Macular Degeneration - Causes and Risk Factors

Causes and Risk Factors

• Aging: Approximately 10% of patients 66 to 74 years of age will have findings of macular degeneration. The prevalence increases to 30% in patients 75 to 85 years of age.
• Family history: The lifetime risk of developing late-stage macular degeneration is 50% for people who have a relative with macular degeneration, versus 12% for people who do not have relatives with macular degeneration. Researchers from the University of Southampton reported they had discovered six mutations of the gene SERPING1 that are associated with AMD. Mutations in this gene can also cause hereditary angioedema.
• Macular degeneration gene: The genes for the complement system proteins factor H (CFH), factor B (CFB) and factor 3 (C3) are strongly associated with a person's risk for developing AMD. CFH is involved in inhibiting the inflammatory response mediated via C3b (and the alternative pathway of complement) both by acting as a cofactor for cleavage of C3b to its inactive form, C3bi, and by weakening the active complex that forms between C3b and factor B. C-reactive protein and polyanionic surface markers such as glycosaminoglycans normally enhance the ability of factor H to inhibit complement. But the mutation in CFH (Tyr402His) reduces the affinity of CFH for CRP and probably also alters the ability of factor H to recognise specific glycosaminoglycans. This change results in reduced ability of CFH to regulate complement on critical surfaces such as the specialised membrane at the back of the eye and leads to increased inflammatory response within the macula. In two 2006 studies, another gene that has implications for the disease, called HTRA1 (encoding a secreted serine protease), was identified.
  The mitochondrial genome (mtDNA) in humans is contained on a single circular chromosome, 16,569 basepairs around, and each mitochondrion contains five to 10 copies of the mitochondrial chromosome. Several essential genes in mtDNA are involved in replication and translation, along with some genes that are crucial for the machinery that converts metabolic energy into ATP. These include NADH dehydrogenase, cytochrome C oxidase, ubiquinol/cytochrome C oxidoreductase, and ATP synthase, as well as the genes for unique ribosomal RNA and transfer RNA particles that are required for translating these genes into proteins.
  Specific diseases are associated with mutations in some of these genes. Below is one of the affected genes and the disease that arises from its mutation.
• Mutation of the ATP synthase gene: Retinitis pigmentosa (RP) is a genetically linked dysfunction of the retina and is related to mutation of the adenosine triphosphate (ATP) synthase gene 615.1617.

• Stargardt's disease (juvenile macular degeneration, STGD) is an autosomal recessive retinal disorder characterized by a juvenile-onset macular dystrophy, alterations of the peripheral retina, and subretinal deposition of lipofuscin-like material. A gene encoding an ATP-binding cassette transporter was mapped to the 2-cM (centiMorgan) interval at 1p13-p21 previously shown by linkage analysis to harbor this gene. This gene, ABCR, is expressed exclusively and at high levels in the retina, in rod but not cone photoreceptors, as detected by in situ hybridization. Mutational analysis of ABCR in STGD families revealed a total of 19 different mutations including homozygous mutations in two families with consanguineous parentage. These data indicate that ABCR is the causal gene of STGD/FFM.

• Drusen: CMSD studies indicate drusen are similar in molecular composition to plaques and deposits in other age-related diseases such as Alzheimer's disease and atherosclerosis. While there is a tendency for drusen to be blamed for the progressive loss of vision, drusen deposits can be present in the retina without vision loss. Some patients with large deposits of drusen have normal visual acuity. If normal retinal reception and image transmission are sometimes possible in a retina when high concentrations of drusen are present, then, even if drusen can be implicated in the loss of visual function, there must be at least one other factor that accounts for the loss of vision.

• Arg80Gly variant of the complement protein C3: Two independent studies published in the New England Journal of Medicine and Nature Genetics in 2007 showed a certain common mutation in the C3 gene, which is a central protein of the complement system, is strongly associated with the occurrence of AMD. The authors of both papers consider their study to underscore the influence of the complement pathway in the pathogenesis of this disease.

• Hypertension (high blood pressure)

• Cholesterol: Elevated cholesterol may increase the risk of AMD

• Obesity: Abdominal obesity is a risk factor, especially among men

• Fat intake Consuming high amounts of certain fats likely contributes to AMD, while monounsaturated fats are potentially protective. In particular, ω-3 fatty acids may decrease the risk of AMD.

• Oxidative stress: Age-related accumulation of low-molecular-weight, phototoxic, pro-oxidant melanin oligomers within lysosomes in the retinal pigment epithelium may be partly responsible for decreasing the digestive rate of photoreceptor outer rod segments (POS) by the RPE. A decrease in the digestive rate of POS has been shown to be associated with lipofuscin formation - a classic sign associated with AMD.

• Fibulin-5 mutation: Rare forms of the disease are caused by geneic defects in fibulin-5, in an autosomal dominant manner. In 2004, Stone et al. performed a screen on 402 AMD patients and revealed a statistically significant correlation between mutations in fibulin-5 and incidence of the disease. Furthermore, the point mutants were found in the calcium-binding sites of the cbEGF domains of the protein. There is no structural basis for the effects of the mutations.

• Race: Macular degeneration is more likely to be found in Caucasians than in people of African descent.

• Exposure to sunlight, especially blue light: Evidence is conflicting as to whether exposure to sunlight contributes to the development of macular degeneration. A recent study on 446 subjects found it does not. Other research, however, has shown high-energy visible light may contribute to AMD.

• Smoking: Smoking tobacco increases the risk of AMD by two to three times that of someone who has never smoked, and may be the most important modifiable factor in its prevention. A review of previous studies found "the literature review confirmed a strong association between current smoking and AMD. ... Cigarette smoking is likely to have toxic effects on the retina."

• Deletion of CFHR3 and CFHR1: Deletion of the complement factor H-related genes CFHR3 and CFHR1 protects against AMD.