PLoS MEDICINE
CFH Y402H Confers Similar Risk of Soft
Drusen and Both Forms of Advanced AMD
Kristinn P. Magnusson1*, Shan Duan2,3,4, Haraldur Sigurdsson5,6, Hjorvar Petursson1, Zhenglin Yang2,3,7, Yu Zhao2,3,
Paul S. Bernstein2, Jian Ge4, Fridbert Jonasson5,6, Einar Stefansson5,6, Gudleif Helgadottir5, Norman A. Zabriskie2,
Thorlakur Jonsson1, Asgeir Björnsson1, Theodora Thorlacius1, Palmi V. Jonsson8, Gudmar Thorleifsson1,
Augustine Kong1, Hreinn Stefansson1, Kang Zhang2,3*[, Kari Stefansson1[, Jeffrey R. Gulcher1*[
1 DeCODE Genetics, Reykjavik, Iceland, 2 Department of Ophthalmology and Visual Science, Moran Eye Center, University of Utah, Salt Lake City, Utah, United States of
America, 3 Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah, United States of America,
4 Zhongshan Ophthalmic Center, Sun Yat-Sen University, Gaung Zhou, China, 5 Department of Ophthalmology, National University Hospital, Reykjavik, Iceland, 6 Faculty of
Medicine, University of Iceland, Reykjavik, Iceland, 7 Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China, 8 Department of
Geriatrics, National University Hospital, Reykjavik, Iceland
Competing Interests: Some authors
receive financial compensation from
DeCODE Genetics. S. Duan, Z. Yang,
P. S. Bernstein, J. Ge, N. A. Zabriskie,
and K. Zhang declare that they have
no competing interests.
Author Contributions: K. P.
Magnusson, K. Zhang, K. Stefansson,
and J. R. Gulcher designed the study.
H. Sigurdsson, P. S. Bernstein, F.
Jonasson, E. Stefansson, G.
Helgadottir, N. A. Zabriskie, P. V.
Jonsson, and K. Zhang enrolled and
phenotyped patients. K. P.
Magnusson, S. Duan, H. Petursson, Z.
Yang, Y. Zhao, J. Ge, T. Jonsson, A.
Björnsson, T. Thorlacius, G.
Thorleifsson, A. Kong, H. Stefansson,
and K. Zhang performed genotyping
and analyzed the data. K. P.
Magnusson, H. Petursson, H.
Stefansson, K. Zhang, K. Stefansson,
and J. R. Gulcher wrote the paper.
Academic Editor: Andrew Lotery,
Southampton General Hospital,
United Kingdom
Citation: Magnusson KP, Duan S,
Sigurdsson H, Petursson H, Yang Z, et
al. (2006) CFH Y402H confers similar
risk of soft drusen and both forms of
advanced AMD. PLoS Med 3(1): e5.
Received: May 23, 2005
Accepted: September 27, 2005
Published: November 29, 2005
DOI:
10.1371/journal.pmed.0030005
ABSTRACT
Background
Age-related macular degeneration (AMD) is the most common cause of irreversible visual
impairment in the developed world. The two forms of advanced AMD, geographic atrophy and
neovascular AMD, represent different pathological processes in the macula that lead to loss of
central vision. Soft drusen, characterized by deposits in the macula without visual loss, are
considered to be a precursor of advanced AMD. Recently, it has been proposed that a common
missense variant, Y402H, in the Complement Factor H (CFH) gene increases the risk for
advanced AMD. However, its impact on soft drusen, GA, or neovascular AMD—or the
relationship between them—is unclear.
Methods and Findings
We genotyped 581 Icelandic patients with advanced AMD (278 neovascular AMD, 203 GA,
and 100 with mixed neovascular AMD/GA), and 435 with early AMD (of whom 220 had soft
drusen). A second cohort of 431 US patients from Utah, 322 with advanced AMD (244
neovascular AMD and 78 GA) and 109 early-AMD cases with soft drusen, were analyzed. We
confirmed that the CFH Y402H variant shows significant association to advanced AMD, with
odds ratio of 2.39 in Icelandic patients (p ¼ 5.9 3 1012) and odds ratio of 2.14 in US patients
from Utah (p ¼ 2.0 3 109) with advanced AMD. Furthermore, we show that the Y402H variant
confers similar risk of soft drusen and both forms of advanced AMD (GA or neovascular AMD).
Conclusion
Soft drusen occur prior to progression to advanced AMD and represent a histological feature
shared by neovascular AMD and GA. Our results suggest that CFH is a major risk factor of soft
drusen, and additional genetic factors and/or environmental factors may be required for
progression to advanced AMD.
Copyright: Ó 2006 Magnusson et al.
This is an open-access article
distributed under the terms of the
Creative Commons Attribution
License, which permits unrestricted
use, distribution, and reproduction in
any medium, provided the original
author and source are credited.
Abbreviations: AMD, age-related
macular degeneration; GA,
geographic atrophy; OR, odds ratio;
RPE, retinal pigment epithelium
* To whom correspondence should
be addressed. E-mail: kristinn.p.
magnusson@decode.is (KPM), kang.
zhang@hmbg.utah.edu (KZ), jeffrey.
gulcher@decode.is (JRG)
[ These authors contributed equally
to this work.
PLoS Medicine | www.plosmedicine.org
0109
January 2006 | Volume 3 | Issue 1 | e5
CFH Confers Risk of Soft Drusen and AMD
DeCODE Genetics has detailed phenotypic information for
2,220 individuals, ie 1,112 patients with neovascular AMD, GA,
or early AMD, and 1,108 of their unaffected relatives.
Probands were recruited from a list of 2,840 consecutive
patients diagnosed with AMD or early AMD at the University
Eye Clinic, Reykjavik, or listed in the Icelandic Registry for the
Blind during the years 1980–2001, together with relatives.
Population controls were not related to the AMD cohort and
did not include any first- or second-degree relative pair. A
second control group (longevous controls) included 171
unrelated individuals, aged 90 y or older, who had no signs
of advanced AMD, diagnosed based on their ability to see fine
detail, including print, as assessed in Section D1 of the
Minimum Data Set of the Resident Assessment Instrument
[22]. Since the prevalence of AMD increases dramatically with
age, this group represents healthy ‘‘supercontrols’’ for AMD.
A second sample of AMD patients were recruited in Utah at
the Moran Eye Center of the University of Utah, and were agematched with controls with normal eye examinations (individuals aged 60 y or older, with no drusen or RPE changes).
All participants in both populations went through a
standard examination protocol and visual-acuity measurements. Slitlamp biomicroscopy of the fundi using 90-diopter
lenses was performed. A pair of stereoscopic color fundus
photographs (508) were taken, centered on the fovea using a
Topcon fundus camera (Topcon TRV-50VT, Topcon Optical
Company, Tokyo, Japan) by a trained ophthalmic photographer. Grading was carried out using a standard grid
classification suggested by the International Age-Related
Maculopathy Epidemiological Study Group for age-related
maculopathy and AMD [23]. All abnormalities in the macula
were recorded, including type, size, and number of drusen as
well as the presence of hyperpigmentation and hypopigmentation, together with advanced AMD.
Introduction
Age-related macular degeneration (AMD) includes a wide
range of phenotypes. Early AMD is characterized mainly by
the presence of soft drusen in the macula without visual loss,
while advanced AMD is characterized by geographic atrophy
(GA or dry AMD) and neovascular AMD (wet AMD) with
visual loss. Despite the rising prevalence of AMD as a result of
increasing life expectancy, its underlying pathogenesis is
poorly understood and there are limited treatment options
available. Nutritional supplements and antagonists of vascular endothelial growth factor have been reported to decrease
visual loss in neovascular AMD somewhat [1]. Drusen are
comprised of small yellowish, extracellular deposits of lipid,
protein, and cellular debris, formed beneath the retinal
pigment epithelium (RPE), a tissue that underlies the photoreceptor cells. Biochemical analysis of drusen have indeed
resulted in identification of complement components and
inflammatory modulators [2–8]. Soft drusen and pigmentary
abnormalities of the RPE are considered to be an early
indication of risk of developing advanced AMD. GA is a
consequence of the degeneration of the photoreceptor cells
and the RPE. Neovascular AMD is characterized by abnormal
growth of capillaries from the choroid and by subsequent
exudation of fluid, lipid, and blood.
Several genome-wide linkage scans for AMD including ours
(unpublished data) have found suggestive linkage on chromosome 1q [9–15]. The addition of markers within the
linkage peak led to recent reports by five groups that there is
an association between a common missense variant (Y402H)
in CFH and AMD in the United States [3,16–19]. The Y402H
allele was present in at least 60% of AMD patients with risk
ratios of between 2.0 and 3.5 for one risk allele, and with risk
ratios of between 3.3 and 7.4 for carriers of two risk alleles. It
has been postulated that the Y402H variant may lead to
decreased binding to CRP and heparin and therefore less
inhibition of the complement pathway, causing overactivity
and deposition of the complement pathway proteins [20].
CFH protein has been detected in choriocapillaris and within
soft drusen [3].
However, the question of how the Y402H allele contributes
to the different subtypes of AMD has not been properly
addressed, owing either to insufficient clinical information or
to sample size, as neovascular AMD dominates the patient
cohorts in most previously reported studies [3,16–19].
In order to investigate the association between CFH and
AMD we performed genotype–phenotype correlations on
different clinical subtypes of early and advanced AMD in US
and European populations.
Genotyping
The Icelandic cohort that was genotyped included 581
patients with advanced AMD and 435 patients with early
AMD, and allele frequencies were compared to that of either
891 population controls or 171 longevous healthy controls
(Table 1). The Utah cohort of 244 patients with neovascular
AMD, 78 patients with GA, and 109 patients with early AMD
with soft drusen was genotyped, and allele frequencies were
compared to 203 age-matched healthy controls. A TaqMan
assay (Applied Biosystems, Foster City, California, United
States) was performed on a 384-well GeneAmp PCR System
9700 (Applied Biosystems) used for PCR to genotype the
Icelandic cohort. A direct DNA- sequencing method was used
on an ABI 3100 genetic analyzer (Applied Biosystems) to
genotype the Utah cohort.
Methods
Patients
Data Analysis
For the single-marker association of the CFH Y402H
variant (rs1061170), we used Fisher’s exact test to calculate
one-sided p-values for the at-risk allele. As the patient cohort
was recruited as families for a linkage analysis, we also
repeated the test for association, correcting for the relatedness of the patients by extending a variance-adjustment
procedure described previously [24] for sib-ships to apply to
general familial relationships. Using the variance-adjustment
procedure, the variance of the test statistic is adjusted to take
into account the decrease in the effective sample size
This study was approved by the Data Protection Authority
of Iceland and the National Bioethics Committee of Iceland,
and the Institutional Review Board of the University of Utah.
All participants signed written informed consent prior to
participation in the study. All personal identifiers associated
with blood samples, medical information, and genealogy were
encrypted. For samples from Iceland, encryption was carried
out by the Data Protection Authority, using a third-party
encryption system [21]. The Icelandic cohort recruited by
PLoS Medicine | www.plosmedicine.org
0110
January 2006 | Volume 3 | Issue 1 | e5
CFH Confers Risk of Soft Drusen and AMD
Table 1. Association between Subphenotypes of AMD and CFH Y402H Variant in the Icelandic Cohort
Phenotype
AMD
Early-AMD changes
Controls
Subphenotype
Advanced AMD
Neovascular only
Mixed neovascular/GA
GA only
Soft drusen
Hard drusen only
Pigments only
Population controls
Healthy controls
n
581
278
100
203
220
93
122
891
171
Population Controls
Healthy Controls
a
Frq
p-Value
p-Value
RR
0.567
0.559
0.615
0.554
0.580
0.462
0.398
0.389
0.354
2.1 3
1.4 3
8.9 3
1.1 3
5.0 3
0.032
0.430
1.2 3
4.7 3
1.2 3
7.7 3
9.0 3
0.035
0.43
2.05
1.99
2.50
1.95
2.16
1.35
1.03
1021
1012
1010
109
1013
1019
1012
109
109
1012
(1.75–2.40)
(1.63–2.43)
(1.85–3.38)
(1.55–2.46)
(1.73–2.70)
(0.98–1.87)
(0.74–1.43)
PAR
p-Value
p-Valuea
OR
0.50
0.48
0.60
0.47
0.53
0.22
0.03
2.5 3 1012
1.3 3 109
2.9 3 109
2.9 3 108
2.4 3 1010
0.0096
0.16
5.9 3 1012
2.1 3 109
3.6 3 109
7.4 3 108
8.5 3 1010
0.0104
0.16
2.39
2.32
2.92
2.27
2.52
1.57
1.21
(1.86–3.07)
(1.75–3.07)
(2.03–4.20)
(1.67–3.08)
(1.87–3.40)
(1.07–2.30)
(0.83–1.76)
Shown are calculations for the C allele of the CFH Y402H variant and the corresponding number of affected individuals (n), the allelic frequency in affected individuals (Frq), one-sided Fisher’s exact p-value, relative risk (RR), OR, and populationattributable risk (PAR). The hard-drusen cohort consisted of individuals solely with hard drusen, with no sign of soft drusen or pigmentary changes. Individuals were included in the pigmentary changes (Pigments only) cohort if they showed
no sign of hard drusen or soft drusen. The healthy (longevous) controls had normal visual acuity.
a
p-Values adjusted for the relatedness of patients.
DOI: 10.1371/journal.pmed.0030005.t001
2.05, respectively (Table 2). Therefore, we conclude that the
CFH variant contributes equally to GA and neovascular AMD
in our European and US cohorts.
Furthermore, the Y402H variant contributes to soft drusen
in early AMD, with similar ORs in the Icelandic and Utah
study groups of 2.52 and 2.10, respectively (see Tables 1 and
2). In contrast, the variant does not show significant
association to pigmentary changes found in early AMD. In
Iceland we observed significant association (p ¼ 0.01) to hard
drusen but with a lower OR (1.57) (Table 1). A significant
difference in CFH Y402H allele frequencies was observed
when patients with soft drusen were compared with an
unrelated set of patients with hard drusen (p ¼ 0.011). This
CFH variant also confers increased risk although this is not
significant when comparing hard drusen to controls in the
Utah cohort (see Table 2).
We also typed the CFH Y402H allele in four ethnically
diverse populations from the International HapMap project
[27]; Caucasians, residents of Utah with ancestry from
northern and western Europe (59), Yorubians, residents of
Nigeria (57), Japanese (31), and Chinese (44). The allele
frequencies for CFH Y402H in Caucasians and Africans were
resulting from the fact that genotypes of relatives are not
independent. Both unadjusted and adjusted p-values are
presented for comparison. We calculate the odds ratio (OR)
of the frequency of the at-risk allele as OR ¼ p/(1p)/s/(1s),
where p and s are the frequency of the at-risk allele in the
patients and in the controls, respectively. In the case of
population controls and assuming the multiplicative model,
in which the risks of the two alleles of the single-nucleotide
polymorphism a person carries multiply [25,26], this corresponds to an estimate of the relative risk of the mutation
compared to the wild-type. Specifically, with population
controls and the multiplicative model, it can be shown
through Bayes’ Rule that the OR, as defined above,
corresponds to Risk(CT)/Risk(TT) ¼ Risk(CC)/Risk(CT), where
C is the mutated allele and T the wild-type, and Risk is the
probability of disease given the genotype.
On the basis of the frequency of the at-risk allele and the
relative risk, we calculate the population-attributable risk or
the reduction in the number of disease cases if the at-risk
allele was removed from the population, again assuming the
multiplicative model. Confidence intervals of relative risks
and ORs were based on the variance-adjusted tests for
association, assuming a log-normal distribution. To avoid
confusion and to be consistent, we report the results as OR
when using healthy controls and as relative risk when using
population controls.
Table 2. Association between Subphenotypes of AMD and CFH
Y402H Variant in the Utah Cohort
Results
Phenotype Subphenotype n
In agreement with previous reports [3–19], the Y402H
allele confers an OR of 2.32 when comparing Icelandic
patients with neovascular AMD to healthy controls. Based on
the comparison with population controls, the relative risk of
the mutation is estimated to be 1.99 with a corresponding
estimated population-attributable risk of 0.48. The Y402H
variant also contributes to GA, with OR of 2.27. The patient
group with mixed GA/neovascular AMD gave similar results
with OR of 2.92. Thus, the Y402H allele contributes equally to
GA and neovascular AMD in Icelandic patients with advanced
AMD (Table 1).
The comparable association to neovascular AMD and GA
was replicated in the Utah cohort, giving ORs of 2.17 and
PLoS Medicine | www.plosmedicine.org
AMD
Early-AMD
changes
Controls
Advanced AMD
Neovascular only
GA only
Soft drusen
Age-Matched Healthy Controls
322
244
78
109
Frq
p-Value
OR
0.587
0.590
0.577
0.583
2.0 3 109
8.5 3 109
0.00011
8.4 3 106
2.14
2.17
2.05
2.10
0.072
1.37 (0.91–2.06)
Hard drusen only 0 65 0.477
Age-matched
203 0.399
healthy controls
(1.66–2.75)
(1.66–2.84)
(1.40–3.00)
(1.50–2.95)
Shown are calculations for the C allele of the CFH Y402H variant and the corresponding number of unrelated
affected individuals (n), the allelic frequency in affected individuals (Frq), p-value, and OR. The control group was
age-matched to the patient group and the individuals had normal eye examinations.
DOI: 10.1371/journal.pmed.0030005.t002
0111
January 2006 | Volume 3 | Issue 1 | e5
CFH Confers Risk of Soft Drusen and AMD
Given that the protein component of soft drusen includes
members of the complement system (including Complement
H), we tested the effect of the CFH variant on risk of soft
drusen without advanced AMD. Interestingly, this CFH
variant confers risk of soft drusen with similar OR (2.52) as
with both forms of advanced AMD, even before the
fundoscopic findings and visual loss fulfil the criteria for
advanced AMD in two independent cohorts. Conversely,
there is little or no impact of the CFH variant on other
features such as pigmentary changes and hard drusen.
Therefore, it appears that the Y402H variant in CFH
contributes to the increased risk of advanced AMD largely
or entirely through its impact on the development of soft
drusen as a precursor of advanced AMD.
This observation may not be surprising given that soft
drusen is comprised, in part, of complement proteins
including CFH and its binding partner, complement 3b [20].
However, many more elderly patients develop soft drusen
than those who ultimately progress to advanced AMD.
Numerous epidemiological studies have shown that the
prevalence of soft drusen is two to three times greater than
that of advanced AMD [33]. The prevalence of soft drusen in
Caucasian populations increases with age at the same rate as
AMD. Most patients with soft drusen are without any visual
symptoms for decades, and only a fraction of individuals who
have soft drusen will eventually progress to AMD with visualacuity loss. For example in the Beaver Dam eye study, only
14% of the patients with soft drusen developed AMD over a
10-y period [30]. Interestingly, in persons of African origin
living in United States and Barbados, prevalence of early
AMD and soft drusen is slightly lower than in whites, but
advanced AMD is rare [34,35]. The allele frequency of the
Y402H is less (0.31 versus 0.39) in African Americans than in
Caucasians. Therefore, the prevalence discrepancy between
the early and advanced AMD in African Americans is
consistent with our hypothesis that CFH Y402H causes softdrusen formation, but it is not sufficient for progression to
advanced AMD. To substantiate this hypothesis further, it will
be interesting to correlate the prevalence of soft drusen with
advanced AMD in Asian populations. Our analysis of the CFH
Y402H variant demonstrated that its frequency is less in
Asian populations: 0.08 in the Japanese samples and 0.07 in
the Chinese. Indeed, AMD in Asians is considered to be
infrequent, but careful genotype–phenotype correlation
studies are needed in non-Caucasian populations.
Significant genetic influence in early AMD has been
demonstrated in a classical twin study comparing concordance of 226 monozygotic and 280 dizygotic twin pairs, with
soft drusen and multiple hard drusen showing strong genetic
influences with heritability of 57% and 81%, respectively [36].
This is comparable to the heritability of advanced AMD [37].
However, we show that the CFH variant is a risk factor for soft
drusen, but not for hard drusen or pigmentary changes, per
se. Therefore, there may be other genes that influence the
appearance of hard drusen and pigmentary changes. In
addition, the difficulty in explaining the difference in the
ratio of the prevalences in neovascular AMD and GA across
populations through the CFH variant alone supports the
notion that additional genetic or environmental factors
contribute to the pathogenesis. It is likely that there are
other important genes, yet to be found, that contribute to the
similar, 39% versus 30.7%, while they were much lower in
Asians—8.1% in the Japanese and 6.8% in the Chinese.
Discussion
We have shown that the CFH Y402H allele confers
significant risk to neovascular AMD, GA, and soft drusen in
early AMD in US and European Caucasian populations. The
effect of the CFH Y402H allele on soft drusen in early AMD is
similar to its effect on the advanced forms of AMD,
neovascular AMD, and GA. Advanced AMD is considered to
be one disease with two different end-stage lesions, i.e.,
choroidal neovasculariztion and GA. Leaky choroidal neovascular blood vessels between Bruch’s membrane and RPE
are seen typically in neovascular AMD, while GA is
characterized by RPE atrophy and overlying photoreceptor
loss. Soft drusen located between the RPE and Bruch’s
membrane are usually precursors of both forms of advanced
AMD. The 5-y incidence of soft drusen in the Reykjavik Eye
Study, a population-based epidemiological study of individuals aged 50 y and older [28,29], was found to be similar to
that of the Beaver Dam Eye Study in the US [30], and the Blue
Mountains Eye Study in Australia [31]. Neovascular AMD
outnumbers GA by approximately three to one in both the
Beaver Dam Eye Study and the Blue Mountains Eye Study.
Similar figures were seen in most other Caucasian populations. In the Icelandic population under consideration here,
however, GA was found to outnumber neovascular AMD by
three to one, as reported in the Reykjavik Eye Study [28,29]. It
is an open question whether the high GA/neovascular AMD
ratio in Iceland is due to genetic or environmental factors
that increase the risk of GA or decrease the risk of
neovascular AMD. Consumption of fresh fish and fishliver
oil with omega-3 polyunsaturated fatty acids among Icelanders is among the highest in the world [28]. Interestingly,
Seddon et al. [32] reported a trend for decreasing odds of
neovascular AMD with increasing amounts of omega-3 and
fresh-fish intake.
The discovery of CFH as an important AMD gene,
contributing to the common form of AMD and its confirmation by several groups, is a major advance towards
understanding the genetic risk and pathogenesis of AMD. It is
apparent that this single common variant confers similar risk
in all of the US populations tested and, furthermore, our
result for the association of the CFH variant to advanced
AMD in a European population is comparable to that in the
US. However, the previously reported studies had not
adequately addressed the effect of the CFH variant on GA
or early AMD. We therefore tested the reported variant in the
CFH region for association to the subtypes of AMD in both of
our cohorts.
Functionally, CFH is thought to aid in keeping the
complement pathway of the innate immune system in check.
It is tempting to postulate that a hypothetical lower activity of
complement H protein with the histidine variant may lead to
increased inflammation that would contribute to the neovascular form of AMD as suggested before [17]. Alternatively,
others have suggested that it may have a direct role in softdrusen formation, which may also be linked to inflammation
[3]. Our results, showing that the CFH variant contributes
equally to GA and to neovascular AMD, would tend to refute
the first hypothesis and lend support to the second.
PLoS Medicine | www.plosmedicine.org
0112
January 2006 | Volume 3 | Issue 1 | e5
CFH Confers Risk of Soft Drusen and AMD
risk of advanced AMD, particularly among those who already
have soft drusen.
14. Abecasis GR, Yashar BM, Zhao Y, Ghiasvand NM, Zareparsi S, et al. (2004)
Age-related macular degeneration: A high-resolution genome scan for
susceptibility loci in a population enriched for late-stage disease. Am J
Hum Genet 74: 482–494.
15. Iyengar SK, Song D, Klein BE, Klein R, Schick JH, et al. (2004) Dissection of
genomewide-scan data in extended families reveals a major locus and
oligogenic susceptibility for age-related macular degeneration. Am J Hum
Genet 74: 20–39.
16. Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, et al. (2005)
Complement factor H polymorphism and age-related macular degeneration. Science 308: 421–424.
17. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, et al. (2005)
Complement factor H variant increases the risk of age-related macular
degeneration. Science 308: 419–421.
18. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, et al. (2005) Complement
factor H polymorphism in age-related macular degeneration. Science 308:
385–389.
19. Zareparsi S, Branham KE, Li M, Shah S, Klein RJ, et al. (2005) Strong
association of the Y402H variant in complement factor H at 1q32 with
susceptibility to age-related macular degeneration. Am J Hum Genet 77:
149–153.
20. Giannakis E, Jokiranta TS, Male DA, Ranganathan S, Ormsby RJ, et al.
(2003) A common site within factor H SCR 7 responsible for binding
heparin, C-reactive protein and streptococcal M protein. Eur J Immunol
33: 962–969.
21. Gulcher JR, Kristjansson K, Gudbjartsson H, Stefansson K (2000) Protection
of privacy by third-party encryption in genetic research in Iceland. Eur J
Hum Genet 8: 739–742.
22. Morris JN, Hawes C, Fries BE, Phillips CD, Mor V, et al. (1990) Designing the
national resident assessment instrument for nursing homes. Gerontologist
30: 293–307.
23. 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.
24. Risch N, Teng J (1998) The relative power of family-based and case-control
designs for linkage disequilibrium studies of complex human diseases I.
DNA pooling. Genome Res 8: 1273–1288.
25. Terwilliger JD, Ott J (1992) A haplotype-based ‘‘haplotype relative risk’’
approach to detecting allelic associations. Hum Hered 42: 337–346.
26. Falk CT, Rubinstein P (1987) Haplotype relative risks: An easy reliable way
to construct a proper control sample for risk calculations. Ann Hum Genet
51: 227–233.
27. Consortium TIH (2003) The International HapMap Project. Nature 426:
789–796.
28. Jonasson F, Arnarsson A, Sasaki H, Peto T, Sasaki K, et al. (2003) The
prevalence of age-related maculopathy in iceland: Reykjavik eye study.
Arch Ophthalmol 121: 379–385.
29. Jonasson F, Arnarsson A, Peto T, Sasaki H, Sasaki K, et al. (2005) 5-year
incidence of age-related maculopathy in the Reykjavik Eye Study.
Ophthalmology 112: 132–138.
30. Klein R, Klein BE, Tomany SC, Meuer SM, Huang GH (2002) Ten-year
incidence and progression of age-related maculopathy: The Beaver Dam
eye study. Ophthalmology 109: 1767–1779.
31. Mitchell P, Smith W, Attebo K, Wang JJ (1995) Prevalence of age-related
maculopathy in Australia. The Blue Mountains Eye Study. Ophthalmology
102: 1450–1460.
32. Seddon JM, Rosner B, Sperduto RD, Yannuzzi L, Haller JA, et al. (2001)
Dietary fat and risk for advanced age-related macular degeneration. Arch
Ophthalmol 119: 1191–1199.
33. Klein R, Peto T, Bird A, Vannewkirk MR (2004) The epidemiology of agerelated macular degeneration. Am J Ophthalmol 137: 486–495.
34. Friedman DS, Katz J, Bressler NM, Rahmani B, Tielsch JM (1999) Racial
differences in the prevalence of age-related macular degeneration: The
Baltimore Eye Survey. Ophthalmology 106: 1049–1055.
35. Leske MC, Wu SY, Hyman L, Hennis A, Nemesure B, et al. (2004) Four-year
incidence of macular changes in the Barbados Eye Studies. Ophthalmology
111: 706–711.
36. Hammond CJ, Webster AR, Snieder H, Bird AC, Gilbert CE, et al. (2002)
Genetic influence on early age-related maculopathy: A twin study.
Ophthalmology 109: 730–736.
37. Seddon JM, Cote J, Page WF, Aggen SH, Neale MC (2005) The US twin study
of age-related macular degeneration: Relative roles of genetic and
environmental influences. Arch Ophthalmol 123: 321–327.
Supporting Information
Accession Numbers
The LocusLink (http://www.ncbi.nlm.nih.gov/entrez) accession
number for the gene discussed in this paper, CFH, is ID 3075. The
OMIM (http://www.ncbi.nlm.nih.gov/entrez) identification number for
AMD, ARMD1, is 603075; and for the CFH gene is 134370.
Acknowledgments
We thank the participating AMD patients and their families. We also
thank DeCODE core facilities for their contributions to this work and
staff at the ophthalmology clinic at the National University Hospital,
Reykjavik: Ingimundur Gislason, Thordur Sverrisson, Gudmundur
Viggosson, and Helga Halblaub. The authors acknowledge the
following grant support (to K. Zhang): National Institutes of Health
(R01EY14428, R01EY14448, core P30EY014800, and GCRC M01RR00064), Foundation Fighting Blindness, the Ruth and Milton
Steinbach Fund, Ronald McDonald House Charities, the Macular
Vision Research Foundation, Knights Templar Eye Research Foundation, Grant Ritter Fund, American Health Assistance Foundation,
the Karl Kirchgessner Foundation, Val and Edith Green Foundation,
and the Simmons Foundation. The funding agencies had no role in
study design, data collection and analysis, decision to publish, or
&
preparation of the manuscript.
References
1. Fine SL, Martin DF, Kirkpatrick P (2005) Pegaptanib sodium. Nat Rev Drug
Discov 4: 187–188.
2. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, et
al. (2001) An integrated hypothesis that considers drusen as biomarkers of
immune-mediated processes at the RPE-Bruch’s membrane interface in
aging and age-related macular degeneration. Prog Retin Eye Res 20: 705–
732.
3. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, et al.
(2005) 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 102: 7227–7232
4. Mullins RF, Russell SR, Anderson DH, Hageman GS (2000) Drusen
associated with aging and age-related macular degeneration contain
proteins common to extracellular deposits associated with atherosclerosis,
elastosis, amyloidosis, and dense deposit disease. Faseb J 14: 835–846.
5. Mullins RF, Aptsiauri N, Hageman GS (2001) Structure and composition of
drusen associated with glomerulonephritis: Implications for the role of
complement activation in drusen biogenesis. Eye 15: 390–395.
6. Anderson DH, Mullins RF, Hageman GS, Johnson LV (2002) A role for local
inflammation in the formation of drusen in the aging eye. Am J
Ophthalmol 134: 411–431.
7. Johnson LV, Leitner WP, Staples MK, Anderson DH (2001) Complement
activation and inflammatory processes in drusen formation and age related
macular degeneration. Exp Eye Res 73: 887–896.
8. Crabb JW, Miyagi M, Gu X, Shadrach K, West KA, et al. (2002) Drusen
proteome analysis: An approach to the etiology of age-related macular
degeneration. Proc Natl Acad Sci U S A 99: 14682–14687.
9. Klein ML, Schultz DW, Edwards A, Matise TC, Rust K, et al. (1998) Agerelated macular degeneration. Clinical features in a large family and
linkage to chromosome 1q. Arch Ophthalmol 116: 1082–1088.
10. Weeks DE, Conley YP, Tsai HJ, Mah TS, Rosenfeld PJ, et al. (2001) Agerelated maculopathy: An expanded genome-wide scan with evidence of
susceptibility loci within the 1q31 and 17q25 regions. Am J Ophthalmol
132: 682–692.
11. Majewski J, Schultz DW, Weleber RG, Schain MB, Edwards AO, et al. (2003)
Age-related macular degeneration—A genome scan in extended families.
Am J Hum Genet 73: 540–550.
12. Seddon JM, Santangelo SL, Book K, Chong S, Cote J (2003) A genomewide
scan for age-related macular degeneration provides evidence for linkage to
several chromosomal regions. Am J Hum Genet 73: 780–790.
13. Schmidt S, Scott WK, Postel EA, Agarwal A, Hauser ER, et al. (2004)
Ordered subset linkage analysis supports a susceptibility locus for agerelated macular degeneration on chromosome 16p12. BMC Genet 5: 18.
PLoS Medicine | www.plosmedicine.org
0113
January 2006 | Volume 3 | Issue 1 | e5
CFH Confers Risk of Soft Drusen and AMD
Patient Summary
Background. The commonest cause of poor eyesight in later life in the
developed world is known as age-related macular degeneration (AMD).
The macula is the central part of the retina (the film-like membrane at
the back of the eye) which is the most sensitive and important for sharp
central vision. An early sign of AMD is what are called ‘‘drusen’’—
deposits of protein, fat, and cells—which doctors can see in the back of
the eye. There are two types of advanced AMD: so-called ‘‘wet’’ or
neovascular AMD (neovascular means ‘‘new vessel’’) and ‘‘dry’’ or
geographic atrophy AMD (atrophy means to waste away). Wet AMD
occurs when abnormal, fragile blood vessels grow under the macula
behind the retina. These blood vessels often leak blood and fluid, which
lift the macula. Dry AMD occurs as the light-sensitive cells in the macula
(the rods and cones) break down.
Why Was This Study Done? Although this disease is common, little is
understood about why it occurs, and current treatments have limited
efficacy. Previous studies have suggested that a gene in a particular part
of Chromosome 1 is linked to the chance of getting AMD. The
responsible gene is Complement Factor H (CFH), which codes for a
protein that is involved in keeping one part of the immune system in
check. A variant of CFH has been previously shown to be present more
frequently in people with advanced AMD compared to normal controls.
These investigators wanted to go further, to find out whether this variant
was more linked to the wet or to the dry type of AMD and to early AMD.
What Did the Researchers Do and Find? They looked at the variant of
CFH in two groups of patients with various types of AMD, 1,118 from
Iceland and 431 from Utah, and compared the results with people
without AMD from the same ethnic groups and age. As had been shown
before, they found that one variant of this gene occurred more
frequently in the wet form of AMD. However, they report two new
observations. First, the variant of CFH also confers risk for the dry form of
AMD and second, the variant confers similar risk to drusen in the early
form of AMD.
What Do These Findings Mean? It appears that this gene variant is
important early on in the development of AMD—which makes sense as
the protein for which this gene codes is involved in keeping the immune
system under control. The particular variant found here may not be as
efficient as the normal one—that is, it makes it more likely that
inflammation will develop in the eye. These findings do not have any
immediate implications for treatment, but they suggest that there are
other genes that cause the severe forms of AMD with blindness.
Where Can I Get More Information Online? Here are several Web sites
with information on macular degeneration.
MedlinePlus:
http://www.nlm.nih.gov/medlineplus/ency/article/001000.htm
National Institutes of Health Senior Health:
http://nihseniorhealth.gov/agerelatedmaculardegeneration/toc.html
National Eye Institute:
http://www.nei.nih.gov/health/maculardegen/armd_facts.asp
Prevent Blindness America:
http://www.preventblindness.org/eye_problems/amdFAQ.html
Foundation Fighting Blindness:
http://www.blindness.org/MacularDegeneration/
PLoS Medicine | www.plosmedicine.org
0114
January 2006 | Volume 3 | Issue 1 | e5