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Debra A. Schaumberg, ScD, OD, MPH; Susan E. Hankinson, ScD; Qun Guo, MSc; Eric Rimm, ScD; David J. Hunter, MBBS, ScD

Arch Ophthalmol. 2007;125(1):55-62.

Objectives  To delineate the magnitude of susceptibility to age-related macular degeneration (AMD) due to common variants in the gene for complement factor H (CFH) and the predicted gene LOC387715 and to determine whether these variants interact with modifiable risk factors.

Methods  We compared cases who developed AMD (n = 457) with 1071 age- and sex-matched control subjects in a prospective nested case-control study within the Nurses' Health Study and the Health Professionals Follow-up Study. We determined the incidence rate ratios and 95% confidence intervals (CIs) for AMD for each genotype and examined the interactions with modifiable risk factors.

Results  Participants with 1 or 2 copies of the Y402H variant of CFH were, respectively, 1.98 (95% CI, 1.64-2.40) and 3.92 (95% CI, 2.69-5.76) times more likely to develop AMD, whereas the incident rate ratios (95% CIs) for 1 and 2 copies of LOC387715 A69S were 2.38 (1.92-2.96) and 5.66 (3.69-8.76), respectively. The fraction of AMD cases attributable to these 2 variants was 63% (95% CI, 58%-68%). Subjects homozygous for both risk alleles had a 50-fold increased risk of AMD (95% CI, 10.8-237), and cigarette smoking and obesity multiplied the risks associated with these variants.

Conclusion  Age-related macular degeneration has emerged as a paradigmatic example of a common disease caused by the interplay of genetic predisposition and exposure to modifiable risk factors.

Author Affiliations: Division of Preventive Medicine (Dr Schaumberg) and Channing Laboratory (Drs Hankinson, Rimm, and Hunter and Ms Guo), Department of Medicine, Brigham and Women's Hospital, and Department of Ophthalmology (Dr Schaumberg), Harvard Medical School, and Program in Molecular and Genetic Epidemiology (Ms Guo and Dr Hunter) and Departments of Epidemiology (Drs Hankinson, Rimm, and Hunter) and Nutrition (Drs Rimm and Hunter), Harvard School of Public Health, Boston, Mass.

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