title: Identifying subtypes of patients with neovascular age-related macular degeneration by genotypic and cardiovascular risk characteristics.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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 (CFH) on chromosome 1q25 and variants in the ARMS2/HtrA serine peptidase 1 (HTRA1) gene(s) on chromosome 10q26. We conducted a multivariate segmentation analysis of 253 of these patients utilizing available epidemiologic and genetic data.
  
  
  RESULTS
  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 ARMS2/HTRA1 rs1049331.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Ocular Molecular Genetics Institute and the Retina Service, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Feehan
authors.forename: John
authors.initials: J
authors.lastname: Hartman
authors.forename: Richard
authors.initials: R
authors.lastname: Durante
authors.forename: Margaux A
authors.initials: MA
authors.lastname: Morrison
authors.forename: Joan W
authors.initials: JW
authors.lastname: Miller
authors.forename: Ivana K
authors.initials: IK
authors.lastname: Kim
authors.forename: Margaret M
authors.initials: MM
authors.lastname: DeAngelis
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000428:Alcohol Drinking; D000483:Alleles; D015992:Body Mass Index; D002318:Cardiovascular Diseases / Q000150:complications*; D002879:Chromosomes, Human, Pair 10; D016000:Cluster Analysis; D005260:Female; D005838:Genotype; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications; D006973:Hypertension / Q000150:complications; D008268:Macular Degeneration / Q000145:classification* / Q000209:etiology / Q000235:genetics; D008297:Male; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D015861:Retinal Neovascularization / Q000145:classification* / Q000209:etiology / Q000235:genetics; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000235:genetics; D012907:Smoking
chemical_list: C514392:ARMS2 protein, human; D011506:Proteins; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases