Link between HF1 and AMD grows

Pursuit of genetic factors involved in a leading cause of blindness points to complement pathway

By | May 2, 2005

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 PNAS this week.

This latest link comes on the heels of three independent reports that connected HF1 to AMD, all of which appeared together in Science Express over a month ago. HF1 is well known to be the major inhibitor of alternative complement pathway, which is an early line of defense against microbial infection. Together, the results now squarely point the finger at the complement pathway's involvement in the development of AMD.

"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 PNAS study. But with the recent flurry of research, it now appears that Hageman was right, said Allikmets.

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 Scientist.

The first results of this pursuit appeared with a trio of Science papers. The most extensive was a genome-wide scan of about 115,000 SNPs in 96 cases and 50 controls. The second and third studies involved allele-association of a case-control population and further linkage analysis, respectively, of 895 cases and 387 controls. All three studies pointed to a single HF1 SNP (rs1061170) that contributed to the difference between AMD-affected and unaffected individuals.

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 Science studies. "It's nice that each of the approaches has been rewarded," he told The Scientist.

"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."

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