AGE-RELATED
MACULAR DEGENERATION
Understanding
the Role of Genetics and Nutritional
Supplementation in the
Development of AMD
Researchers
uncover new links in the campaign to stop vision loss.
BY
JUDITH RIDDLE, SENIOR EDITOR
Age-related
macular degeneration (AMD) is the leading cause of blindness in the Western world
in people over age 60. The disease affects 1.75 million patients in the United States,
and seven million more remain at risk.1
These facts are well established.
What has not been fully established — or understood —
but continues to evolve, is the research on the role of genetic and nutritional
factors in the development and progression of AMD.
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Figure
1. Complement factor H directly inhibits both the the classical and alternate pathways,
and indirectly inhibits the lectin pathway. Lack of this inhibition can result
in uncontrolled activation of the complement cascade.
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CANDIDATE GENE APPROACH
Researchers have long known that certain
families are genetically predisposed to AMD. Knowing that fact has spurred their
attempts to isolate a single gene or family of genes that might be responsible for
initiating advanced forms of the disease, said Darius Moshfeghi, MD, at the May
2006 Retinal Physician Symposium.
Using the "candidate gene approach," researchers have tried to
identify a heritable disease with early onset that had traits similar to AMD, such
as drusen and retinal pigment epithelial (RPE) changes. Yet, no disease matched
these characteristics, Dr. Moshfeghi said. AMD is characterized by late onset and
polygenic origin, neither of which is ideal to identify candidate genes.
RARE BUT SIMILAR DISEASE
The logical next step for researchers was
to focus on the inflammatory origins of AMD. In doing so, they discovered that drusen
are a product of a localized inflammatory response following RPE injury,2,3
that "complement cascade activation" is implicated in drusen formation4
and drusen contain numerous inflammatory modulators, such as complement pathway
components and the membrane attack complex, Dr. Moshfeghi said.
Although researchers could not identify a heritable disease with
AMD characteristics, they did discover that the rare disease membranoproliferative
glomerulonephritis type II (MPGN) had AMD-like ocular signs.5,6
The disease is characterized by uncontrolled activation of the alternative complement
pathway. And the drusen seen in MPGN are indistinguishable from those seen in AMD.
Recent research has shown that a point mutation in the complement factor H gene
(HF1) led to MPGN in pigs.7 In fact, mice deficient in complement factor
H developed severe MPGN.8
COMPLEMENT FACTOR H GENE
With these findings in mind, researchers
began looking for a connection between HF1 and the origins of AMD. They discovered
HF1 was a major inhibitor of three alternative complement pathways (classical, lectin
and alternate) that have been shown to precipitate inflammatory processes and lead
to drusen formation, Dr. Moshfeghi said (Figure 1).
"Four
groups of researchers identified the location of the [HF1] gene on chromosome 1
and the corresponding tyrosine-histidine [single nucleotide] polymorphism (SNP),"
Dr. Moshfeghi continued. "To date, 50% of AMD can be attributed to this SNP, with
a 7.4 odds ratio for developing the disease.9"
Recently, researchers associated nonsynonymous SNPs located at
chromosome 10q26 with AMD. "[They also] reported an odds ratio of 5 and a 57% attributable
risk for the plekha1/loc387715 SNP — a gene that codes for a protein involved
in focal lymphocyte activation, again highlighting the role of inflammation in AMD,10"
Dr. Moshfeghi explained.
RISK VS. PROTECTIVE FACTORS
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Figure
2. Categories 3 and 4 were combined and compared across four treatment groups. The
placebo group had the highest rate of progression. Both zinc alone and antioxidants
plus zinc demonstrated significant improvements in the rate of progression to advanced
AMD. |
Researchers also found that factor B is
a major activator of the alternate complement pathway, while complement component
C2 is an activator of the classical pathway.11
However, the L9H variant of complement factor B and the E318D variant of component
C2 have been shown to be protective for AMD.11
"While 60% of the risk in affected patients and 65% of the protection
in controls is attributable to complement factor H, 40% of the risk and 35% of the
protection is attributable to C2/BF locus," Dr. Moshfeghi said. "And this is borne
out by the genetic algorithm analysis demonstrating that C2 and BF contribute from
35% to 40% of the risk for AMD."
UNEXPLAINED RISK
Despite these advances in our knowledge
of the role genetics play in AMD development, however, 50% of the remaining risk
for the disease remains unexplained, Dr. Moshfeghi continued. As demonstrated, not
all SNPs in the complement factor H gene are bad, which explains why some patients
with pathogenic variants do not develop AMD. In fact, four complement factor H SNPs
have been identified as protective against AMD.12
What we know for sure is that AMD risk is associated with local
inflammatory insult to RPE, complement pathway activation and polygenic factors.
Genes contributing risk have been identified on chromosomes 1, 6 and 10, and all
are associated with either the complement pathways or lymphocyte activation.
Just as the research on genetics continues to evolve so does our
knowledge of how much nutritional supplements impact AMD development.
NUTRITIONAL SUPPLEMENTS
Environmental influences, such as oxidative
cell damage, have been implicated in the pathogenesis of AMD. For instance, oral
zinc supplementation has been shown to decrease vision loss from the disease.13
In the Age-Related Eye Disease Study (AREDS) — the first
randomized clinical trial to test the efficacy of a high-dose antioxidant-combination
formula — researchers showed that patients at high risk for developing advanced
AMD lowered their odds after taking vitamin C (500 mg), vitamin E (400 IU), beta-carotene
(15 mg), zinc (80 mg) and copper (2 mg).14
Patients who received a combination of antioxidants plus zinc
saw a 34% and 38% reduction in risk for developing advanced AMD and neovascular
AMD, respectively, Dr. Moshfeghi said.
Treatment groups were divided into antioxidants, zinc, antioxidants
plus zinc, and placebo. Patients with intermediate and advanced AMD in one eye realized
benefits from taking antioxidants plus zinc, and zinc alone. The nutrients had no
benefit, however, to those who had either no AMD or early signs of AMD, Dr. Moshfeghi
continued.
ANTIOXIDANTS
AND VISUAL ACUITY
Researchers also assessed the effects of
antioxidants plus zinc on visual acuity (VA). The primary outcome measure included
a loss of at least three lines of vision from baseline. The secondary outcomes were
VA loss with an AMD event and VA worse than 20/100.
Researchers found that patients with either intermediate or advanced
AMD who received the antioxidant plus zinc formulation showed a significant improvement
in the primary and secondary outcomes. In fact, the antioxidant plus zinc combination
was superior to placebo and other formulations for every functional outcome measure
with the exception of vision worse than 20/100 (Figure 2).
CLINICAL APPLICATIONS
These results clearly suggest that physicians
should prescribe antioxidants plus zinc to patients with intermediate or advanced
AMD, or vision loss from AMD in one eye.
If the at-risk population in the United States took this AREDS
formulation, as many as 300,000 AMD patients could avoid losing their vision.15
It's an astonishing number that has led physicians to recommend the AREDS formula
to patients who fit the study criteria, Dr. Moshfeghi said.
The success of combining antioxidants and zinc to prevent vision
loss has also led to questions about the role other nutrients might play. To answer
these questions, Dr. Moshfeghi said, researchers will conduct an AREDS II study
to evaluate the effects of dietary xanthophylls (lutein and zeaxanthin) and omega-3
fatty acids on AMD progression.
REFERENCES
1. Friedman DS, O'Colmain BJ, Muñoz
B, et al. The Eye Diseases Prevalence Research Group. Arch Ophthalmol. 2004;122:564-572.
2. Hageman GS, Luthert PJ, Victor Chong NH, et al. 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. 2001;20:705-732.
3. Anderson DH, Mullins RF, Hageman GS. A role of local inflammation
in the formation of drusen in the aging eye. Am J Ophthalmol. 2002;134:411-431.
4. Crabb JW, Miyagi M, Gu X, et al. Drusen proteome analysis:
An approach to the etiology of age-related macular degeneration. Proc Natl Acad
Sci USA. 2002;99:14682-14687.
5. Mullins RF, Aptsiauri N, Hageman GS. Structure and composition
of drusen associated with glomerulonephritis: implications for the role of complement
activation in drusen biogenesis. Eye 2001;15:390-395.
6. Colville D, Guymer R, Sinclair RA, et al. Visual impairment
caused by retinal abnormalities in mesangiocapillary (membranoproliferative) glomerulonephritis
type II ("dense deposit disease"). Am J Kidney Dis. 2003;42:E2-E5.
7. Jansen JH, Hogasen K, Harboe M. In situ complement activation
in procine membranoproliferative glomerulonephritis type II. Kidney Int. 1998;53:331-349.
8. Pickering MC, Cook HT, Warren J, et al. Uncontrolled C3 activation
causes membranoproliferative glomerulonephritis in mice deficient in complement
factor H. Nature Genetics. 2002;31:424-428.
9. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism
in age-related macular degeneration. Science. 2005;308:385-389, 419-421, 421-424.
10. Jakobsdottir J, Conley YP, Weeks DE, et al. Susceptibility
genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet. 2005;77:389-407.
11. Nature Genetics 2006 Advance Publication.
12. Hageman GS, Anderson DH, Johnson LV, et al. A common haplotype
in the complement regulatory gen factor H (HF1/CFH) predisposes individuals to age-related
macular degeneration. Proc Natl Acad Sci USA. 2005;102:7227-7232.
13. Newsome DA, Swartz M, Leone NC, et al. Oral zinc in macular
degeneration. Arch Ophthalmol. 1988;106:192-198.
14. Age-related Eye Disease Study Research Group. A randomized,
placebo-controlled, clinical trial of high-dose supplementation with vitamins C
and E, beta carotene, and zinc for age-related macular degeneration and vision loss:
AREDS report no. 8. Arch Ophthalmol. 2001;119:1417-1436.
15. Bressler NM, Bressler SB, Congdon NG, et al. Potential public
health impact of age-related eye disease study results: AREDS report no. 11. Arch
Ophthalmol. 2003;11:1634-1636.
Retinal Physician, Issue: September 2006