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Rare Variant Studies Underscore Immune Pathway Role in Age-related Macular Degeneration

NEW YORK (GenomeWeb News) – A trio of studies published online yesterday in Nature Genetics are revealing new, rare risk loci for age-related macular degeneration.

For the first of these, researchers from the University of Michigan, Washington University, the National Institutes of Health's National Eye Institute, and elsewhere did targeted sequencing on 2,335 individuals with AMD and nearly 800 unaffected controls, focusing on 10 suspicious sites in the genome.

To help in the analysis of these sequences, which spanned 57 genes, the group pulled in exome sequencing data for thousands more ancestry-matched controls — a search that ultimately led to a known risk variant in the CFH gene and a previously unappreciated risk variant in the inflammation and immune-related gene C3.

Both changes are rare, but appear to have a pronounced effect on an individual's propensity for developing AMD, the researchers reported, with the presence of both variants dialing up AMD risk by roughly three-fold.

Along with variants implicated in AMD through prior studies, the risk alleles also offered clues about the processes that go awry as the eye condition develops.

In particular, findings from the study suggest that the AMD-associated variant in C3 dampens the control that the CFH-encoded complement factor H can exert over it. That, in turn, seems to bump up activity by an alternative arm of the complement system, an immune pathway implicated in AMD in the past.

"[T]here is a clear relationship between the complement pathway and the onset of this disease," co-senior author Elaine Mardis, co-director of the Genome Institute at Washington University, said in a statement.

"The complement system is part of the immune system that helps amplify or 'complement' the efforts of immune cells to fight infections," she said. "So the idea is that the gene variant interferes with the complement pathway’s normal function throughout life, and that can damage the retina over time, which ultimately leads to AMD's emergence."

Going forward, Mardis and other members of that research team reportedly plan to scrutinize sequence data for another 2,000 individuals with or without AMD with an eye to identifying still more contributors to the condition.

"We hope to identify new genes — perhaps more genes in the complement pathway, perhaps genes in other inflammatory response pathways, or in areas we wouldn't have anticipated finding any genes related to AMD," Mardis said in a statement. "We're taking a wide look at the genome to see what turns up."

In another study, the Broad Institute's Soumya Raychaudhuri and colleagues targeted coding sequences from 681 genes in nearly 2,500 AMD cases and controls in their own look at rare variants with a role in the degenerative eye disease, followed by genotyping on samples from another 5,115 individuals.

That search, which centered on loci and pathways linked to AMD through past studies, uncovered rare, high-risk variants in the complement factors genes CKI, C3, and C9. And based on results from their follow-up experiments, authors of that study, too, concluded that "loss of C3 protein regulation and excessive alternative complement activation" contribute to AMD pathogenesis.

"[O]ur study did not identify rare variants outside of the complement pathway, despite the large set of genes queried within other AMD-associated loci and genes involved in angiogenesis, lipid metabolism, and extracellular matrix signaling," they noted. "One possibility to explore, as sequencing studies scale up in size, is that rare coding variants with even more modest effect sizes than those reported here may modulate AMD risk within those other genes as well."

Finally, an international team led by investigators at Decode Genetics reported on a rare non-synonymous variant in the C3-coding complement pathway gene, which was detected in the Icelandic population using low-coverage, whole-genome sequencing data for 2,230 Icelanders and genotype information imputed with the help of long-range phased haplotypes for that population.

That group of researchers subsequently verified the rare C3 SNP's role in AMD using genotyping information for thousands of American individuals of European ancestry who did or did not have AMD. They noted that "[t]his signal is independent of the previously reported common SNPs in C3 … that associated with AMD."

Findings from their experiments in the lab also supported the notion that reduced inhibition of the C3 protein by complement factor H can contribute to AMD via surplus activation of components in the complement pathway.

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