AMD treatment response to Lucentis influenced by genetics
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from genetic and environmental influences. This past decade have seen
several genes associated with the disease. Variants in five genes have
been confirmed to play a major role. It is hoped that such research
will define the genetic biomarker spectrum to allow treatment
individualization and optimize visual outcomes.
The objective of this study was to evaluate whether genes influence
treatment response to ranibizumab for neovascular AMD.
PHARMACOGENETICS OVERVIEW
The theory of complex traits is based upon the idea that multiple
variations in the genetic code (most frequently single-nucleotide
polymorphisms [SNPs], insertions or deletions [“indels”], and copy
number variants) act in concert to determine a particular phenotype.
Evidence suggests that these variants result in functionally important
alterations in, among other things, the activity, expression levels,
stability, and splicing of the RNA and proteins they encode. The
action of these variants is, however, not independent of external and
environmental influences.
This forms the basis of pharmacogenetics, which attempts to define the
genetic variants that influence variable response to medication. The
ultimate goal of pharmacogenetic studies is to identify those who
respond best and avoid adverse reactions.
There are several significant social consequences of successful
pharmacogenetics research. There will be a major change in the way
individuals view their health and the taking of medicines. The hope
would be that the large numbers of adverse drug reactions would be
reduced. There is a possibility that when whole genome sequencing
becomes a routine and inexpensive undertaking, a pharmacogenetic
profile might be constructed in early life in readiness for future
therapeutic need.
GENETICS OF AMD
That genetics has a significant etiological role in AMD is now beyond
question. Studies to identify causal variants initially concentrated
on genome-wide linkage and association analyses. A meta-analysis of
these and other results showed reassuring replication of similar
chromosomal loci, several of which remain under investigation.
The first specific replicated genetic variant to be associated with
advanced AMD was the SNP rs1061170 (T1277C; Y402H) in the complement
factor H (CFH) gene. Additional SNPs and haplotypes in CFH and
neighboring genes have also been associated with drusen formation and
advanced AMD. CFH is a regulator of complement, dysfunction of which
has been linked to retinal pathology. Recently, SNPs in other
complement components have been associated with advanced AMD:
complement factors 2 (C2), B (CFB), 3 (C3), and I (CFI).
A major AMD-susceptibility locus has also been identified on
chromosome 10q26, a region where linkage disequilibrium has made it
difficult to distinguish the causal genetic variant: the SNP,
rs10490924 (A69S), is within the gene, ARM-susceptibility 2 (ARMS2).
This putative gene has unknown function, and its protein product has
been identified in several subcellular compartments or the cytoplasm.
The SNP, rs11200638, is located in the promoter of the gene HTRA1, a
serine protease found in the retina (among other tissues), and the SNP
may alter gene expression. In complete linkage disequilibrium with
this SNP is an indel in ARMS2 that may affect translation of the ARMS2
protein.
PHARMACOGENETICS IN AMD
Genetic variants contribute substantially to the etiology of AMD. As a
result, there has been interest in examining whether these common SNPs
and other candidate genes may play a pharmacogenetic role. Three
treatments are currently utilized for the treatment of AMD:
Age-Related Eye Disease Study (AREDS) supplementation, anti-VEGF
therapy, and photodynamic therapy (PDT). Studies thus far have largely
been limited to retrospective analyses.
AREDS Supplements
The AREDS study (a large prospective multicenter randomized trial)
found a beneficial effect of zinc and antioxidants (beta carotene,
vitamin C, and vitamin E) in slowing progression of disease as
compared with placebo alone. Using this progression data and combining
it with genetic analyses of samples from the cohort, it has been
possible to suggest that those individuals taking the supplements who
had the low-risk genotype in CFH experienced less disease progression.
One potential conclusion is that any genetic predisposition to AMD
reduces the effectiveness of the supplements that remain commonly used
for dry AMD in the United States.
Photodynamic Therapy
PDT has largely been replaced by anti-VEGF therapy, though it still
has a role for certain patients with AMD, potentially in combination
with other agents and in those where other treatments may be
contraindicated.
Experience has shown variability in treatment success, leading some
observers to begin to hypothesize that effectiveness might be altered
by an individual’s ability to activate coagulation factors in
response to PDT. A number of single gene disorders result in
coagulapathies and their prevalence was evaluated in two studies.
Patients determined to be PDT responders and nonresponders were
genotyped for a number of coagulation factor mutations. The results
suggested that those carrying the G185T mutation of factor XIII-A,
which results in a hyperfibrinolytic state, were more likely not to
respond to PDT, whereas those with factor V 1691A and prothrombin
20210A, both prothrombotic state, did better.
Anti-VEGF Agents
This treatment has been shown to have significant efficacy and has
been the subject of interest as to whether genetics may play a role in
outcomes. In a study of 86 patients treated with bevacizumab
(Avastin), those with the risk CC genotype in CFH had worse visual
outcomes than those with other genotypes. This appears to be
replicated by a larger study of patients receiving ranibizumab.
Although these are associations rather than causal findings, these
studies introduce the idea that common AMD-susceptibility genes may
play a role in determining treatment outcome.
METHODS & RESULTS
The study was a two-site prospective open-label observational study of
patients newly diagnosed with exudative (neovascular) AMD receiving
intravitreal ranibizumab therapy. Treatment-naïve patients were
enrolled at presentation and received monthly "as needed" therapy.
Clinical data was collected monthly and DNA extracted. Genotyping was
performed using the Illumina (San Diego, California) 660-Quad
single-nucleotide polymorphism (SNP) chip. Regression analyses were
performed to identify SNPs associated with treatment-response end
points.
Sixty-five patients were enrolled. No serious adverse events were
recorded. The primary outcome measure was change in ETDRS visual
acuity at 12 months. A SNP in the CFH gene was found to be associated
with less improvement in visual acuity while receiving ranibizumab
therapy. The C3 gene, among others, was associated with reduced
thickening and improved retinal architecture. VEGFA, FLT1, and CFH
were associated with requiring fewer ranibizumab injections over the
12-month study.
DISCUSSION & CONCLUSIONS
To date, two pharmacogenetic studies of anti-VEGF therapy for
neovascular AMD have been published. Both were retrospective. The
first reported the results of 86 patients treated with bevacizumab
(Avastin), the humanized monoclonal antibody from which ranibizumab
(Lucentis) was developed. The second included 156 patients who
received bevacizumab.110 It was the intent of this study to overcome
many of these problems with prospective enrollment and clearly stated
inclusion/exclusion criteria that limit phenotypic heterogeneity while
achieving a reasonable enrollment rate.
When outcomes are examined independent of genotype, the eyes enrolled
performed similarly to other studies. On average, individuals gained
almost 6 ETDRS letters, and the OCT central macular thickness reduced
by about 110 µm. On average, six or seven ranibizumab injections were
required over the year, which indicates that treating
physicians/investigators adhered to clinical practice norms. Overall,
these are typical results for eyes with neovascular AMD.
In line with the two previous retrospective studies, the CFH gene was
implicated in determining poorer visual outcomes together with a SNP
in the CTGF gene. It is not known why the CFH gene, which has been
identified in numerous studies as one of the two major susceptibility
variants for AMD development, might influence treatment response. It
is tempting to speculate that this is because genotypes in CFH dictate
the severity or persistence of the CNV.
In analyses on the change in central macular thickness (at both 6 and
12 months), a good surrogate for improved anatomy of the central
macular region and in turn crudely correlated with better vision, the
minor allele of a SNP in complement factor 3 (C3) appears associated
with reduced thickening and improved architecture. This same SNP has
been previously implicated as an AMD susceptibility variant.
The candidate gene analysis strongly implicates FLT1 (VEGFA receptor)
in the treatment response, identifying several SNPs associated with
persistent leakage on fluorescein angiography at both 6 and 12 months.
No other genes are identified on genome-wide analysis.
One of the most pertinent pharmacogenetic findings would be the
identification of genetic variants that might be used to predict which
eyes might receive less frequent injections. In this regard, this
study reveals three biologically plausible candidates warranting
further investigation: VEGFA, its receptor FLT1, and CFH.
The findings from this study have several uses. Once validated,
screening for these specific genetic variants can be performed quickly
and easily in the clinical environment to identify patients’
response characteristics. In those with favorable genetic
predisposition, in the case of ranibizumab, fewer injections need to
be scheduled and perhaps the intervals between treatments and visits
can be lengthened. In the case of those with worse genotypes, more
frequent interventions can be considered, including potentially
involving the use of other modalities. Additionally, this form of
research can identify new avenues for drug development by implicating
novel genes and the proteins they encode in disease pathogenesis and
susceptibility.
In summary, this study is a prospective pharmacogenetic study of
genetically determined treatment response to intravitreal ranibizumab
for neovascular AMD. Although small in nature, the aim was principally
to demonstrate the methodology needed to conduct such studies.
Encouragingly, the results identify a number of putative genetic
variants, which will be further examined by replication and functional
studies to elucidate the complete pharmacogenetic architecture of
therapy for AMD.
Trans Am Ophthalmol Soc. 2011 Dec;109:115-56
http://www.ncbi.nlm.nih.gov/pubmed/22253485
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