q. This result is in agreement with a recent study of drusen ≥63 μm in very early AMD. 23  
In the present study, the prevalence of peripheral drusen, most of which were found immediately outside the temporal vascular arcades or on the nasal side of the optic disc, increased with age, and it was higher in the women than in the men. The presence of peripheral drusen was associated with CFHY402H, with a fourfold increase in the odds of peripheral drusen among subjects homozygotic for CFHY402H compared with those in subjects without this polymorphism. Previously, a threefold increase has been observed in a study of elderly subjects. 33 The coupling of peripheral drusen to CFHY402H may explain why peripheral drusen are significantly more common among AMD patients with affected family members than in isolated cases of AMD. 34 It is thus increasingly evident that peripheral drusen are part of the morphologic and genetic spectrum of AMD. 
Fundus stippling, which appears like hundreds or thousands of minute drusen spread over the entire fundus or large parts of it, was found in 3.5% of subjects independent of age, sex, and AMD genotypes and without any detectable association with macular drusen >63 μm. This finding indicates that fundus stippling is a nondegenerative condition without any association with AMD. 
The present study had the power to exclude major associations between small, hard drusen and known AMD genotypes, whereas weak associations may have escaped detection. Another limitation is that the number of subjects with drusen was too small, in our opinion, to justify classification and analysis by subtype (e.g., intermediate, confluent, reticular, cuticular). Furthermore, subjects with increased cardiovascular risk were overrepresented in the study. Nevertheless, the prevalence of small, hard drusen and peripheral drusen did not differ from that in previous studies. 9,33  
In summary, we examined fundus lesions that precede, but are not included in the current definition of AMD, and the results confirmed the association of CFHY402H with macular drusen >63 μm and with peripheral drusen. On the contrary, we did not observe an association between CFHY402H and numerous small, hard macular drusen, despite such drusen predisposing for the development of larger drusen. Specifically, our data showed no association between having 20 or more small, hard macular drusen per eye and the AMD-related polymorphisms CFHY402H and LOC387715A69S. We conclude that there may be unknown genetic determinants of this hereditary AMD-precursor. 
Footnotes
 Supported by the Velux Foundation, Øjenfonden, Øjenforeningen, Diabetesforeningen, and the Faculty of Health Sciences, University of Copenhagen.
Footnotes
 Disclosure: I.C. Munch, None; J. Ek, None; L. Kessel, None; B. Sander, None; G.J. Almind, None; K. Brøndum-Nielsen, None; A. Linneberg, None; M. Larsen, None
References
Sarks SH Arnold JJ Killingsworth MC Sarks JP . Early drusen formation in the normal and aging eye and their relation to age related maculopathy: a clinicopathological study. Br J Ophthalmol. 1999;83:358–368. [CrossRef] [PubMed]
Klein R Klein BE Linton KL . Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology. 1992;99:933–943. [CrossRef] [PubMed]
Bressler NM Munoz B Maguire MG . Five-year incidence and disappearance of drusen and retinal pigment epithelial abnormalities: Waterman study. Arch Ophthalmol. 1995;113:301–308. [CrossRef] [PubMed]
Klein R Klein BE Tomany SC . Ten-year incidence and progression of age-related maculopathy: The Beaver Dam eye study. Ophthalmology. 2002;109:1767–1779. [CrossRef] [PubMed]
Klein R Klein BE Knudtson MD . Fifteen-year cumulative incidence of age-related macular degeneration: the Beaver Dam Eye Study. Ophthalmology. 2007;114:253–262. [CrossRef] [PubMed]
Sarks JP Sarks SH Killingsworth MC . Evolution of soft drusen in age-related macular degeneration. Eye. 1994;8:269–283. [CrossRef] [PubMed]
van Leeuwen R Klaver CC Vingerling JR . The risk and natural course of age-related maculopathy: follow-up at 6 1/2 years in the Rotterdam study. Arch Ophthalmol. 2003;121:519–526. [CrossRef] [PubMed]
Munch IC Sander B Kessel L . Heredity of small hard drusen in twins aged 20–46 years. Invest Ophthalmol Vis Sci. 2007;48:833–838. [CrossRef] [PubMed]
Hammond CJ Webster AR Snieder H . Genetic influence on early age-related maculopathy: a twin study. Ophthalmology. 2002;109:730–736. [CrossRef] [PubMed]
Edwards AO Ritter RIII Abel KJ . Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308:421–424. [CrossRef] [PubMed]
Hageman GS Anderson DH Johnson LV . A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005;102:7227–7232. [CrossRef] [PubMed]
Haines JL Hauser MA Schmidt S . Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308:419–421. [CrossRef] [PubMed]
Klein RJ Zeiss C Chew EY . Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385–389. [CrossRef] [PubMed]
Gold B Merriam JE Zernant J . Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006;38:458–462. [CrossRef] [PubMed]
Rivera A Fisher SA Fritsche LG . Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet. 2005;14:3227–3236. [CrossRef] [PubMed]
Jorgensen T Borch-Johnsen K Thomsen TF . A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99 (1). Eur J Cardiovasc Prev Rehabil. 2003;10:377–386. [CrossRef] [PubMed]
Kessel L Hougaard JL Mortensen C . Visual acuity and refractive errors in a suburban Danish population: Inter99 Eye Study. Acta Ophthalmol Scand. 2004;82:19–24. [CrossRef] [PubMed]
Klein R Davis MD Magli YL . The Wisconsin age-related maculopathy grading system. Ophthalmology. 1991;98:1128–1134. [CrossRef] [PubMed]
Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO Consultation, Part 1: Diagnosis and classification of diabetes mellitus. Geneva: World Health Organization; 1999, WHO/NCD/NCS/99.2.
Klein R Klein BE Tomany SC Moss SE . Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study. Am J Epidemiol. 2002;156:589–598. [CrossRef] [PubMed]
Jun G Klein BE Klein R . Genome-wide analyses demonstrate novel loci that predispose to drusen formation. Invest Ophthalmol Vis Sci. 2005;46:3081–3088. [CrossRef] [PubMed]
Fisher SA Abecasis GR Yashar BM . Meta-analysis of genome scans of age-related macular degeneration. Hum Mol Genet. 2005;14:2257–2264. [CrossRef] [PubMed]
Farwick A Dasch B Weber BH . Variations in five genes and the severity of age-related macular degeneration: results from the Muenster aging and retina study. Eye. 2009;23(12):2238–2244. [CrossRef] [PubMed]
Despriet DD Klaver CC Witteman JC . Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. JAMA. 2006;296:301–309. [CrossRef] [PubMed]
Klein R Knudtson MD Klein BE . Inflammation, complement factor h, and age-related macular degeneration: the Multi-ethnic Study of Atherosclerosis. Ophthalmology. 2008;115:1742–1749. [CrossRef] [PubMed]
Xing C Sivakumaran TA Wang JJ . Complement factor H polymorphisms, renal phenotypes and age-related macular degeneration: the Blue Mountains Eye Study. Genes Immun. 2008;9:231–239. [CrossRef] [PubMed]
Shuler RKJr Schmidt S Gallins P . Peripheral reticular pigmentary change is associated with complement factor H polymorphism (Y402H) in age-related macular degeneration. Ophthalmology. 2008;115:520–524. [CrossRef] [PubMed]
Droz I Mantel I Ambresin A . Genotype-phenotype correlation of age-related macular degeneration: influence of complement factor H polymorphism. Br J Ophthalmol. 2008;92:513–517. [CrossRef] [PubMed]
Buch H Nielsen NV Vinding T . 14-year incidence, progression, and visual morbidity of age-related maculopathy: the Copenhagen City Eye Study. Ophthalmology. 2005;112:787–798. [CrossRef] [PubMed]
Sparrow JM Dickinson AJ Duke AM . Seven year follow-up of age-related maculopathy in an elderly British population. Eye. 1997;11(Pt 3):315–324. [CrossRef] [PubMed]
Seddon JM Reynolds R Maller J . Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci. 2009;50:2044–2055. [CrossRef] [PubMed]
Kim IK Ji F Morrison MA . Comprehensive analysis of CRP, CFH Y402H and environmental risk factors on risk of neovascular age-related macular degeneration. Mol Vis. 2008;14:1487–1496. [PubMed]
Seddon JM Reynolds R Rosner B . Peripheral retinal drusen and reticular pigment: association with CFH Y402H and CFHrs1410996 genotypes in family and twin studies. Invest Ophthalmol Vis Sci. 2009;50:586–591. [CrossRef] [PubMed]
Postel EA Agarwal A Schmidt S . Comparing age-related macular degeneration phenotype in probands from singleton and multiplex families. Am J Ophthalmol. 2005;139:820–825. [CrossRef] [PubMed]
Table 1.
 
Characteristics of the Study Population
Table 1.
 
Characteristics of the Study Population
Characteristic Included (n = 1007) Not Included (n = 5777) P *
Age, y mean (SD) 48.4 (7.95) 45.7 (8.0) <0.0001*
BMI, kg/m2 mean (SD) 28.0 (5.3) 26.1 (4.5) <0.0001*
Systolic blood pressure, mm Hg mean (SD) 133 (17.8) 128 (15.6) <0.0001*
Diastolic blood pressure, mm Hg mean (SD) 84.1 (11.1) 80.8 (10.5) <0.0001*
Sex, n (%) 0.42†
    Males 502 (49.8) 2800 (48.5)
    Females 505 (50.2) 2977 (51.5)
Smoking, n (%) 398 (39.8) 2233 (39.0) 0.61†
Diabetes, n (%) 307 (30.5) 181 (3.13) <0.0001†
CFHY402H:rs1061170, TT/TC/CC (%) 355/436/152 (38/46/16) 2085/2587/783 (38/47/14) 0.36†
Number with genotype information 943 5455
LOC387715A69S:rs10490924, CC/CT/TT (%) 610/286/45 (65/30/5) 3443/1783/255 (63/33/5) 0.43†
Number with genotype information 941 5481
HtrA1:rs11200638, GG/GA/AA (%) 589/279/44 (65/31/5) 3348/1706/247 (63/32/5) 0.63†
Number with genotype information 912 5301
CFBR32Q:rs641153, GG/GA/AA (%) 824/127/3 (86/13/0.31) 4742/737/26 (86/13/0.47) 0.79†
Number with genotype information 954 5505
CFBL9H:rs4151667, TT/TA/AA (%) 874/78/4 (91/8.2/0.42) 5051/446/13 (92/8.1/0.24) 0.59†
Number with genotype information 956 5510
Table 2.
 
Distribution of Drusen
Table 2.
 
Distribution of Drusen
Age Group (y) n Males n (%) Macular Drusen >63 μm n (%) Peripheral Drusen n (%) Stippling n (%) ≥20 Small, Hard Macular Drusen n (%)
30–36 87 26 (29) 4 (4.6) 0 1 (1.2) 5 (5.8)
40–46 356 174 (49) 35 (9.8) 4 (1.1) 13 (3.7) 47 (13)
50–56 437 225 (51) 72 (16) 15 (3.4) 16 (3.7) 61 (14)
60–66 127 77 (61) 38 (30) 14 (11) 5 (3.9) 24 (19)
Total 1007 502 (50) 149 (15) 33 (3.3) 35 (3.5) 137 (14)
Sex adjusted for age group, OR (95% CI)
    Male 1 1 1 1
    Female 1.4 (0.96–2.0) 2.6 (1.2–5.6) 1.3 (0.64–2.5) 1.4 (0.96–2.0)
P = 0.087 P = 0.012 P = 0.51 P = 0.081
Age group adjusted for sex, OR (95% CI)
    30–36 0.42 (0.14–1.2) 0.29 (0.038–2.3) 0.38 (0.15–0.98)
    40–46 1 1 1 1
    50–56 1.8 (1.2–2.8)) 3.2 (1.1–9.8) 1.0 (0.48–2.1) 1.1 (0.71–1.6)
    60–66 4.1 (2.4–6.9) 12 (4.0–39) 1.1 (0.30–3.2) 1.6 (0.93–2.7)
P < 0.0001* P < 0.0001* P = 0.68* P = 0.0084*
Table 3.
 
Association of Macular Drusen ≤63 μm and >63 μm with the Presence of Other Drusen
Table 3.
 
Association of Macular Drusen ≤63 μm and >63 μm with the Presence of Other Drusen
All Macular Drusen ≤63 μm n (%) Macular Drusen >63 μm n (%)
≥20 Small, hard macular drusen OR (95% CI)* 106/858 (12) 31/149 (21)
1 1.7 (1.1–2.6)
P = 0.029
Peripheral drusen OR (95% CI)* 20/858 (2.3) 13/149 (8.7)
1 2.5 (1.2–5.4)
P = 0.015
Stippling OR (95% CI)* 29/858 (3.4) 6/149 (4)
1 1.1 (0.44–2.8)
P = 0.83
Table 4.
 
Drusen Phenotypes in Relation to CFHY402H by Recruitment Subgroup
Table 4.
 
Drusen Phenotypes in Relation to CFHY402H by Recruitment Subgroup
CFHY402H:rs1061170
TT TC CC
Macular Drusen >63 μm
All participants
    n (%) 44/355 (12) 63/436 (14) 31/152 (20)
    OR (95% CI) 1 1.2 (0.79–1.8) 1.8 (1.1–3.0)
    P (trend) 0.029
Stratified by recruitment group, P-value for interaction = 0.0045
Cardiovascular disease high-risk characteristics
    n (%) 17/167 (10) 36/210 (17) 21/72 (29)
    OR (95% CI) 1 1.8 (0.99–3.4) 3.6 (1.8–7.4)
    P (trend) 0.0004
Population-matched
    n (%) 27/188 (14) 27/226 (12) 10/80 (13)
    OR (95% CI) 1 0.81 (0.46–1.4) 0.85 (0.39–1.9)
    P (trend) 0.57
≥20 Small Hard Drusen *
All participants
    n (%) 43/355 (12) 72/436 (17) 14/152 (9)
    OR (95% CI) 1 1.4 (0.94–2.1) 0.69 (0.36–1.3)
    P (trend) 0.70
Stratified by recruitment group P-value for interaction = 0.24
Cardiovascular disease high-risk characteristics
    n (%) 24/167 (14) 37/210 (18) 6/72 (8.3)
    OR (95% CI) 1 1.2 (0.70–2.2) 0.49 (0.19–1.3)
    P (trend) 0.36
Population-matched
    n (%) 19/188 (10) 35/226 (15) 8/80 (10)
    OR (95% CI) 1 1.7 (0.93–3.11) 1.0 (0.42–2.4)
    P (trend) 0.56
Stippling *
All participants
    n (%) 11/355 (3.1) 16/436 (3.7) 7/152 (4.6)
    OR (95% CI) 1 1.2 (0.55–2.6) 1.5 (0.57–4.0)
    P (trend) 0.41
Peripheral Drusen *
All participants
    n (%) 5/355 (1.4) 15/436 (3.4) 10/152 (6.6)
    OR (95 % CI) 1 2.4 (0.87–6.7) 4.3 (1.4–13)
    P (trend) 0.0073
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