Macular Degeneration—Ag... Health Article

Genetic profile

AMD is considered a complex disorder, caused by a combination of genetic and environmental factors. AMD exhibits multifactorial inheritance, and the many factors interact with one another and cause the condition. The aging process is one of the strongest risk factors for developing AMD. There is also genetic heterogeneity among different families with AMD, meaning that different genes can lead to the same or similar disease among different families. Overall, it has been estimated that siblings of individuals with AMD have four times the risk of developing AMD, compared to other individuals.

In 1998, a family in which a unique form of AMD was passed from one generation to the next was discovered. Although most families with AMD do not display an obvious inheritance pattern, this particular family's pedigree showed an autosomal dominant form of AMD. Autosomal dominant refers to a specific type of inheritance in which only one allele (one copy of a gene pair) needs to have a mutation for the disease to develop. An affected person with an autosomal dominant condition thus has one allele with a mutation and one allele that functions properly. There is a 50% chance for this individual to pass on the allele with the mutation and a 50% chance to pass on the normal allele to each offspring. Genetic testing revealed that the autosomal dominant gene was located on chromosome 1q25-q31, in a locus now known as the ARMD1 gene locus. In 2004, possible AMD linkage evidence was discovered in four chromosomal regions: 1q31, 9p13, 10q26, and 17q25. In 1997, mutations in the gene for the retinal ATP-binding cassette transporter, also on chromosome one, were found in individuals diagnosed with AMD. However, as of 2005, it is clear that the retinal ABCR gene is not a major susceptibility gene for AMD.

In March 2005, the National Eye Institute (NEI) described the discovery of a gene for AMD in Caucasians. The genomes from AMD patients were screened by three separate research groups. All three groups discovered a commonly inherited variant of the same gene, called complement factor H (CFH). The CFH gene encodes a protein that regulates inflammation in the portion of the immune system that disposes of diseased and damaged cells. In some individuals with AMD, eye inflammation may trigger a biological process leading to AMD. This variation is in a region of CFH that binds the Creactive protein involved in inflammation. CFH functions as a brake on the immune system. The variation in CFH found in AMD causes the brake to be defective. The CFH gene is located on chromosome 1q25-31 in the ARMD1 locus that is repeatedly linked to AMD in family-based studies. Individuals with the variant gene have two to seven times the risk of macular degeneration, with the greatest risk in individuals with two copies of the variation. The CFH gene variation may account for a large percentage of risk for AMD, but is not an absolute determinant. Not all individuals with AMD have the CFH variant, and not all those with the variant have AMD. However, there is accumulating evidence that macular degeneration, much like atherosclerosis, is at least partly caused by inflammation.

It is also possible that although one particular gene may be the main cause of susceptibility for AMD, other genes or environmental factors may help alter the age of onset of symptoms or eye defects. Studies have revealed numerous risk factors for AMD, including:

• Obesity
• Heart disease
• High blood pressure
• Cataracts
• Farsightedness
• Light skin and eye color
• Cigarette use
• High fat/high cholesterol diet
• Ultraviolet (UV) exposure (sunlight)
• Low levels of dietary antioxidant vitamins and minerals
• Female gender

The exact amount of risk associated with many of these factors is still undetermined, though studies have consistently found a strong association between AMD and smoking. Risk factors in combination with a family history of AMD place an individual at highest risk.