NEW YORK (GenomeWeb) – The latest genetic study of age-related macular degeneration (AMD) is highlighting common and rare genetic variants involved in the risk of developing different forms of the progressive eye disease.
Members of the International AMD Genomics Consortium brought together genotyping data from more than 12 million sites in the genome for tens of thousands of individuals with or without AMD. The search, described online today in Nature Genetics, led to AMD-associated loci at nearly three-dozen sites in the genome.
Most showed ties to both wet and dry subtypes of AMD. Nevertheless, the researchers uncovered a signal near the extracellular matrix gene MMP9 that was specifically associated with wet AMD, a form of the disease involving new blood vessel formation. A handful of other variants near extracellular matrix proteins were linked to advanced AMD but did not show ties to intermediate forms of the disease.
"The possible connection between AMD and these extracellular matrix genes may allow for predictive genetic tests and more effective therapies for people with this type of AMD," co-first author Jessica Cooke Bailey, a post-doctoral researcher in epidemiology and biostatistics at Case Western Reserve University, said in a statement.
AMD is a progressive vision loss disease caused by damage to cells in a macula region at the center of eye's retina — an area that normally focuses images to be sent to the brain. Such damage may involve fatty deposits called drusen that form in response to local inflammation.
In individuals with the wet AMD, such damage occurs relatively quickly, in part due to unusual blood vessel formation in the macula. Dry AMD, also known as geographic dystrophy, typically shows slower progression and does not include excess blood vessel formation.
Past genome-wide association and exome sequencing studies have provided clues to the genes and pathways involved in AMD risk. They have also uncovered genetic variants that appear more common in those who progress to advanced forms of the disease, sparking interest in molecular diagnostic tests for AMD.
Meanwhile, studies published this fall suggest environmental factors such as diet, exercise, smoking behavior, and/or vitamin D levels can interact with genetic factors to further mediate AMD risk.
For the current analysis, the researchers considered patterns at more than 12 million directly genotyped or imputed SNPs in 16,144 individuals of European descent with advanced AMD and 17,832 unaffected individuals from the same population.
They also scrutinized common and rare variant patterns in more than 2,900 non-Europeans and in 6,657 individuals with European ancestry who had intermediate forms of the disease.
Within the advanced AMD cases, the team narrowed in on 52 variants at 34 loci with independent ties to the disease, including known risk sites and 16 loci not previously implicated in AMD.
The 370 genes found closest to these risk loci included genes involved in everything from complement immunity and high-density lipoprotein transport to the extracellular matrix pathway activity, the researchers reported.
And while most risk loci for wet and dry AMD overlapped with one another, an association near the MMP9 gene — one of the extracellular matrix gene family members — was significant only in individuals with wet AMD.
The team suspects this wet AMD-specific association might reflect interactions between MMP9's gene product and a blood vessel-related protein called vascular endothelial growth factor.
Similarly, the team saw genetic overlap between intermediate and advanced forms of AMD. But 10 variants — including seven SNPs near extracellular matrix genes — seemed to influence advanced disease alone.
The latter variants may be more common in individuals with wet AMD who do not show early disease symptoms, the researchers noted, offering hints for understanding and treating disease in such cases.
"The possible connection between AMD and these extracellular matrix genes may allow for predictive genetic tests and more effective therapies for people with this type of AMD," Cooke Bailey said.