AMD: Altered Genes Raise Risks via Immune Dysregulation

Linda Roach

October 03, 2013

Three research groups investigating the genetics of age-related macular degeneration (AMD) from different angles independently report evidence that a chronic, low-level immune attack in the retina might underlie some cases of AMD.

Their studies were published online September 15 in Nature Genetics.

By examining genes in the vicinity of previously implicated AMD-risk genes, 2 of the research teams discovered a rare large-effect coding variant in the complement 3 (C3) gene. The variant leads to C3 protein molecules in which a single amino acid is substituted for another (glutamine for lysine in the case of the variant p.Lys155Gln).

A third group of researchers confirmed the discovery of this same C3 coding variant and reported finding 2 additional variants associated with AMD, including an allele that was present in 7.8% of the sampled cases.

These newly identified variants occurred in genes that code for proteins essential to activating and deactivating the part of the immune system known as the alternative complement pathway.

"Now there are 3 different papers from 3 different populations, all validating that C3 is a very important part of this entire cascade. Moreover, the same mutation is showing up in all 3 studies," commented another AMD gene researcher, Sudha K. Iyengar, PhD, in an interview with Medscape Medical News. Dr. Iyengar is a professor of epidemiology and biostatistics at Case Western Reserve University in Cleveland, Ohio.

"When you have a pathway that involves immunity, you have to have a mechanism to turn it off, a mechanism that will increase one thing and decrease something else to turn off parts of the pathway. They've found a genetic variant that is actually prohibiting that from happening," said Dr. Iyengar, who was not involved in the studies.

In the first of the p.Lys155Gln-focused studies, Hannes Helgason, PhD, from deCODE Genetics/Amgen and the University of Iceland in Reykjavik and colleagues performed whole-genome sequencing of 2230 Iceland residents to find gene variants associated with AMD. They then evaluated the gene variants in more than 51,435 control participants and 1143 participants with AMD, uncovering an association between AMD and p.Lys155Gln encoded by C3 (odds ratio [OR], 3.45; P = 1.1 × 10−7).

They also found that the frequency of the mutation encoding p.Lys155Gln was significantly higher in patients with AMD with geographic atrophy than in those with choroidal neovascularization (P = .0047). In addition, targeted sequencing for the allele in individuals from California, Utah, the Netherlands, and Germany (2854 patients with AMD and 2977 control participants) revealed a slightly higher AMD-risk profile for the variant in these populations (OR, 4.22; 95% confidence interval, 2.71 - 6.56; P = 1.6 × 10−10) than was seen in the Icelandic population.

In the second study on p.Lys155Gln, Xiaowei Zhan, PhD, from the University of Michigan School of Public Health in Ann Arbor, and colleagues report arriving at a similar conclusion through targeted sequencing of 2268 ancestry-matched pairs of patients with AMD and unaffected control participants. The researchers found a significant association between AMD and p.Lys155Gln encoded by C3 (observed in 18 control patients and 48 patients with AMD; OR, 2.68; P = 2.7 × 10−4).

Finally, in the third study, Johanna M. Seddon, MD, ScM, from the New England Eye Center, Tufts Medical Center, and Tufts University School of Medicine in Boston, Massachusetts, and colleagues confirmed the AMD risk associated with p.Lys155Gln (OR, 3.8; P = 5.2 × 10−9), as were variants in the genes for complement factor I (CFI) and C9. The CFI variants were present in 7.8% of AMD cases compared with 2.3% of individuals without AMD (n = 2493; OR, 3.6; P = 2 × 10−8). The other variant associated with increased AMD risk was in the C9 gene, encoding p.Pro167Ser (OR, 2.2; P = 6.5 × 10−7).

Despite using different approaches and study populations, the 3 research groups converged on a common hypothesis to account for the AMD risk associated with the gene variants: In molecules in the alternative complement pathway, gene variants impair important protein–protein interactions that regulate the pathway's activity. Unchecked, the pathway produces a chronic excess of pathogen-killing molecules that cause low-level damage to retinal cells over time, which cumulatively cause advanced AMD.

This persistent immune response can include a self-reinforcing molecular feedback loop, explained investigator Elaine R. Mardis, PhD, in an interview with Medscape Medical News. The resulting chronic, low-level inflammation likely would take many years to manifest as AMD, she said.

Dr. Mardis was co–senior investigator in the research reported by Dr. Zhan and colleagues and is a professor of genetics and codirector of The Genome Institute at Washington University School of Medicine in St. Louis, Missouri.

"The role of inflammation in the body is not well understood, but we know that in situations where the inflammation is chronic, and this could be one example of that, this ultimately leads to some sort of disease onset," Dr. Mardis explained.

"This continued malfunctioning of the pathway is not enough to shut cells down immediately. It doesn't cause immediate, egregious health problems throughout your life. Instead, you accumulate damage," she added.

Indeed, Dr. Seddon's group found supporting evidence for the immune hypothesis with fluid-phase cofactor assays and surface plasmon resonance testing. These tests showed that CFI molecules, which normally inactivate C3 and thereby inhibit the alternative complement pathway, caused significantly less proteolytic inactivation of C3 when the protein contained the p.Lys155Gln substitution.

"These results implicate loss of C3 protein regulation and excessive alternative complement activation in AMD pathogenesis, thus informing both the direction of effect and mechanistic underpinnings of this disorder," the authors conclude.

The study by Dr. Helgason and colleagues was funded by grants from the US National Eye Institute and Department of Veterans Affairs, the National Science Foundation of China, the Netherlands Organization for Scientific Research, and the Foundation Fighting Blindness. Several authors are employees of deCODE Genetics/Amgen. The other authors have disclosed no relevant financial relationships. The study by Dr. Zhan and colleagues was funded by grants from the US National Eye Institute, the National Human Genome Research Institute, and the Computational Medicine Initiative of the US National Eye Institute Intramural Research Program; by governmental research funding in the United Kingdom, Germany, and Australia; and grants from private foundations, including Research to Prevent Blindness and the Alcon Research Institute. Dr. Zhan and 3 coauthors are potential beneficiaries of a pending University of Michigan patent that describes the association between the variant p.Lys155Gln encoded by the complementary 3 genes and AMD. The other authors have disclosed no relevant financial relationships. The study by Dr. Seddon and colleagues was funded by grants from the National Institutes of Health, several eye research foundations, and research programs affiliated with the New England Eye Center. The authors have disclosed no relevant financial relationships.

Nat Genet. Published online September 15, 2013. Helgason abstract, Zhan abstract, Seddon abstract

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