Researchers Discover Gene Believed Responsible for Age-Related Macular Degeneration
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(Boston) – Researchers from Boston University School of Medicine (BUSM), UT Southwestern Medical Center at Dallas, and SEQUENOM, Inc. (NASDAQ:SQNM), report the discovery of a genetic variation, that is the strongest known risk factor associated with age-related macular degeneration (AMD). Published in the March 10, 2005, online issue of the journal Science, the study entitled “Complement Factor H Polymorphism and Age-Related Macular Degeneration,” details the discovery of the gene that may account for approximately fifty percent of the cases of AMD in the population.
“Considering that AMD is such a common and complex condition with multiple risk factors, we did not expect that we would identify a gene that is responsible for almost half of the cases,” said author Lindsay A. Farrer, PhD, chief of the genetics program at BUSM, and a professor of medicine, neurology, genetics and genomics, epidemiology and biostatistics at BUSM.
The biological basis of this disorder, which is the most common cause of blindness in the elderly, is unclear. However, it was strongly suspected that genetics did play a role. The researchers tested single nucleotide polymorphisms (SNPs) for association of AMD in a region of 14 million base pairs on chromosome 1q25-31 where a gene for AMD had been previously localized in families with multiple persons affected with AMD.
Using two independent case-control populations, the researchers found that possession of at least one copy of histidine at position 402 of complement factor H (CFH) increased the risk of AMD almost three-fold.
“Given the rapid aging of the population, an estimated 3 million people will have complications of AMD by the year 2020. We hope our findings will create new avenues for developing preventative and therapeutic strategies for AMD,” added co-author and retina specialist Albert O. Edwards, MD, PhD, currently the President of the Institute for Retina Research at the Presbyterian Hospital of Dallas, Texas. Edwards conducted his research while on faculty at UT Southwestern.
“We are pleased to be part of this important collaboration with BU School of Medicine and UT Southwestern, and that the use of our MassARRAY System helped contribute to the discovery of the genetic variations associated with AMD,” said Charles Cantor, PhD, SEQUENOMS’s chief scientific officer.
This research was funded by UT Southwestern grants from the National Eye Institute and Research to Prevent Blindness.
About Boston University School of Medicine
Boston University School of Medicine is a leading academic and research institution, with an enrollment of nearly 630 students and nearly 2,400 full-time, part-time and volunteer faculty members. The School of Medicine is nationally known for its programs in Alzheimer’s disease, arthritis, cardiovascular disease, cancer, human genetics, pulmonary diseases and dermatology, among others. The School is affiliated with Boston Medical Center, its principal teaching hospital, and Boston Veterans Administration Medical Center. Along with Boston Medical Center, the School of Medicine is a partner in Boston HealthNet, a consumer-driven urban health network.
About Presbyterian Hospital of Dallas
Established in 1966, Presbyterian Hospital of Dallas (PHD) has provided nearly 39 years of service and is the anchor hospital of Presbyterian Healthcare System, a part of the faith-based, non-profit Texas Health Resources system. PHD is a recognized clinical program leader, providing technologically advanced care in services to patients in Women and Infants, Cardiovascular, Orthopedic, Neuroscience, Digestive/Surgery, Oncology, and Ambulatory Care. PHD is a regional referral hospital for North Texas and beyond. The 866-bed facility maintains approximately 4,000 employees and an active medical staff of more than 1,000 physicians.
SEQUENOM is committed to providing the best genetic analysis products that translate genomic science into superior solutions for biomedical research, molecular medicine and agricultural applications. The Company’s proprietary MassARRAY system is a high-performance DNA analysis platform that efficiently and precisely measures the amount of genetic target material and variations therein. The system is able to deliver reliable and specific data from complex biological samples and from genetic target material that is only available in trace amounts.
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Complement Factor H Polymorphism and Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is one of the leading causes of blindness in older individuals. It is a common, late-onset, complex trait with multiple risk factors. In the United States, more than seven million individuals have retinal features that place them at risk for developing vision loss from complications of AMD. These complications include wet or exudative macular degeneration and death of the retina referred as geographic atrophy by retinologists.
The study appearing in the March 10, 2005 issue of Science, tested single nucleotide polymorphisms (SNPs) at the ARMD1 locus for association with AMD in two case-control populations.
Significant association (p = 4.95 x 10-10) was identified within the regulation of complement activation locus and centered over a Tyr402His protein polymorphism in the gene encoding complement factor H. Individuals having at least one histidine at amino acid 402 demonstrated an increased risk of AMD by 2.7-fold and accounted for half (50%) of the attributable risk of AMD.
• An association study was conducted on a case-control population. This involved a discovery sample of 224 cases and 134 controls that were selected for initial genotyping. A replication study involving 176 cases and 68 controls was also conducted to verify findings.
• Previous research had initially identified the ARMD1 locus in a large AMD family1 and subsequently confirmed in several AMD genetic studies. Initial genotyping in the discovery sample suggested the regulation of complement activation (RCA) locus contained one or more genetic variants leading to an increased risk of developing AMD.
• The RCA locus contains several genes including the one encoding for complement factor H (CFH). A total of 86 SNPs located across the RCA locus were genotyped and twenty-nine demonstrated an association with AMD, including a non-synonymous coding SNP rs1061170.
• The genotype frequency data for rs1061170 demonstrated that the association with AMD was largely due to an excess of CC homozygotes and CT heterozygotes in cases compared to controls.
• The SNPs most significantly associated with AMD were in CFH or within 221 kb downstream of CFH. This was further analyzed and evidence suggested that multiple signals in the RCA locus were related to a single haplotype and likely caused by a single genetic effect.
• Upon completion of the replication sample, it was concluded that the relative risk for AMD was 2.7 for individuals with at least one C allele.
The current study provides evidence that individuals with a SNP located at amino acid 402 of CFH have an increased risk of developing AMD. The attributable risk for the C allele (His) in the study is fifty percent (50%). This suggests that individuals either homozygous or heterozygous for histidine at amino acid 402 of CFH account for half of all AMD cases. The research proposes new avenues for developing preventative and therapeutic strategies for AMD.
1. M.L. Klein D. Schultz, AO Edwards et al., Arch Ophthalmol, 116,1082 (1998).