High AMD risk genotypes respond better to Lucentis therapy
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risk genotypes response better to Lucentis (ranibizumab) therapy than
patients with lower risk genotypes.
Epidemiological and association studies have shown that both genetic
and environmental factors play a major role in the development of AMD.
Association studies have implicated variants in a number of genes,
with the largest effects observed with alleles of the complement
factor H (CFH), HTRA1 and Apolipoprotein E genes. Association with AMD
has also been reported for polymorphisms in the VEGF gene.
This study compared genotypes for CFH, HTRA1 and VEGF, and other
potential variables, with visual acuity response after 6 months of
intravitreal ranibizumab therapy for neovascular AMD.
Methods & Results
Best corrected visual acuity letter score was recorded at baseline and
each subsequent visit. Age, sex, smoking history, lesion type and the
number of injections were also recorded. Genotypes were obtained for
rs11200638 in HTRA1, rs1061170 in CFH and rs1413711 in VEGF. Data were
analysed with treatment response at month 6 as both a binary (>5
letter improvement vs =5 letter gain) and a linear trait.
This initial study cohort consisted of 104 Caucasian neovascular AMD
patients treated with intravitreal ranibizumab. Trends towards a more
favourable outcome were seen with the higher AMD risk genotypes in CFH
and VEGF in both the linear and binary models and in HTRA1 in the
linear model alone. For CFH, mean letter score change after 6 months
was +1.6, +5.9 and +7.2 letters for the TT, TC and CC genotypes and a
>5 letter gain was seen in 34.6%, 56.6% and 56%, respectively. For
VEGF, mean letter score change after 6 months was +1.3, +5.8 and +7.4
letters for the TT, TC and CC genotypes and a >5 letter gain was seen
in 40%, 55.8% and 51.9%, respectively. For HTRA1, mean letter score
change was +2.2, +7.5 and +2.9 letters for the GG, GA and AA
genotypes. (TABLE)
Discussion & Conclusions
In the ANCHOR and MARINA studies, the response to treatment seemed to
be consistent despite baseline variation in lesion size, visual acuity
and lesion characteristics. Although current evidence still suggests
that regular monthly treatment is associated with the optimum visual
acuity response, a number of other studies have suggested that a
proportion of patients may not need such regular dosage after the
initial loading phase to maintain the early gain in visual acuity. In
the PIER study, 40% of patients maintained their initial gain with
quarterly treatment after the initial loading phase although 60% lost
their initial gain. We hypothesised that the variable acuity responses
seen in these trials may be related to genotype. The results of our
pilot study suggest that the visual acuity change after 6 months of
ranibizumab therapy may indeed be influenced by polymorphisms in three
genes that are known to increase the risk of developing neovascular
AMD.
Prior studies have investigated a possible association between the CFH
genotype and response to verteporfin photodynamic therapy (PDT) and
both intravitreal bevacizumab and ranibizumab therapies. For PDT, the
results are conflicting. Goverdhan reported greater loss of visual
acuity after PDT in patients with the CC and CT CFH genotypes and Feng
reported a trend towards an association between a negative PDT
response and the CC genotype. However, Brantley identified a worse
outcome with the TT CFH genotype and Seitsonen found a lower
proportion of PDT responders in the TT genotype group. With
intravitreal bevacizumab, Brantley and Nischler reported a trend
towards reduced visual acuity and a lower percentage of subjects with
improved acuity for the CC genotype. Lee identified that patients with
the CC genotype required one more ranibizumab injection over the first
9 months, but the CFH genotype was not significantly associated with
post-treatment visual acuity at either 6 or 9 months, after adjusting
for pretreatment acuity. In our study, we did not find an association
between CFH genotype and the number of injections in the first 6
months, but we did find a trend towards a better visual acuity
response with the higher risk TC or CC genotypes.
Although the VEGF gene does not appear to be a major genetic
contributor to the development of neovascular AMD, the +674 C/T
polymorphism has been most strongly associated with neovascular AMD in
a Caucasian population. To our knowledge, no other group has
investigated the influence of this polymorphism on the response to
ranibizumab therapy for AMD. However, Immonen has recently identified
a potential link between other intronic and promoter site VEGF
polymorphisms and the anatomic response to PDT.
Polymorphisms in the promoter region of the HTRA1 (high-temperature
requirement factor A-1) gene have been shown to increase
susceptibility to AMD, especially the neovascular form, in Caucasian
and other populations. Possession of the high-risk A allele is
associated with increased levels of the HTRA1 protein in drusen,
retinal pigment epithelium and choroidal neovascular membranes of eyes
with AMD. In our series, a trend towards better visual acuity outcome
after 6 months of intravitreal ranibizumab therapy was seen for the
increasing AMD risk HTRA1 genotypes, using the linear model alone.
Although the total number of injections was similar for all three
HTRA1 genotypes, there was a large gain in visual acuity in the
individuals who were heterozygous for the high AMD risk A allele and a
more modest gain in homozygotes. The apparent advantage of
heterozygotes over homozygotes for either HTRA1 genotype is
unexpected.
In this pilot study, we have identified preliminary evidence of
associations between visual acuity outcome after 6 months of
intravitreal ranibizumab and polymorphisms in the CFH, VEGF and HTRA1
genes. For each gene, a trend towards a better outcome was seen with
the polymorphisms considered to increase the risk of developing
neovascular or advanced AMD. Although the mechanism by which these
polymorphisms contribute to AMD susceptibility is not known, these
findings may imply that neovascular AMD is not one disease but rather
several different diseases with a common end point. There may be a
common form of AMD that results from the action of one or more
high-risk alleles at HTRA1, CFH and VEGF. This form of AMD may be
characterised by high levels of intraocular VEGF and may respond
favourably to ranibizumab therapy. Another form of AMD, secondary to
other susceptibility genes, may not be characterised by high
intraocular VEGF and may respond differently to treatment.
In this study, we have identified trends suggesting a more favourable
visual acuity outcome after 6 months of intravitreal ranibizumab
therapy with the higher AMD risk CFH, VEGF and HTRA1 genotypes. These
findings may imply that the mechanisms underlying the more common
form(s) of AMD, due largely to the action of risk alleles at the loci
tested in this study, are those best targeted by anti-VEGF therapy.
Neovascular AMD in individuals without these high-risk alleles may in
part be due to mechanisms that respond less favourably to anti-VEGF
therapy.
Br J Ophthalmol. 2012 Feb;96(2):208-12
http://www.ncbi.nlm.nih.gov/pubmed/21558292
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