Abstract
Background: :
A common variant Y402H of complement factor H (CFH) has been strongly associated with age–related macular degeneration (AMD) in recent studies. Prospective studies of incident cases from large defined cohorts can help further delineate the strength of the association and determine how this variant may interact with modifiable risk factors for AMD.
Methods: :
We performed a prospective nested case–control study of 446 men and women (participants in the Nurses’ Health Study and the Health Professionals Follow–up Study) who developed AMD associated with a visual acuity of 20/30 or worse, and 1059 age– and sex–matched controls. We determined genotypes for the common exonic T>C single nucleotide polymorphism (SNP) within CFH (rs1061170; protein Y402H). We used logistic regression models to evaluate the CFH variant for association with incident AMD while adjusting for other risk factors, and to examine interactions between CFH Y402H and modifiable risk factors for AMD. We also calculated the population attributable risk for CFH Y402H.
Results: :
The prevalence of carrying at least one high–risk C allele was 78% among cases and 58% among controls. Assuming a multiplicative (i.e. log–additive) genetic model, the multivariable–adjusted RR (CI) for AMD was 2.02 (1.69 to 2.43) among heterozygotes, and 4.08 (2.85 to 5.90) among participants homozygous for the risk allele. The estimated fraction of AMD cases in the population attributable to the CFH variant was 47%. Analyses of interactions between CFH Y402H and cigarette smoking, obesity, and dietary intake of omega–3 fatty acids or fruits suggested a multiplicative relationship between the RRs for CFH Y402H and these modifiable risk factors for AMD. For example, subjects homozygous for CFH Y402H had a >4–fold increased risk of AMD if they were not obese, but an ∼11–fold increase in risk of AMD if they were obese. Similar estimates were found for non–smokers versus smokers.
Conclusions: :
These are the first prospective data to confirm a strong association between the CFH Y402H and AMD. Given the high prevalence of CFH Y402H in the population, and the dearth of effective early interventions for AMD, these data demonstrating that risks associated with common modifiable risk factors for AMD multiply the risk conferred by Y402H highlight the need for continued attention to risk modification strategies to reduce the public health impact of AMD.
Keywords: age-related macular degeneration • genetics • clinical (human) or epidemiologic studies: risk factor assessment