title: Prospective assessment of genetic effects on progression to different stages of age-related macular degeneration using multistate Markov models.
abstract: OBJECTIVE
  Understanding the effect of genes on progression to different stages of age-related macular degeneration (AMD) may suggest stage-specific therapeutic targets and more precise prediction of the development of this disease.
  
  
  METHODS
  Progression events and time to each stage of AMD were derived from the longitudinal data of 2560 subjects without advanced AMD. SNPs in 12 AMD risk loci were genotyped. A multistate Markov model for progression from normal to intermediate drusen, then to large drusen, and eventually to neovascular disease (NV) or geographic atrophy (GA) was applied to estimate stage-specific hazard ratios for each SNP. The effects of these genetic factors were also estimated by a multivariate multistate Markov model adjusted for baseline age, sex, smoking, body mass index (BMI), education, antioxidant treatment, and the status of AMD in the fellow eye.
  
  
  RESULTS
  Controlling for demographic and behavioral factors and other SNPs, the TT genotype of rs10468017 in LIPC was associated with decreased risk of progression from large drusen to NV (HR = 0.57, P = 0.04) and tended to reduce the risk of progression from normal to intermediate drusen (HR = 0.72, P = 0.07). The SNP rs1883025 (T allele) in ABCA1 was associated with decreased risk of progression from normal to intermediate drusen (HR per allele = 0.82 per allele, P = 9.7 × 10(-3)) and from intermediate drusen to large drusen (HR per allele = 0.77, P = 5.2 × 10(-3)). The genes CFH, C3, CFB, and ARMS2/HTRA1 were associated with progression from intermediate drusen to large drusen and from large drusen to GA or NV.
  
  
  CONCLUSIONS
  Genes in different pathways influence progression to different stages of AMD.
authors.affiliation: Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Department of Ophthalmology, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.forename: Robyn
authors.initials: R
authors.lastname: Reynolds
authors.forename: Bernard
authors.initials: B
authors.lastname: Rosner
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Seddon
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D008076:Cholesterol, HDL / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008297:Male; D008390:Markov Chains; D008875:Middle Aged; D015233:Models, Statistical; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies
chemical_list: D008076:Cholesterol, HDL