|Variations in Genes Can Influence the Risk of Developing Age-Related
Macular Degeneration and Other Disease Such as Cancer
A team of researchers has determined that variations in certain genes involved
in fighting infection can successfully predict the risk of developing age-related
macular degeneration (AMD), the leading cause of blindness in white Americans
over the age of 60. The team*, led by Bert Gold, Ph.D., and
Michael Dean, Ph.D., of the National Cancer Institute (NCI), part of the National
Institutes of Health (NIH), identified a genetic variant that is associated with
an increased risk of developing AMD. They also found two genetic variants that
protect against developing this disease. Study results appear online March 5,
2006 in Nature Genetics**.
The genes analyzed in this study — Complement Factor B (BF) and Complement
Component 2 (C2) — contain the instructions to make proteins that activate
the body’s immune defense against microbial infections. These defense responses
are part of a system called the complement pathways. These pathways involve numerous
proteins in the blood that work in association with the body’s immune cells and
antibodies to destroy bacteria, viruses or fungi invading the body. Some complement
proteins can stimulate inflammation, the redness and swelling that result in
tissues when they are infected.
Previous studies have shown that genetic variations in complement pathway genes
can cause a dysfunction in the inflammatory response that plays a central role
in the pathology of AMD***. Based on these findings, investigators
initiated this study, which screened almost 900 patients with AMD and 400 unaffected
individuals for genetic variants in the BF and C2 genes. Data analysis revealed
that specific variants in each gene were associated with AMD. One genetic variant
conferred an increased risk for AMD, while two genetic variants showed protection
against developing this disease. These results, when analyzed in association
with results linking AMD and genetic variants of Complement Factor H — a
gene than contains the instructions to make a protein that inhibits the complement
system — showed that 56 percent of the unaffected individuals had a variant
that conferred protection to AMD while 74 percent of those with AMD had no protective
“These studies confirm that AMD has a strong genetic component,” said Paul
Sieving, M.D., Ph.D., director, National Eye Institute, at NIH. “This may support
the development of screening tests for risk of developing AMD, which would allow
us to administer treatment early in the course of disease. Knowing the underlying
genetic alterations for risk could also aid in developing preventive therapies
tailored to an individual’s genetic background.”
AMD is a disease that blurs or destroys sharp, central vision. Approximately
7.3 million Americans have intermediate stages of AMD with a high risk of increasing
vision loss, while 1.8 million are visually impaired due to this disease. There
is no known cure for AMD.
“We were studying a very common disease, but no one knew its cause. It was unexpected
to find that the immune system was involved in causing AMD,” said Gold, Laboratory
of Genomic Diversity at NCI and lead author of this study. “Understanding how
genetic variations in complement pathway genes are causing this common, complex
disease could be very helpful in understanding other complex diseases, such as
In the cancer field, there is increasing interest in how infection and chronic
inflammation could promote tumor growth. Studies have shown that inflammatory
cells can promote tumor growth by producing a favorable growth environment. Complement
proteins play an important role in inflammation. This discovery of a link between
genetic variants in complement genes and AMD may be relevant to the role of complement
in cancer progression.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
* Researchers are from the Departments of Ophthalmology and Pathology & Cell
Biology, Columbia University, New York, N.Y.; the Department of Ophthalmology and Visual
Sciences, Center for Macular Degeneration, University of Iowa, Iowa City, Iowa; Sapio
Sciences LLC, York, Pd.; F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute,
University of Pennsylvania School of Medicine, Philadelphia, Pa.; and the Laboratory
of Genomic Diversity, NCI, Frederick, Maryland.
** Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K,
Cramer K, Neel J, Bergeron J, Barile GR, Smith RT, Chang S, Yannuzzi LA, Merriam JC,
Barbazetto I, Lerner LE, Russell S, Hoballah J, Hageman J, Stockman H, Hageman GS, Dean
M, and Allikmets R. Variation in the Factor B (BF) and Complement Component
2 (C2) genes in the MHC Class III Locus is associated with age-related macular
degeneration. Nature Genetics, online March 5, 2006.
*** Hageman, GS et. al., Common haplotype in the complement regulatory
gene, Factor H (HF1/CFH), predisposes Individuals to age-related macular degeneration. Proc.
Natl. Acad. Sci. USA, May 17, 2005; 102 (20) 7227-7232.