AMD Genetic / Risk Factors Khodabande Farabi Eye Hospital TUMS

Modifiable RFs ? Genetic bases? Genetic testing, to do or not to do? Risk Score?

Risk Factors Development Progression

Non-Modifiable RFs

Age The number one risk factor is age. One-third of adults over 75 are affected by AMD.

Gender Females are more likely to develop AMD than males. This factor may be because females live longer than males, and thus have more time to develop the disease.

Presence of AMD in One Eye If a person has AMD in one eye, he or she is more likely to develop it in the other eye.

Race Caucasians are more likely to develop AMD than other races. This factor may be related to differences in genetic background or pigmentation.

Family History of AMD A person is more likely to develop AMD if someone in his or her immediate family has had it. First degree 3 times

Eye Color People with light-colored eyes are more likely to develop the dry type of AMD. This factor may be because light-pigmented eyes offer less protection from damaging UV light.

Clinical Examination (AREDS 1) Large drusen Pigmentary changes (hypo, hyper, non central GA) Score 0 / < 1% Score 1 / 5% Score 2 /12% Score 3 / 25% Score 4 / 50%

Modifiable RFs

Smoking two to five fold. Smoking causes oxidative damage, which may contribute to the development and progression of this disease. two to five fold.

Diet Avoid: Fat, Cholesterol and high glycemic index foods Recommend : antioxidants and green leafy vegetables

High-glycemic index foods: white rice, bread and pasta Low-glycemic foods: whole grain breads or oatmeal

AREDS 1 Conclusions Persons older than 55 years should have dilated eye examinations to determine their risk of developing advanced AMD. Increased intake of antioxidants and zinc lowered the risk for disease progression by 25% in patients with intermediate or advanced AMD

2. Those with extensive intermediate size drusen at least 1 large drusen noncentral geographic atrophy advanced AMD or vision loss due to AMD and without contraindications such as smoking, should consider taking a supplement of antioxidants plus zinc such as that used in this study. in 1 or both eyes in 1 eye

AREDS2 / Primary goal: if the addition of 10mg lutein 2mg zeaxanthin 1,000mg omega-3 long-chain fatty acids (350mg DHA and 650mg EPA) to the original AREDS formulation would further reduce the risk of progression to advanced AMD.

AREDS 2 Results Omega-3 fatty acid supplementation did not yield a statistically significant reduction in the progression of AMD. Addition of lutein, zeaxanthin to the AREDS formulation in primary analyses did not further reduce risk of progression to advanced AMD.

But…. Lutein and zeaxanthin have a role in AMD management, and should replace beta-carotene in the original AREDS formula.

Vitamin C 500 mg Vitamin E 400 IU Zn 80 mg Lutein 10 mg Zeaxanthin 2 mg

Prolonged Sun Exposure Although the evidence is not conclusive, some studies suggest an association between AMD and cumulative eye damage from ultraviolet (UV) and other light.

Inactivity In dry AMD, the retina does not receive adequate oxygen, leading to the death of cells in the macula. Exercise improves cardiovascular health and might help prevent AMD.

Obesity A person with a BMI of greater than 30 is 2.5 times more likely to develop the disease than a person with a lower BMI.

High Blood Pressure High blood pressure, like smoking, leads to a constriction (narrowing) of the blood vessels that nourish the retina, restricting oxygen flow.

Family studies reporting increased risk of 2–3 fold among first-degree relatives of patients. Increased monozygotic vs. dizygotic twin concordance.

Genetic and epidemiological research has established the undeniable role of genetic variation in the etiology of AMD, with the heritable component estimated to be between 45% and 70% . The odds ratio homozygous : between 3.5 and 7.4

q arm,ch 1 : alternative complement system genes: CFH gene, factor B (BF)/complement component 2 (C2),complement component 3 (C3), and complement factor I q arm, ch10 : ARMS2 and HTRA1. genes involved in transporting and processing HDL (hepatic lipase C (LIPC) ). Tissue inhibitor of metalloproteinase 3 (TIMP3) :early-onset form of macular degeneration known as Sorsby's fundus dystrophy

heterozygote : a 2.5-fold increase in developing AMD homozygous : a six-fold increase in developing AMD

CFH Non-neovascular AMD (GA) ARMS2 Neovascular AMD (CNV)

Awh et al: No CFH risk alleles and with 1 or 2 ARMS2 risk alleles derived maximum benefit from zinc- only supplementation.

One or two CFH risk alleles and no ARMS2 risk alleles derived maximum benefit from antioxidant-only supplementation. Treatment with zinc was associated with increased progression to advanced AMD.

Carl C. Awh, MD Emily Y. Chew, MD

AREDS and AREDS2 supplements, remains the only proven beneficial formulation regardless of genotype. Genetic testing is not recommended for initiating or determining the appropriateness of the AREDS formulation. One should not deprive patients of a therapy that has been proven to have significant public health impact on the basis of a statistically flawed, not replicated retrospective analysis of existing data.

Genetic testing / Drawbacks Until there is a true cure for AMD, knowing an individual’s risk factors may do little but worry a patient. Telling a patient that he is at low risk based on our current knowledge may give them a false sense of security. We may be unnecessarily frightening our patients who may test at higher risk, but never develop the disease. The biggest downfall, some point out, may be that once this information is obtained, it could fall into the hands of insurance companies that provide medical, disability and life insurance.

Risk Scores Risk scores have the potential to aid in evaluating the contribution of multiple factors to disease development and outcomes, progression, and response to treatment.

Take home messages Modifiable RFs: CFH / GA ARMS2/ CNV Smoking cessation Diet low in fat, high in antioxidant Supplements Weight control Blood pressure control Exercise CFH / GA ARMS2/ CNV Genetic testing is not recommended for initiating or determining the appropriateness of the AREDS formulation.