title: Phenotypic Characterization of Complement Factor H R1210C Rare Genetic Variant in Age-Related Macular Degeneration.
abstract: OBJECTIVE
  The complement factor H R1210C rare variant confers the strongest genetic risk for age-related macular degeneration and earlier age at onset; however, its associated phenotype has not been well characterized.
  
  
  OBJECTIVE
  To describe specific fundus features of a white population with the R1210C rare variant.
  
  
  METHODS
  Fundus features specific for diagnosis and disease staging were retrospectively characterized by systematic review of all available fundus images for each patient, including color photography, fluorescein angiography, fundus autofluorescence, and optical coherence tomography, at a tertiary ophthalmologic referral center. For this retrospective observational study conducted from 2012 to 2014, enrolled patients with the variant and their family members without the variant were identified from the Age-Related Macular Degeneration Study for a family-based study arm. For patients with the variant but without a family member enrolled in the study, age-matched comparison individuals without the variant were selected randomly from the database.
  
  
  METHODS
  The presence of drusen in the macula (macular drusen score) and estimated number (total macular drusen score) were assessed. The presence of drusen in the extramacular regions (extramacular drusen score), pigmentary abnormalities, and disease staging were also evaluated. Binary logistic regression models were used to evaluate the association between rare variant status and ocular phenotypes.
  
  
  RESULTS
  Images from a total of 143 patients (283 eyes), including 62 patients with the rare variant, were analyzed. Drusen score covariates were associated with the R1210C rare variant. A larger proportion of patients carrying the variant had the highest level of macular and total macular drusen scores compared with those without the variant (57.9% vs 16.7% and 52.9% vs 14.2%, respectively; P for trend < .001 for both scores). Patients carrying the rare variant had a much greater likelihood of having advanced disease (odds ratio, 7.0; 95% CI, 3.1-16.2; P < .001). A higher prevalence of geographic atrophy was observed among patients carrying the variant (odds ratio, 13.7; 95% CI, 5.0-37.7; P < .001).
  
  
  CONCLUSIONS
  The typical phenotype of the complement factor H R1210C rare variant is associated with extensive drusen accumulation in the macula and throughout the fundus, as well as with a high risk for having advanced disease. Better characterization of genetic profiles in age-related macular degeneration may be important for screening and future therapeutic strategies for this vision-threatening condition.
authors.affiliation: New England Eye Center, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Daniela
authors.initials: D
authors.lastname: Ferrara
authors.affiliation: New England Eye Center, Tufts University School of Medicine, Boston, Massachusetts2Ophthalmic Epidemiology and Genetics Service, Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Seddon
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000502:physiology; D015331:Cohort Studies; D017242:Complement Factor H / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005451:Fluorescein Angiography / Q000379:methods; D005654:Fundus Oculi; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005820:Genetic Testing / Q000379:methods*; D014644:Genetic Variation; D015577:Geriatric Assessment / Q000379:methods; D006579:Heterozygote; D006801:Humans; D008268:Macular Degeneration / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010375:Pedigree; D010641:Phenotype; D015995:Prevalence; D011379:Prognosis; D015593:Retinal Drusen / Q000235:genetics* / Q000503:physiopathology; D012189:Retrospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D014481:United States
chemical_list: D017242:Complement Factor H