For the fourth time, variants of the complement Factor H gene (HF1/CFH) have been linked to the likelihood of developing age-related macular degeneration (AMD), researchers report in the early edition of
This latest link comes on the heels of three independent reports that connected HF1 to AMD, all of which appeared together in
"Gregory Hageman had a theory that inflammation was involved in AMD, but nobody really believed him, including me," said Rando Allikmets, from Columbia University and senior author of the
AMD is the leading cause of blindness in the elderly and is estimated to afflict upwards of 10 million Americans. It's a complex disease whose risk factors include smoking, diet, and age, and there is a strong indication of a genetic contribution. However, although a few genes have been linked to AMD, progress in understanding the genetic contributions to AMD has been slow—that is, until the recent completion of the human genome.
Indeed, using genome-wide linkage analysis several research groups previously zoned in on chromosomal region 1q25-q31 as being involved in AMD. "It was suggested the gene in this region was a variant of the gene Hemicentin-1," said Stephen Daiger, from the University of Texas Health Science Center, who was not involved in the studies. "But it's been known for 6 to 9 months that when people tried to verify the role of Hemicentin-1, it didn't pan out," he said.
"So, every group that is aware of AMD and had family [a genetic cohort of AMD patients] knew there was another gene," said Daiger.
With the availability of the human genome and tools like haplotype mapping and single nucleotide polymorphism (SNP) analysis, a "very healthy and reasonable" race began to find the AMD-related gene somewhere in chromosomal region 1q25-q31, Daiger told
The first results of this pursuit appeared with a trio of
In the latest study, Allikmets, lead author Gregory Hageman, and their colleagues used a candidate gene approach and chose only to look at HF1. They found a significant association between eight HF1 SNPs and AMD patients, with the most common at-risk haplotype found in 50% of AMD patients and 29% of controls. They also found the accumulation of HF1 in ocular drusen—hallmark deposits associated with early AMD.
"Different people have been approaching how to identify the genetic variants accounting for the linkage to AMD on chromosome 1q by different manners," said Albert Edwards, from Presbyterian Hospital of Dallas and lead author of one the
"There is no doubt now that HF1 has a role in AMD," said Anand Swaroop at University of Michigan, who was not involved in the studies. In fact, Swaroop's lab is about to publish a study providing the fifth independent confirmation of HF1's link to AMD. "However, what HF1 does is still anyone's guess," he said.
Allikmets suggests that in some people, haplotypes of HF1 are not able to shut off the complement pathway as effectively, and "therefore with age, people may accumulate damage which leads to chronic disease like AMD." However, he agrees more research is needed to confirm this.
Nevertheless, "although it would have been hard to justify ambitious drug studies related to the complement system before," said Daiger, "it's about time to begin to tease out the specific responses of the complement system that might be protective or slow down the progression of AMD."