Association of Complement Factor H and

LOC387715 Genotypes with Response of

Exudative Age-Related Macular
Degeneration to Intravitreal Bevacizumab
Milam A. Brantley, Jr, MD, PhD,1,2 Amy M. Fang, MD,1 Jennifer M. King, BS,1 Asheesh Tewari, MD,1,2
Steven M. Kymes, PhD, MHA,1 Alan Shiels, PhD1

Purpose: To investigate whether there is an association between complement factor H (CFH) or

LOC387715 genotypes with response to treatment with intravitreal bevacizumab for exudative age-related
macular degeneration (AMD).
Design: Retrospective cohort study.
Participants: The study cohort consisted of 86 patients being treated for neovascular AMD with bevaci-
zumab alone.
Methods: Genotype determination for the CFH Y402H and LOC387715 A69S polymorphisms was per-
formed by allele-specific digestion of polymerase chain reaction products. All patients were treated with 1.25 mg
intravitreal bevacizumab at 6-week intervals until choroidal neovascularization was no longer active.
Main Outcome Measures: CFH Y402H and LOC387715 A69S polymorphisms. Choroidal neovascular
lesion characteristics were ascertained by fluorescein angiography. Snellen visual acuity (VA) was measured
before and after treatment.
Results: For the CFH Y402H polymorphism, patients with the CFH TT genotype had the largest choroidal
neovascular lesions (P ⫽ 0.02). With treatment, VA improved from 20/248 to 20/166 for the CFH TT genotype and
from 20/206 to 20/170 for the TC genotype, but fell from 20/206 to 20/341 for the CFH CC genotype (P ⫽ 0.016).
Only 10.5% of patients with the CFH CC genotype demonstrated improved VA with treatment, compared with
53.7% of CFH TT and TC genotypes (P ⫽ 0.004). For the LOC387715 A69S variant, patients with the TT genotype
had the largest choroidal neovascular lesions (P ⫽ 0.012). There was no significant difference in response to
bevacizumab treatment according to LOC387715 genotype.
Conclusions: The AMD-associated CFH Y402H and LOC387715 A69S variants were associated with
differences in choroidal neovascular lesion size in this study. Patients with the CFH CC genotype fared
significantly worse with intravitreal bevacizumab than did those with the CFH TC and TT genotypes, suggesting
a potential pharmacogenetic relationship. Prospective studies to confirm or refute this observation should be
considered. Ophthalmology 2007;114:2168 –2173 © 2007 by the American Academy of Ophthalmology.

Age-related macular degeneration (AMD) is the most com-
mon irreversible cause of severe vision loss throughout the
world in individuals ⬎50 years old. Advanced AMD in-
cludes geographic atrophy, characterized by extensive loss
of the choriocapillaris and overlying retinal pigment epithe-
lium, and exudative (neovascular) AMD, characterized by
Originally received: June 8, 2007.
Final revision: September 12, 2007.
Accepted: September 12, 2007. Manuscript no. 2007-771.
1
Department of Ophthalmology and Visual Sciences, Washington Univer-
sity School of Medicine, St. Louis, Missouri.
2
Barnes Retina Institute, St. Louis, Missouri.
Presented at: Association of Research in Vision and Ophthalmology meet-
ing, May 2007, Fort Lauderdale, Florida.
Supported by the National Eye Institute, Bethesda, Maryland (grant no.
EY012284, NEI Core Grant 5 P30 EY02687), and a grant from Re-
search to Prevent Blindness, New York, New York, to the Department
invasion of blood vessels into subretinal spaces. Along with
dietary and environmental risk factors for AMD, heredity is
a primary contributor to AMD susceptibility.1 Recently, a
coding variation in the complement factor H (CFH) gene on
chromosome 1q32 was found to be strongly associated with
AMD.2–5 The predicted tyrosine-to-histidine substitution
at amino acid position 402 (Y402H) in the CFH protein
is the result of a T-to-C transition at nucleotide position
1277 in exon-9 of the gene. Additional reports have
confirmed this association in numerous populations
of Ophthalmology and Visual Sciences, Washington University School
of Medicine.
No conflicting relationship exists for any author.
Correspondence to Milam A. Brantley, Jr, MD, PhD, Department of
Ophthalmology and Visual Sciences/Campus Box 8096, Washington Uni-
versity School of Medicine, 660 South Euclid Avenue, St. Louis, MO
63110. E-mail: Brantley@vision.wustl.edu.

2168 © 2007 by the American Academy of Ophthalmology ISSN 0161-6420/07/$–see front matter
Published by Elsevier Inc. doi:10.1016/j.ophtha.2007.09.008
 Brantley et al 䡠 CFH and LOC387715 Genotypes and Response to Intravitreal Bevacizumab
throughout the world,6 –23 although this relationship
seems to be absent in the Japanese population.24 –26 The
CFH Y402H polymorphism has been associated with
both exudative8,15 and advanced atrophic10 AMD, as
well as AMD progression,20 but limited data are avail-
able evaluating AMD phenotypes with regard to CFH
genotype.21–23
Linkage studies have identified a region within chro-
mosome 10q26 as a second major locus contributing to
AMD pathogenesis. In initial reports,27,28 a single nucle-
otide polymorphism (rs10490924) within the hypotheti-
cal gene LOC387715 was found to confer an increased
risk for development of AMD. Further studies have sup-
ported the association of this alanine-to-serine substitution
(A69S) with AMD,17,18,20,29 –33 and have suggested that
cigarette smoking may influence susceptibility to AMD
conferred by LOC387715.29 This two-exon gene encodes a
distinct 107-amino acid protein with no matches in public
protein or protein motif databases.27 LOC387715 appears to
be a phylogenetically recent gene with conservation re-
stricted to the primate lineage.27 Expression of the mRNA is
abundant in placental tissue and has been found in human
retina. This locus has been renamed ARMS2 (age-related
maculopathy susceptibility gene 2), but biochemical data
still are necessary to confirm that this putative protein plays
a role in the pathogenesis of AMD.
A recent genome-wide association study in patients from the
United States and Hong Kong identified another single nucleotide
polymorphism (rs11200638), located approximately 5.5 kilo-
bases downstream of the LOC387715 rs10490924 single
nucleotide polymorphism in the putative GC-rich promoter
region of the HTRA1 gene, which codes for a serine pro-
tease.34,35 Additional studies have linked HTRA1 with
AMD,36,37 but it remains unclear if either of the polymor-
phisms in the 10q26 region (rs10490924 and rs11200638) is
causally associated with AMD.
The addition of antivascular endothelial growth factor
(anti-VEGF) therapy to the treatment armamentarium for
choroidal neovascularization has revolutionized treatment
of exudative AMD. Bevacizumab (Avastin, Genentech,
South San Francisco, CA) is a recombinant, humanized
monoclonal anti-VEGF antibody that binds all VEGF iso-
forms and exerts its neutralizing effect by inhibiting the
VEGF–receptor interaction, thus blocking both increased
vascular permeability and angiogenesis. The drug is ap-
proved by the United States Food and Drug Administration
for intravenous use for metastatic colorectal cancer. Bev-
acizumab has been administered off label for the treatment
of neovascular AMD38 – 42 and other retinal vascular condi-
tions43– 45 with encouraging results.
Genotype–phenotype correlation studies have suggested
that the AMD-associated CFH genetic variant may play a
role in the type or size of neovascular complex that forms in
exudative AMD.21–23 The purpose of this study was in-
vestigate whether there is an association between re-
sponse to treatment for neovascular AMD with bevaci-
zumab and the CFH Y402H variant. For comparison, we
also evaluated one of the chromosome 10q26 polymor-
phic loci, LOC387715 A69S, for potential relationships
to treatment response.
Materials and Methods
Patients, Clinical Examination, and Treatment
This retrospective cohort study was approved by the Washington
University Human Research Protection Office and the Barnes
Retina Institute Study Center. Research adhered to the tenets of the
Declaration of Helsinki and was conducted in accordance with
Health Insurance Portability and Accountability Act regulations.
All participants were enrolled from the clinical offices of the
Barnes Retina Institute and signed written informed consent before
participation.
Mouthwash samples for genotyping were collected from 86
Caucasian patients with a diagnosis of exudative AMD who were
undergoing treatment for an active neovascular lesion with intra-
vitreal bevacizumab. Only eyes that had received no previous
therapeutic intervention for AMD were enrolled in the study. For
each patient, an intravitreal injection of 1.25 mg bevacizumab was
performed at the initial presentation of an active choroidal neo-
vascular complex, and subsequent injections were performed at
6-week intervals until there was no longer evidence of active
neovascularization. Each patient was followed for a minimum of 6
months for inclusion in the study.
The AMD phenotypes were characterized by clinical examina-
tion, including dilated fundus examination, fundus photography,
and fluorescein angiography. Fluorescein angiograms obtained at
initial presentation of active choroidal neovascular lesions were
classified as either predominantly classic (⬎50% classic, a defin-
able vascular complex appearing early in the angiogram followed
by late leakage), minimally classic (⬍50% classic), or occult
(leakage appearing only late in the angiogram). Angiograms were
read independently by two retina specialists (MAB and AT)
masked to patients’ genotype (intergrader ␬ ⫽ 0.92). Any discrep-
ancies in lesion classification were openly adjudicated. Fluorescein
angiograms were obtained digitally with a Zeiss fundus camera
and imaging software (OIS, Sacramento, CA). Snellen visual acu-
ity (VA) was recorded in a standardized manner for all patients at
initial presentation and follow-up visits. For all calculations and
comparisons, Snellen acuities were converted to log minimal angle
of resolution values. These values were converted back to Snellen
acuities for reporting the results.
DNA Preparation and Genotyping
Participants provided buccal tissue samples by expectorating into
50-ml Falcon conical tubes (BD Biosciences, Franklin Lakes, NJ)
after vigorously rinsing for 30 seconds with ⬃20 ml Scope mouth-
wash (Procter & Gamble, Cincinnati, OH). Genomic DNA was
prepared from buccal cells using the Puregene mouthwash kit
(Gentra Systems, Minneapolis, MN) and quantified by absorbance
at 260 nm (GeneQuant pro, GE Healthcare, Waukesha, WI).
Exon-9 of CFH was amplified by polymerase chain reaction using
AmpliTaq Gold Universal PCR Master Mix (Applied Biosystems,
Foster City, CA) and gene-specific primers located in intron-8
(5=-ctttgttagtaactttagttcgtcttcag) and intron-9 (5=-acaaggtgacataaa-
cattttgcc). Similarly, exon-1 of LOC387715 was amplified using
primers located in the 5=-untranslated region (5=-tgagtgagatg-
gcagctgg) and intron-1 (5=-tccagctattcaaccagagg). For restriction
fragment length analysis, CFH amplicons (443 base pairs) and
LOC387715 amplicons (547 base pairs) were digested with Hsp92
II (Promega, Madison, WI) and Pvu II (New England Biolabs,
Ipswich, MA), respectively, according to the manufacturers’ in-
structions, then visualized on 2.5% agarose-gels stained with
SYBR Gold (Molecular Probes, Eugene, OR).
2169
 Ophthalmology Volume 114, Number 12, December 2007

Table 1. Demographics and Age-related Macular Degeneration in the study eye was the first evidence of exudative AMD in 73.3%
(AMD) Phenotypes of Study Participants of patients. Subjects received a mean of 2.8 injections over a mean
follow-up period of 9.3 months.
Variable Value Table 2 displays the distribution of demographic and clinical
Number of patients 86
phenotype data for the AMD patients according to CFH Y402H
Mean age (yr) 79.8 genotype. The high-risk CFH CC genotype was seen in 22.1% of
Female 64.0% AMD patients, and the overall frequency of the C allele in this
Exudative AMD in contralateral eye (%) 23 (26.7) population was 55.2%. Mean age and gender distributions were
Predominantly classic lesions (% of gradable lesions) 31/77 (40.3) similar among the 3 CFH genotypes. The percentage of predom-
Mean GLD 3104 inantly classic lesions did not differ among the CFH genotypes.
Mean disc area 3.90 Choroidal neovascular lesions in patients with he CFH TT geno-
Mean number of treatments 2.85 type had the largest mean greatest linear dimension (GLD; P ⫽
Mean follow-up (mos) 9.33 0.02) and disc area (P ⫽ 0.03) on fluorescein angiograms obtained
Treatments/month 0.305 at the time of initial presentation (n ⫽ 77). There was no difference
in the mean follow-up period (P ⫽ 0.17) or mean number of
GLD ⫽ greatest linear dimension. treatments per months of follow-up (P ⫽ 0.82) among the CFH
genotypes.
We examined the pretreatment and posttreatment VA for all
eyes in the study by CFH genotype (Fig 1). Mean pretreatment VA
Data Analysis for the CFH CC genotype (n ⫽ 19) and for the CFH TC genotype
(n ⫽ 57) was 20/206 (Snellen acuity converted from log minimal
Descriptive statistics for all demographic and clinical variables
angle of resolution). The mean pretreatment VA (20/248) for the
were calculated and comparisons made using the t test for means
CFH TT genotype (n ⫽ 10) was somewhat worse than this, but this
with continuous data (e.g., age, VA) and the chi-square test for
difference was not significant (P ⫽ 0.86). After treatment, mean
categorical data (e.g., gender). Comparisons between genotypes
VA for the CFH TC genotype (20/170) and the CFH TT genotype
were adjusted for multiple comparisons using the Bonferroni ap-
(20/166) improved substantially, whereas the mean posttreatment
proach. The association between genotype and VA was assessed
VA for the CFH CC group fell to 20/341. Adjusting for age,
using generalized linear modeling techniques, with VA expressed
pretreatment VA, and lesion size, we found that the mean post-
in log minimal angle of resolution units. The posttreatment VA
treatment VA for the CFH CC genotype was significantly worse
was modeled after adjustment for pretreatment acuity. Univariate
than mean posttreatment VA of the TC and TT genotypes (P ⫽
analysis was conducted and any risk factor for change in VA with
0.016), indicating that bevacizumab was much less effective as
an association at the Pⱕ0.10 level was included in the final
measured by VA in patients with the CFH CC genotype than in
multivariate model. Genotype was included in the model with a
patients with the CFH TC or TT genotypes. In fact, although a
dummy variable for the homozygous candidate allele (CC for
majority (53.7%) of patients in the CFH TC and TT groups showed
CFH, TT for LOC387715) with the P-value associated with the
improvement in VA with bevacizumab treatment, only 10.5% of
coefficient indicating if posttreatment VA was influenced by the
CFH CC patients demonstrated VA improvement (P ⫽ 0.004).
candidate allele (Pⱕ0.05 indicating a significant association).
Comparing patients with known exudative AMD in the contralat-
eral eye at the time of study enrollment to those with a new
diagnosis of exudative AMD, we found no effect of contralateral
Results eye status on posttreatment VA.
Table 3 displays the distribution of demographic and clinical
Eighty-six patients with exudative macular degeneration undergo- phenotype data for the AMD patients according to LOC387715
ing treatment with intravitreal bevacizumab in one eye were en- A69S genotype. The high-risk LOC387715 TT genotype was seen
rolled in the study. Demographic information and characterization in 17.4% of AMD patients and the overall frequency of the T allele
of AMD phenotypes are presented in Table 1. Neovascularization in this population was 39.5%. Mean age and gender distributions

Table 2. Clinical Phenotypes of Age-related Macular Degeneration Patients by Complement Factor

H Genotype

Characteristic CC TC TT P
Total number of patients (%) 19 (22.1) 57 (66.3) 10 (11.6)
Mean age 78.2 79.9 82.0 0.35
Female (%) 52.6 64.9 80.0 0.27
Eyes with predominantly classic lesions 6/16 (37.5) 22/52 (42.3) 3/9 (33.3) 0.94
(% of gradable lesions)
GLD of lesions (␮m) 3528 2718 4414 0.02
Disc area 5.00 2.88 7.56 0.03
Follow-up period (mos) 8.68 9.79 7.90 0.17
Mean treatments/month 0.27 0.32 0.28 0.82
Pretreatment VA 20/206 20/206 20/248 0.86
Posttreatment VA 20/341 20/170 20/166 0.016
Eyes with improved VA (%) 2 (10.5) 31 (54.4) 5 (50.0) 0.004

GLD ⫽ greatest linear dimension; VA ⫽ visual acuity.

2170
 Brantley et al 䡠 CFH and LOC387715 Genotypes and Response to Intravitreal Bevacizumab

(P ⫽ 0.021) on angiograms obtained at the time of initial presen-

tation (n ⫽ 77). There was no difference in the mean follow-up
period (P ⫽ 0.20) or mean number of treatments per month of
follow-up (P ⫽ 0.76) among the LOC387715 genotypes.
Mean pretreatment VA for the LOC387715 GG genotype (n ⫽
33) was 20/197 and for the GT genotype (n ⫽ 38), 20/196. The
mean pretreatment VA (20/288) for the LOC387715 TT genotype
(n ⫽ 15) was worse than this, but this difference was not signif-
icant (P ⫽ 0.51). Mean posttreatment VA for the LOC387715 GG
group (20/191) and the GT group (20/166) improved, whereas the
mean posttreatment VA for the TT group fell to 20/344. However,
when adjusting for age, pretreatment VA, and lesion size, we
found that the mean posttreatment VA for the LOC387715 TT
genotype was not significantly different than for those without the
TT genotype (P ⫽ 0.18). A similar percentage of patients in each
LOC387715 genotype group demonstrated improvement in VA
with treatment (P ⫽ 0.94). As with the CFH genotypes, we found
no effect of contralateral eye status on posttreatment VA for
LOC387715.
We examined the combination of CFH and LOC387715 geno-
types to determine if the total number of risk alleles (CFH “C” and
LOC387715 “T”) was associated with a difference in posttreat-
ment VA. Evaluating 3 groups (0 –1 risk allele, 2 risk alleles, or
3– 4 risk alleles), we found no relationship between the number of
risk alleles and posttreatment VA.

Figure 1. Graphs demonstrating visual acuity (VA) before (e) and after ()
treatment with intravitreal bevacizumab. A, Pretreatment and posttreatment
VA according to complement factor H (CFH) genotype. *The difference in
posttreatment VA between patients with the CFH CC genotype and those
with the CFH TC or TT genotype was significant (P ⫽ 0.016). B, Pretreat-
ment and posttreatment VA according to LOC387715 genotype. logMAR ⫽
logarithm of the minimum angle of resolution.
were similar among the 3 LOC387715 genotypes. The percentage
of predominantly classic lesions was not significantly different
among the LOC387715 genotypes (P ⫽ 0.07). The LOC387715
TT genotype had the largest mean GLD (P ⫽ 0.012) and disc area
Discussion
In our study population, we identified a significant associ-
ation between CFH Y402H genotype and response to treat-
ment for neovascular AMD with bevacizumab. Although a
small number of reports have correlated AMD clinical phe-
notypes with CFH Y402H genotype,21–23 and one study
showed a possible association between response to photo-
dynamic therapy and CFH genotype,22 there are no avail-
able data on response to VEGF inhibitors and genotype.
The overall frequency of the CFH Y402H C allele in our
population (55.2%) is consistent with previous reports. We
found no significant difference in the percentage of eyes in
each CFH genotype group with predominantly classic le-
sions. This contrasts with our and other earlier reports21–23
that found a higher percentage of predominantly classic
lesions in the CFH CC group, and may be related to the

Table 3. Clinical Phenotypes of Age-related Macular Degeneration Patients by LOC387715 Genotype

Characteristic TT GT GG P
Total number of patients (%) 15 (17.4) 38 (44.2) 33 (38.4)
Mean age 77.4 81.1 79.4 0.32
Female (%) 66.7 60.5 66.7 0.85
Eyes with predominantly classic lesions 3/14 (21.4) 17/31 (54.9) 11/32 (34.3) 0.07
(% of gradable lesions)
GLD of lesions (␮m) 4603 2768 2909 0.012
Disc area 7.92 3.06 3.37 0.021
Follow-up period (mos) 10.33 9.03 9.21 0.20
Mean treatments/month 0.332 0.306 0.302 0.76
Pretreatment VA 20/288 20/196 20/197 0.51
Posttreatment VA 20/344 20/166 20/191 0.18
Eyes with improved VA (%) 6 (40.0) 17 (44.7) 15 (45.5) 0.94

GLD ⫽ greatest linear dimension; VA ⫽ visual acuity.

2171
 Ophthalmology Volume 114, Number 12, December 2007
smaller size of our patient cohort in the present study.
Interestingly, patients with no high-risk CFH Y402H alleles
(CFH TT) had the largest mean neovascular lesion size as
measured by GLD and disc area, consistent with our previ-
ous study.23 This suggests that, in this population, the pres-
ence of CFH Y402H high-risk alleles does not correlate
with increased choroidal neovascular lesion size.
Visual acuity at presentation was not significantly differ-
ent among the CFH genotypes. Mean posttreatment VA
improved for both the CFH TT (⫹1.7 lines) and TC (⫹0.8
lines) genotypes, but fell (⫺2.2 lines) for the CC genotype.
The fact that post-bevacizumab VA was significantly worse
in the CFH CC genotype than for the CFH TC or TT
genotypes (P ⫽ 0.016) suggests that genetic factors may
play a critical role in the efficacy of therapeutic interven-
tions for exudative AMD. One possibility is that patients
with the CFH CC genotype have critical alterations in local
inflammatory mediators owing to an abundance of the vari-
ant CFH protein, and that additional or more frequent bev-
acizumab therapy is required to achieve VA improvement.
Alternatively, it may be that bevacizumab is simply not as
effective in patients with the CFH CC genotype, and that
more intensive treatment will not be beneficial. A prospec-
tive study evaluating response to standardized treatment
regimens according to CFH genotype would help to distin-
guish between these possibilities.
The overall frequency of the LOC387715 high-risk T
allele in our population was 39.5%, consistent with previous
reports. There was no significant difference in the percent-
age of predominantly classic lesions among the LOC387715
genotypes. Patients with two copies of the LOC387715 risk
allele (LOC387715 TT) had a significantly larger mean
lesion size as measured by GLD and disc area (P ⫽ 0.01).
This is interesting and suggests that the LOC387715 A69S
variant, in contrast to the CFH Y402H variant, could be
associated with anatomic or metabolic changes that lead to
the development of larger neovascular lesions. Lesion type
could potentially play a role; the LOC387715 TT group had
the highest percentage of occult lesions (78.6%; P ⫽ 0.07),
which can often be larger than predominantly classic lesions
at the time of discovery.
Initial VA was somewhat worse in the LOC387715 TT
group compared with the other groups, and again, this
difference may be due to the larger lesion size in this group.
Mean posttreatment VA improved for both the LOC387715
GG (⫹0.1 lines) and GT (⫹0.7 lines) genotypes, but fell
(⫺0.8 lines) for the LOC387715 TT genotype. This differ-
ence in response to treatment, however, did not reach sta-
tistical significance. The percentage of patients in each
LOC387715 genotype group whose VA improved was also
similar.
This retrospective study was limited by the size of the
patient cohort; additional genotype–phenotype correlations
might be detected with a larger sample size. Despite this, we
did identify significant differences in lesion size among the
CFH and LOC387715 genotypes and, most strikingly, in the
response of the CFH CC genotype to intravitreal bevaci-
zumab. We assessed the interaction of the CFH Y402H
and LOC387715 A69S variants and found no relationship
between the total number of risk alleles and posttreatment
2172
VA. From this we believe that, in this sample, the CFH
Y402H variant influences posttreatment VA, but the
LOC387715 A69S variant does not. Further investigation
with a larger patient cohort may allow for a better eval-
uation of such gene interactions and their relationship to
treatment response.
In summary, we have evaluated AMD clinical pheno-
typic characteristics and response to treatment with intrav-
itreal bevacizumab with respect to the CFH Y402H and
LOC387715 A69S genotypes. We found a relationship be-
tween choroidal neovascular lesion size and CFH and
LOC387715 genotypes. Most important, we found that the
response to intravitreal bevacizumab was significantly
worse for the CFH Y402H CC genotype compared with the
TC and CC genotypes. Further investigation of this poten-
tial pharmacogenetic effect is warranted.
Acknowledgments. The authors thank Michael Plotzke for
statistical assistance.
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