Identifying subtypes of patients with neovascular age-related macular degeneration by genotypic and cardiovascular risk characteristics

<p>Abstract</p> <p>Background</p> <p>One of the challenges in the interpretation of studies showing associations between environmental and genotypic data with disease outcomes such as neovascular age-related macular degeneration (AMD) is understanding the phenotypic heterogeneity within a patient population with regard to any risk factor associated with the condition. This is critical when considering the potential therapeutic response of patients to any drug developed to treat the condition. In the present study, we identify patient subtypes or clusters which could represent several different targets for treatment development, based on genetic pathways in AMD and cardiovascular pathology.</p> <p>Methods</p> <p>We identified a sample of patients with neovascular AMD, that in previous studies had been shown to be at elevated risk for the disease through environmental factors such as cigarette smoking and genetic variants including the complement factor H gene (<it>CFH</it>) on chromosome 1q25 and variants in the <it>ARMS2</it>/HtrA serine peptidase 1 (<it>HTRA1</it>) gene(s) on chromosome 10q26. We conducted a multivariate segmentation analysis of 253 of these patients utilizing available epidemiologic and genetic data.</p> <p>Results</p> <p>In a multivariate model, cigarette smoking failed to differentiate subtypes of patients. However, four meaningfully distinct clusters of patients were identified that were most strongly differentiated by their cardiovascular health status (histories of hypercholesterolemia and hypertension), and the alleles of <it>ARMS2</it>/<it>HTRA1 </it>rs1049331.</p> <p>Conclusions</p> <p>These results have significant personalized medicine implications for drug developers attempting to determine the effective size of the treatable neovascular AMD population. Patient subtypes or clusters may represent different targets for therapeutic development based on genetic pathways in AMD and cardiovascular pathology, and treatments developed that may elevate CV risk, may be ill advised for certain of the clusters identified.</p

Hypertension, antihypertensive medications use and risk of age-related macular degeneration in California Teachers Cohort.

Sustained and inadequately controlled hypertension can promote the development of age-related macular degeneration (AMD) through multiple biologic pathways. Epidemiologic studies of high blood pressure, antihypertensive therapies, and the risk of AMD thus far have been inconclusive. However, few studies evaluated risks according to the use of different classes of antihypertensive drugs or took combinations of use into account. We performed a prospective cohort study by linking the California Teachers Study (CTS) cohort (N = 88 481) to statewide hospital discharge records up to December 31, 2012. History of high blood pressure, regular use of antihypertensive medications, and comprehensive risk factor information was collected via self-administered questionnaires at baseline in 1995-1996, and information on specific classes of antihypertensive drugs was provided by a subsample of CTS participants who completed a follow-up questionnaire in 2000. We identified 1762 female teachers with AMD during 14.8 years of follow-up on average. Applying Cox proportional hazard regression, we estimated increased risks of AMD among women treated for hypertension at baseline (HR = 1.15, 95% CI: 1.03, 1.30); the magnitude of the association increased with longer duration of antihypertensive treatment. In the subsample with more specific information on type of medication use, we estimated a 45% increased risk of AMD among women receiving diuretics as monotherapy compared to women with medications more potent than diuretics (HR = 1.45, 95% CI 1.10, 1.90). In women treated with a combination of antihypertensive drugs, we observed no increased risk of AMD for any individual class of drugs