Age-related macular degeneration (AMD) is the most common form of visual impairment and blindness in developed countries, affecting around half a million people in the UK alone, and is the leading cause of blindness in people over the age of 60. Macular degeneration is a blanket name for a large number of individual conditions involving damage to the macula, a small area of the retina at the back of the eye. Around 90% of macular degeneration is termed AMD, and typically occurs in people over the age of 50.
A new study by researchers from Columbia University Medical Center and the University of Iowa in the US [Gold B et al. (2006) Nature Genetics advanced online publication doi:10.1038/ng1750] reports the identification of two key genetic risk factors that could be involved in three-quarters of all cases of AMD. The pathology of AMD is thought to involve dysfunction of normal inflammatory pathways. An earlier study by the same researchers linked certain common variants in the gene for one component of these pathways, complement factor H or CFH, to a significantly increased risk of AMD [Hageman GS et al. (2005) Proc. Natl. Acad. Sci. USA 102, 7227–7232]. However, as around a third of individuals with the disease-associated Factor H gene variant did not have AMD, they decided to investigate whether variations in genes for other factors from the same pathway that could have a similar effect, complement factor B (BF) and complement component 2 (C2), also played a role in risk of AMD. Factor H is involved in the inhibition of immune responses when infectious agents have been eliminated. It is thought that this process of down regulation is impaired in people with certain variant forms of Factor H, and this poorer control of inflammation may be involved in AMD. Factor B acts in opposition to Factor H, activating the immune response pathway.
The genotypes of 548 individuals with AMD and 275 controls with respect to the within the BF and C2 genes were determined, by using SNP (single nucleotide polymorphism) tags. Two pairs of variants were found to be significantly associated with AMD; the BF gene L9H and C2 gene E318D alleles, and the BF gene R32Q allele and C2 gene intron 10 SNP variant rs547154. The analysis was repeated in an independent group of 350 individuals with AMD and 114 controls, and the same findings confirmed. Haplotypes across the C2 and BF genes were examined using pooled data from both patient / control cohorts, a total of almost 1300 people. The common haplotype H1 was found to confer a significant risk for AMD. The H7 haplotype (containing the BF R32Q allele and C2 rs547154 SNP) was conferred a high degree of protection against AMD, whilst the H10 haplotype (containing the C2 E318D and BF L9H alleles) was also significantly protective.
The research team developed and refined an algorithm for combined analysis of the previously identified CFH and the newly implicated C2/BF alleles, which showed that several different combinations of these alleles gave some degree of protection from AMD. Among AMD patients, 74% were found to lack any protective haplotype, whilst just over half (56%) of the control group had at least one protective CFH or C2/BF haplotype. Because the two genes have opposing actions, possession of a protective gene variant in one can ameliorate the effect of a risk-associated variant in the other. Analysis of the relative contributions of the two loci to the overall genetic risk component for AMD estimated that the CFH locus accounts for 60-65% and the C2/BF locus for 35-40%.
Lead author Rando Allikmets commented: "These findings are significant because they absolutely confirm the roles of these two genes and, consequently, the central role of a specific immune response pathway, in the development of AMD…We now have clear targets for early therapeutic intervention".
Comment: These results extend previous understanding of the genetic causes of AMD by identifying an additional gene and risk-associated variants within that gene. If further studies replicate the results of this publication, it will confirm the importance of a specific immune response pathway in the pathogenesis of the disease and probably aid the development of novel therapeutic measures. However, it does not provide all the answers. For example, how does the possession of particular genetic combinations affect onset and development of the disease? How do genetic and environmental risk factors interact to cause AMD? The research team is reportedly now seeking to identify which viral and bacterial infections may trigger the immune responses associated with the disease (see BBC news report).